Embryology - User contributions [en-gb]

User:Z3332863

2012-10-16T23:08:51Z

Z3332863: /* Lab Attendance */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

'''lab 12'''--[[User:Z3332863|Z3332863]] 10:08, 17 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Research article:'''

<pubmed>21572395</pubmed>

This research article has found that iPS cells can be subject to immune rejection by the recipient from which the iPS cells were derived. This is surprising because iPS cells are reprogrammed from cells that came from the same recipient. So technically, the iPS cells should have the same genetic content as the recipient and not be sujected to immune rejection. This immune rejection is not seen in embryonic stem cells (ESC). The scientists generated ESCs from inbred mice and when these ESC were implanted into the mice, these embryonic stem cells were not rejected. The aim of this paper was to find out why there is an immune rejection associated with iPS cells but not with ESCs.

To carry out this investigation, Zhao et al reprogrammed C57BL/6 (B6) mouse embryonic fibroblasts into iPS cells using 2 different methods. The retroviral method involves integration of the viral genome into the host cell's DNA and gives ViPSCs. This retroviral method involved using retroviruses carrying genetic information that encoded the Yamanaka factors (Oct4, SOX2, Klf4, c-Myc). Zhao et al also performed a new non-integrative, episomal method to give episomally derived iPS cells (EiPSCs). This episomal appraoch uses an episome vector which encoded the 4 Yamanaka factors. When Zhao et al placed these iPSCs into the recipient mice from which these cells were derived, they observed immune rejection with the teratomas formed by the ViPSCs. The teratomas formed by EiPSCs stimulated an immune response involving T cell infiltration and damage to tissues. when they put the EiPSC into mice with CD4+ and CD8+ T-cells knocked out, they didn't notice any regression of the EiPSC teratomas. Conversely, the teratomas formed by ESCs were not immune rejected at all.

These scientists then conducted a 'global gene expression analysis' on the EiPSC and ESC teratomas. From this analysis they found that EiPSCs overexpressed many genes that were not over expressed in the ESCs. These difference in gene expression could be a result of epigenetic reprogramming, although this wasn't tested in their study. It may also be possible that the genes of the iPSC have undergone mutations which lead to abnormal gene expression. They concluded that this gene over-expression may contribute to the induction of a T cell response against the EiPSC teratoma and so the immungenicty of iPS cells must be analysed for each patient before using these cells as a treatment.
----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-13T00:38:38Z

Z3332863: /* Lab 11 Assessment */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Research article:'''

<pubmed>21572395</pubmed>

This research article has found that iPS cells can be subject to immune rejection by the recipient from which the iPS cells were derived. This is surprising because iPS cells are reprogrammed from cells that came from the same recipient. So technically, the iPS cells should have the same genetic content as the recipient and not be sujected to immune rejection. This immune rejection is not seen in embryonic stem cells (ESC). The scientists generated ESCs from inbred mice and when these ESC were implanted into the mice, these embryonic stem cells were not rejected. The aim of this paper was to find out why there is an immune rejection associated with iPS cells but not with ESCs.

To carry out this investigation, Zhao et al reprogrammed C57BL/6 (B6) mouse embryonic fibroblasts into iPS cells using 2 different methods. The retroviral method involves integration of the viral genome into the host cell's DNA and gives ViPSCs. This retroviral method involved using retroviruses carrying genetic information that encoded the Yamanaka factors (Oct4, SOX2, Klf4, c-Myc). Zhao et al also performed a new non-integrative, episomal method to give episomally derived iPS cells (EiPSCs). This episomal appraoch uses an episome vector which encoded the 4 Yamanaka factors. When Zhao et al placed these iPSCs into the recipient mice from which these cells were derived, they observed immune rejection with the teratomas formed by the ViPSCs. The teratomas formed by EiPSCs stimulated an immune response involving T cell infiltration and damage to tissues. when they put the EiPSC into mice with CD4+ and CD8+ T-cells knocked out, they didn't notice any regression of the EiPSC teratomas. Conversely, the teratomas formed by ESCs were not immune rejected at all.

These scientists then conducted a 'global gene expression analysis' on the EiPSC and ESC teratomas. From this analysis they found that EiPSCs overexpressed many genes that were not over expressed in the ESCs. These difference in gene expression could be a result of epigenetic reprogramming, although this wasn't tested in their study. It may also be possible that the genes of the iPSC have undergone mutations which lead to abnormal gene expression. They concluded that this gene over-expression may contribute to the induction of a T cell response against the EiPSC teratoma and so the immungenicty of iPS cells must be analysed for each patient before using these cells as a treatment.
----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-13T00:34:40Z

Z3332863: /* Lab 11 Assessment */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Research article:'''

<pubmed>21572395</pubmed>

This research article has found that iPS cells can be subject to immune rejection by the recipient from which the iPS cells were derived. This is surprising because iPS cells are reprogrammed from cells that came from the same recipient. So technically, the iPS cells should have the same genetic content as the recipient and not be sujected to immune rejection. This immune rejection is not seen in embryonic stem cells (ESC). The scientists generated ESCs from inbred mice and when these ESC were implanted into the mice, these embryonic stem cells were not rejected. The aim of this paper was to find out why there is an immune rejection associated with iPS cells but not with ESCs.

To carry out this investigation, Zhao et al reprogrammed C57BL/6 (B6) mouse embryonic fibroblasts into iPS cells using the retroviral method (which gives ViPSCs) which involves integration of the viral genome into the host cell's DNA or a new non-integrative, episomal method (gives EiPSCs). The retroviral method involved using retroviruses carrying genetic information that encoded the Yamanaka factors (Oct4, SOX2, Klf4, c-Myc). The episomal appraoch uses an episome vector which encoded the 4 Yamanaka factors. When Zhao et al placed these iPSCs into the recipient mice from which these cells were derived, they observed immune rejection with the teratomas formed by the ViPSCs. The teratomas formed by EiPSCs stimulated an immune response involving T cell infiltration and damage to tissues. when they put the EiPSC into mice with CD4+ and CD8+ T-cells knocked out, they didn't notice any regression of the EiPSC teratomas. Conversely, the teratomas formed by ESCs were not immune rejected at all.

These scientists then conducted a 'global gene expression analysis' on the EiPSC and ESC teratomas. From this analysis they found that EiPSCs overexpressed many genes that were not over expressed in the ESCs. These difference in gene expression could be a result of epigenetic reprogramming, although this wasn't tested in their study. It may also be possible that the genes of the iPSC have undergone mutations which lead to abnormal gene expression. They concluded that this gene over-expression may contribute to the induction of a T cell response against the EiPSC teratoma and so the immungenicty of iPS cells must be analysed for each patient before using these cells as a treatment.
----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-13T00:29:01Z

Z3332863: /* Lab 11 Assessment */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Research article:'''

<pubmed>21572395</pubmed>

This research article has found that iPS cells can be subject to immune rejection by the recipient from which the iPS cells were derived. This is surprising because iPS cells are reprogrammed from somatic cells that came from the same recipient. So technically, the iPS cells should have the same genetic content as the recipient and not be sujected to immune rejection. This immune rejection is not seen in embryonic stem cells (ESC). The scientists generated ESCs from inbred mice and when these ESC were implanted into the mice, these embryonic stem cells were not rejected. The aim of this paper was to find out why there is an immune rejection associated with iPS cells but not with ESCs.

To carry out this investigation, Zhao et al reprogrammed C57BL/6 (B6) mouse embryonic fibroblasts into iPS cells using the retroviral method (which gives ViPSCs) which involves integration of the viral genome into the host cell's DNA or a new non-integrative, episomal method (gives EiPSCs). The retroviral method involved using retroviruses carrying genetic information that encoded the Yamanaka factors (Oct4, SOX2, Klf4, c-Myc). The episomal appraoch uses an episome vector which encoded the 4 Yamanaka factors. When Zhao et al placed these iPSCs into the recipient mice from which these cells were derived, they observed immune rejection with the teratomas formed by the ViPSCs. The teratomas formed by EiPSCs stimulated an immune response involving T cell infiltration and damage to tissues. Convwersely, the teratomas formed by ESCs were immune rejected at all.

These scientists then conducted a 'global gene expression analysis' on the EiPSC and ESC teratomas. From this analysis they found that EiPSCs overexpressed many genes that were not pver expressed in the ESCs. They concluded that this gene over-expression may contribute to the induction of a T cell response against the EiPSC teratoma and so the immungenicty of iPS cells must be analysed for each patient before using these cells as a treatment.
----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-13T00:25:16Z

Z3332863: /* Lab 11 Assessment */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Research article:'''

<pubmed>21572395</pubmed>

This research article has found that iPS cells can be subject to immune rejection by the recipient from which the iPS cells were derived. This is surprising because iPS cells are reprogrammed from somatic cells that came from the same recipient. So technically, the iPS cells should have the same genetic content as the recipient and not be sujected to immune rejection. This immune rejection is not seen in embryonic stem cells (ESC). The scientists generated ESCs from inbred mice and when these ESC were implanted into the mice, these embryonic stem cells were not rejected. The aim of this paper was to find out why there is an immune rejection associated with iPS cells but not with ESCs.

To carry out this investigation, Zhao et al reprogrammed C57BL/6 (B6) mouse embryonic fibroblasts into iPS cells using the retroviral method (which gives ViPSCs) which involves integration of the viral genome into the host cell's DNA or a new non-integrative, episomal method (gives EiPSCs). When they placed these iPSCs into the recipient mice from which these cells were derived, they observed immune rejection with the teratomas formed by the ViPSCs. The teratomas formed by EiPSCs stimulated an immune response involving T cell infiltration and damage to tissues. Convwersely, the teratomas formed by ESCs were immune rejected at all.

These scientists then conducted a 'global gene expression analysis' on the EiPSC and ESC teratomas. From this analysis they found that EiPSCs overexpressed many genes that were not pver expressed in the ESCs. They concluded that this gene over-expression may contribute to the induction of a T cell response against the EiPSC teratoma and so the immungenicty of iPS cells must be analysed for each patient before using these cells as a treatment.
----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-13T00:11:49Z

Z3332863: /* Lab 11 Assessment */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Research article:'''

<pubmed>21572395</pubmed>

This research article has found that iPS cells can be subject to immune rejection by the recipient from which the iPS cells were derived. This is surprising because iPS cells are reprogrammed from somatic cells that came from the same recipient. So technically, the iPS cells should have the same genetic content as the recipient and not be sujected to immune rejection. This immune rejection is not seen in embryonic stem cells (ESC). The scientists generated ESCs from inbred mice and when these ESC were implanted into the mice, these embryonic stem cells were not rejected. The aim of this paper was to find out why there is an immune rejection associated with iPS cells but not with ESCs.

----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-12T23:56:57Z

Z3332863: /* Lab 11 Assessment */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Research article:'''

<pubmed>21572395</pubmed>

----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-12T23:37:04Z

Z3332863: /* Individual Assessments and Practical work */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus

====Lab 11 Assessment====

'''Q. Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

User:Z3332863

2012-10-09T23:04:19Z

Z3332863: /* Lab Attendance */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

'''Lab 11''' --[[User:Z3332863|Z3332863]] 10:04, 10 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus
----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

2012 Group Project 2

2012-10-04T09:31:27Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T09:30:12Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T09:29:09Z

Z3332863:

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<br />
<br />
<br />
<br />
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<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T09:25:22Z

Z3332863: /* Pain */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:15:51Z

Z3332863: /* Glossary */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:14:54Z

Z3332863: /* Glossary */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia - a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:13:03Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:10:42Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FF7F" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#98FB98"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#F0FFF0"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#98FB98"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:08:10Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#87CEEB" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#ADD8E6"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#B0E0E6"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#ADD8E6"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:06:11Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00BFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#87CEFA"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#B0E0E6"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#87CEFA"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:05:15Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#1E90FF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#87CEFA"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#B0E0E6"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#87CEFA"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T00:02:43Z

Z3332863: /* Abnormalities of the Somatosensory Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#1E90FF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description'''
| width= 20%|'''Cause and Link to Embryology'''
|- bgcolor="#87CEFA"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|- bgcolor="#B0E0E6"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#87CEFA"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T23:21:55Z

Z3332863: /* Abnormalities of the Somatosensory system */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T23:03:49Z

Z3332863:

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory system ==

This table shows diseases that can affect the development of the Somatosensory system

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T06:20:56Z

Z3332863: /* Sensing Pain: The Development of Nociceptor */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T05:56:40Z

Z3332863: /* Pain */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Sensing Pain: The Development of Nociceptor ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T05:44:46Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T05:42:16Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T05:41:04Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T05:39:35Z

Z3332863: /* Pain */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T05:35:53Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T05:28:26Z

Z3332863: /* Development of Nociceptors - Summary */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 2

2012-10-03T05:27:33Z

Z3332863: /* Development of Nociceptors - Summary */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic while '''P''' stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T02:03:51Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two gens that have been considered in recent findings are c-Maf transcription factor and Shox-2.

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
|'''E11-13''' in Mouse
|'''Days 30-42'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|''' E14.5''' in Mouse
|'''Day 52'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E17''' in Rat
|'''Day 55'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''NA'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E18-20''' in Mouse
|'''NA'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|''' NA'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
|'''P4-10''' in Rat
|'''NA'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

File:Chemical physiological phenotype of nociceptors.JPG

2012-10-03T02:01:58Z

Z3332863: The development of chemical and physiological phenotypes occurs via both intrinsic and extrinsic mechanisms. Intrinsically, nociceptors can express some level of neuropeptides such as Substance P (SP) and calcitonin gene-related peptide (CGRP). Contact wi

The development of chemical and physiological phenotypes occurs via both intrinsic and extrinsic mechanisms. Intrinsically, nociceptors can express some level of neuropeptides such as Substance P (SP) and calcitonin gene-related peptide (CGRP). Contact with epidermal cells (extrinsic cues) increases this neuropeptide expression. Development of physiological phenotype involves expression of Nav1.8 and TRVP1 in response to neurotrophins.

This is a student drawn diagram by z3332863, based on information from:

Kelvin Y Kwan, Andrew J Allchorne, Melissa A Vollrath, Adam P Christensen, Duan-Sun Zhang, Clifford J Woolf, David P Corey TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron: 2006, 50(2);277-89 PMID:16630838

S C Benn, M Costigan, S Tate, M Fitzgerald, C J Woolf Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons. J. Neurosci.: 2001, 21(16);6077-85 PMID:11487631

A K Hall, X Ai, G E Hickman, S E MacPhedran, C O Nduaguba, C P Robertson The generation of neuronal heterogeneity in a rat sensory ganglion. J. Neurosci.: 1997, 17(8);2775-84 PMID:9092599

O Taherzadeh, W R Otto, U Anand, J Nanchahal, P Anand Influence of human skin injury on regeneration of sensory neurons. Cell Tissue Res.: 2003, 312(3);275-80 PMID:12733058

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2012 Group Project 2

2012-10-03T01:57:46Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two gens that have been considered in recent findings are c-Maf transcription factor and Shox-2.

====c-Maf====

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
|'''E11-13''' in Mouse
|'''Days 30-42'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|''' E14.5''' in Mouse
|'''Day 52'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E17''' in Rat
|'''Day 55'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''NA'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E18-20''' in Mouse
|'''NA'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|''' NA'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
|'''P4-10''' in Rat
|'''NA'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

File:Nociceptor Innervation Increases.JPG

2012-10-03T01:56:34Z

Z3332863: Innervation of peripheral tissue by nociceptors is increased in response to local neurotrophins. This is a student drawn diagram by z3332863, based on information from: <pubmed>10407031</pubmed> ---------------------------------------------------------

Innervation of peripheral tissue by nociceptors is increased in response to local neurotrophins.

This is a student drawn diagram by z3332863, based on information from:

<pubmed>10407031</pubmed>

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Note - This image was originally uploaded as part of an undergraduate science student project and may contain inaccuracies in either description or acknowledgements. Students have been advised in writing concerning the reuse of content and may accidentally have misunderstood the original terms of use. If image reuse on this non-commercial educational site infringes your existing copyright, please contact the site editor for immediate removal.
Copyright: This is a student drawn image and free for non-profit reuse.

Talk:2012 Group Project 2

2012-10-03T01:49:13Z

Z3332863: /* Search */

{{2012GroupDiscussion}}

--[[User:Z8600021|Mark Hill]] 09:57, 18 September 2012 (EST) This is a recent review on touch. http://jcb.rupress.org/content/191/2/237.full JCB content allows reuse.

==Group evaluation==

The introduction is ok, there is an imbalance between text and pictures. Particularly there is a sentence which reads “The following picture shows the general organization of the somatosensory system” however there is no picture. Also in terms of sentence structure, there are four sentences in a row which begin with “the somatosensory system...” or “the system...” Try to alternate how different ideas are expressed as at the moment the paragraph reads as a disjunct of ideas.

As a whole the page’s visual appeal needs ameliorating. There is far too much text and only two pictures, one of which is very large and appears to be compensating for a lack of smaller relevant diagrams within the body of each section. Having said this, the neural development section was very well done. It was detailed without being verbose and showed it was well researched. The hand drawn diagram is excellent. The cell biology part was also very well written and well structured however again, it simply need some visuals to aid in some descriptions of molecular processes.

There appears not to be a continuous referencing style on the page. The introduction has in-text referencing whilst the rest of the page contains endnotes. A minor problem which could be fixed easily, though quite important nonetheless.

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I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

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Initial impression is it’s too textual for a wiki. The lack of consistent referencing styles is hard to follow.
Relates the developing somatosensation to the nervous system, which was good and very interesting.
Tables and mind maps/flow carts would be beneficial in sections 1.3.1-1.3.3.
And a section on abnormalities of touch would be nice and/or methods of detecting touch and pain etc (ie: clinical methods) and maybe sensitivity to touch.

However, the way this project was divided was logical and easy to follow. But more defined and succinct paragraphs need to be made as it tends to go on for a bit, but that is a sign of good research into the project.

In the section of thermoreceptors it would be better if there was an image from the article for graphical representation.

Summary: MORE IMAGES!!! Be more succinct.

Good luck with the rest ☺

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"The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!"

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- The introduction is small yet detailed --- I like how its an overview of the development. You do need to fix up the references though.

- You have in the intro section “the following picture….” But there is no picture there….if the picture is further ahead maybe write Fig 1 shows….and also label the picture.

- History section needs a bit work on – you should start with the earliest data and proceed in a chronological order so everyone can see the advancement in development of somatosensory organs.

- In the section of “Development of the primary somatosensory cortex” you have mentioned that there are intrinsic and extrinsic mechanisms --- you should mention what those signalling mechanisms are. Also if you are using the one ref for the whole paragraph do not put the ref after each line. Just put it in the end. Also it would be good to give the origin of the neurons like ecto, endo or meso.

- Its good how your description is divided into stages – it might help to give the weeks as well.

- For the touch section you have a lot of detail on what the receptors are which is fine but there is nothing about their development (which is what the project is about). The same thing is noted with “Pain” section – there is nothing on development. I’m sure you can put some genes or signalling molecules that are important for differentiation of cells into the different receptors.

At the moment your project is focused on what the different somatosensory receptors do but very little detail on how they develop, which is what you need to focus on.

More pictures are needed to break up the text.

Good luck!

--[[User:Z3333794|Z3333794]] 09:51, 23 September 2012 (EST)

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Overall, the key points relating to the topic area are being addressed. The use of current research to develop ideas and provide detail to the separate sub-headings is helpful. However, I would suggest better collaboration amongst team members about what is going to be addressed under each sub-heading because some repetition has taken place, particularly between touch and pressure where overlaps are expected occur.

Additionally, there is clear imbalance between text and images and there are some areas where dot points, tables, images or videos will be better received by the audience than paragraphs of information.

More specifically, the history of discoveries can be tabulated and should include more historic events that may have taken place before Weber and possibly led to his research.
In the section on pain, the bulk of the information can look more easy to read if the different fibres are bolded and put on separate lines with their accompanied descriptions or images or videos are used to replace the text.

A diagram or flow chart may be used in the hot/cold section accompanying or replacing the description on the sensation of temperature.

The section on pressure has all information cramped up in one paragraph which presents different ideas. I suggest each idea being put under a different heading or paragraph. For example, a paragraph on development, one on different structures and their functions (if needed since already addressed), one on research and applications. Images could be helpful!

So far current research looks promising and with the inclusions of more projects, would be interesting. I would suggest only including images in the research section when they can be simply understood and impact on the reader’s understanding or interpretation of the project.

The student diagram used in describing the somatosensory pathway is well done and makes a big difference to the page. The layout of this section is also organised and easy to follow and comprehend.

The references, although extremely extensive, is inconsistent between sections and a consensus should be met amongst team members, additionally, the glossary needs to be built upon. The inclusions of more definitions may help in limiting the text in each section.

Overall, there is no critique on the information presented on the page, it is all very interesting and current, however, a change in organisation of information will help bring this to the attention of the reader.
Good luck!

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Your introduction is quite expansive and the first paragraph gives an excellent overview of what the somatosensory system actually is. At the end of the first paragraph you do refer to a picture; however, there is no picture. Please add this to show the somatosensory organisation within the body. In the second paragraph you mention some key timepoints related to the somatosensory development, which is good. After this (“Development of the system entails…lemniscal system.”) the text is probably too specific for the introduction. This can be used as an introduction for your development subheading. Please make sure that you edit the in-text references to proper references which we can access via your reference list. Also make sure you start adding terms to the glossary, eg. dorsal column-medial lemniscal system (I do not know what this means!)

You have started on your history section, but it would be more interesting and easier to read if you put this in a table. For instance: date – description – significant person. Also try to add a few more important discoveries. Again, please provide proper references. See the ‘editing basics’ section on this embryology website.

The central somatosensory differentiation is good and I can see that a lot of effort has been put into this section. The picture is very helpful and complements the text. To some extend it does seem like the sensory neurons only come from the dorsal aspect (going into the dorsal root ganglion), so maybe put a note in there that the dorsal and ventral rami are mixed nerves and both of them will contain sensory neurons that go to the dorsal root ganglion. With this image, you also have to include the student template. Text and references are good in this section and I particularly found the ‘making connections’ section very clear, organised and enjoyable to read. Do make sure that you add to the glossary – in particular terms from the ‘development of the primary cortex section’, and if possible add more images.

The touch section has a fair amount of text, but no images to complement it. This made it a bit boring to read. Make sure the subheadings stand out by making them bold. Most of the text has not been references at all, which is concerning and could potentially indicate plagiarism. I also did not read anything about the development of the various receptors (or hypotheses it no distinct evidence has been provided yet). Keep in mind we are looking at the development of the system, not the physiology. You did put in some interesting facts, such as that cell abnormalities can lead to Merkel-cell carcinoma.

Pain and hot/cold are similar to touch: good description of the physiology, but no development included. References are only provided as in-text citations or listed below, which will need to be edited to include them into the reference list. Include images to complement your text and engage the reader – this also concerns the touch section.

The pressure section has limited information regarding the development. Please include how this develops – what factors are included etc. In my opinion there is too much focus on the adult physiology. We are studying embryology… As mentioned above, please edit references and include appropriate images.

Current research looks good with an interesting image and the appropriate references, copyright and student template. The description helps to understand the image. Maybe add another research project to this section.

Add to the glossary, references and actually name the external links listed as 1) 2) and 3).

Hope this helps!
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The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?

The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

Group Assessment Criteria:
# ''The key points relating to the topic that your group was allocated are clearly described.'' The introduction outlines the importance of the somatosensory system and provides a good summary of the developmental stages. More emphasis could be made on the key points of the project page.
# ''The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'' The content shows an understanding of the topic area, however the layout makes the text difficult to follow. There is not a clear connection between the ‘Central Somatosensory Differentiation’ and the somatosensory system. There is a lack of diagrams, tables and graphs to explain the written content.
# ''Content is correctly cited and referenced.'' Some sections are correctly referenced whilst others are completely lacking. This area needs working on.
# ''The wiki has an element of teaching at a peer level using the student’s own innovative diagrams, tables or figures and/or using interesting examples or explanations.'' The information is broken down well by headings and subheadings, however there is a lack of relating images to compliment the information. The one student drawn image is very useful.
# ''Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'' The information provided is well researched and satisfies the aims of the project in terms of developmental stages, however in order to go ‘beyond the formal teaching activities’ it needs to include sections such as abnormal development and more on the history, current and future research.
# ''Relates the topics and content of the Wiki entry to learning aims of embryology.'' The topics and content relate to the learning aims of embryology by describing the developmental stages if the somatosensory cortex.
# ''The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.'' There has been a fair amount of research into the topic, however a bulk of the information is focused on descriptions of each of the senses. More emphasis should be placed on the development of each of these sense as that is the key topic area.

Additional points:
* The Introduction and Central Somatosensory Differentiation sections were well written and the accompanying diagram was very useful.
* The layout of the page could be improved with the use of tables and diagrams to reduce/replace the amount of text
* The project seems largely incomplete; more research needs to go into the History and research sections and there is a lack of images

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Somatosensory review:

The key points are clearly presented at the top of the page efficiently formatted allowing viewer a perfect insight to the entire pages content. There is a severe lack of visual stimuli; this makes the page present as boring and text heavy.
Image citation is commendable although throughout the text there is unacceptable links to external sites that are not explained with a messy reference section. The information presented is quite detailed and promotes a significant amount of research and understanding, it is put forward in an excellent matter, sections that could easily be expanded are glossary, and perhaps a section specifically on development.
Attempt to relate to the learning aims of embryology are apparent. There is a large amount of information presented in a fantastic way although the lack of visual stimuli takes away from the final product, perhaps a more summarised presentation matter would be appropriate to break up large amount of text; this along with the tidy up of referencing needs to be addressed.

--[[User:Z3330795|Z3330795]] 10:36, 24 September 2012 (EST)

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The introduction provides a good overview however using the wiki in-text citation system will make it neater.

The history section has made a good start but this can be elaborated on further. Once again, referencing can be improved here.

The central somatosensory section has been well researched and the referencing is good. It would be preferable to label figures as "figure 1" etc as this makes it easy to refer to. The drawing is good and has a good explanation however the "student template" should be added.

The touch/pain/hot and cold/pressure sections have a lot of information on their function but not so much information relating to embryological development. Some sections are well referenced, other bits are referenced without the wiki format, and other sections aren't really referenced at all. This can be improved. Adding pictures to these sections to illustrate points will also be helpful.

The current research section, although small, is very good, well referenced, good inclusion of the figure however this could be given a name such as "figure 2". Adding more current research with variation in the topics covered will make this section even more interesting.

The glossary and external links are good - keep adding to these throughout the project.

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This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

----------------------
The introduction for somatosensory is very informative and the overview of its development is great. The information is also great, however i do notice a bit of overlap throughout the page. It is important to go through the information and remove information that is repeated.

At times it feels like there is far too much information and not enough images, tables and diagrams. Dot points would be an alternative way to present your information as organisation is necessary. Including some tables and breaking up the texts into more subheadings would make the information easier to absorb.

The history section requires some attention, and it is important to put it in a chronological order.
A number of references were not cited correctly and this needs to be corrected. It is important that you refer back to the tutorial on referencing as the citations are very important. Your glossary needs to be worked on and extended, it simply does not cover enough words within your project.

Where is the development section? This is one of the most important topics in the project in addition to function which need to cover signalling molecules and genes. The section on pressure however, is great, but the information needs to be put into tables or under more subheadings to make the information easier to read. At the moment information seems to be all over the place.

The current research section is great and should be expanded upon. The self drawn diagram about the somatosensory pathway is very informative and easy to understand. The references are great but some are included more than once and these need to be organised at the end of the page.
Beside the limited diagrams, images, tables and organisation this page looks very promising. Good luck

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'''Somatosensory'''

Sectioning off the touch, pain, hot/cold and pressure was a very well thought out idea, but wouldn't hot/cold come under a temperature? Just an idea to change the heading to something a bit more formal. Overall the content was very well written. And most sections were referenced properly. Other sections were not, such as the introduction and pressure. The content in these paragraphs is so well written, I fell it is left down by the referencing problem. I found that there were only a few references used in some sections, and sometimes being only one. That may be because there is not enough information out there, I'm just not entirely satisfied with the amount of references. I feel there's more out there.
The hand drawn picture was very well done and I like it.
The Touch section was well done but had no developmental development, current research is lacking and as is the glossary.
There needs to more pictures also.

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The introduction is thorough and explains what your topic is about. The history of discoveries part if that is all the info you can find, why not put it in a table it would format the section so the reader can get an overview on how our understanding on somatosensory began.

Your page could do with adding some more pictures in relation to the different sections of somatosensory. for e.g. you mention Meissner's corpuscles in the touch section, you could add a picture with labels so that people could have a visual to understand, as you state where they are located but lay people would not understand what dermal papillae are.

I see you have an embryology and development part with no information, hopefully this will be added to in the near future otherwise don't forget to delete it.

You should also add more to the glossary and have a part called external links and place your links there.
--[[User:Z3220343|Z3220343]] 21:30, 25 September 2012 (EST)

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Your introductory paragraph is very detailed and has appropriate references. It would be nice to add an image to complement it somehow. Because it’s not very easy to read a big block of text without any image supporting the text. It would look more balanced that way. Also, providing clickable links to the references would be better and make it easier for users to find the original references by clicking on the citation rather than scrolling down and manually looking for the citation in the references.

History of discoveries section is somewhat lacking in content, you need to add more information. It would be nice to do a timeline format to make it easier to see the transition of new discoveries over the past years. Again, adding some images to support this section would make it more interesting to read. Again, providing clickable links to the references would be better and make it easier for users to find the original references by clicking on the citation rather than scrolling down and manually looking for the citation in the references.
“Central Somatosensory Differentiation” is the best section so far. It is very well detailed with appropriate references and has an image to support the text. It even has clickable reference links which is good, as it makes it easier to find the references. It would be good to add a little bit more information to describe the image. And perhaps add a few more images to support this section.
Overall, you only have one image on your entire page. It would be good if you add some more images to support your text.

Current Research section needs more articles about current research. One article doesn’t seem sufficient. It is good that your image from the article has the appropriate reference.
Glossary section needs more words and definitions, there is not enough so far.
Some of the external links needs to be fixed. You need to change the format of the links and explain where the links would take you or what those web pages are about.

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Group 2- Somatosensory

-Great introduction. Really puts the project in context and justifies the importance of your research. Citations need to be formatted like the rest of the page

-History of discoveries-very poor syntax, word repetition and no paragraphs. What is Weber's full name? This is entitled "history of discoveries" when it is actually just a very brief, nonspecific summary of "Weber". What about the other interesting discoveries from various scientists over decades?

-Adult Central Somatosensory systems- ascending in what? Position? Importance? Activity? Sensitivity? This needs a more informative opening sentence.

-Trigeminal system and Development of the Primary Somatosensory Cortex- are well explained and ideas are presented in a logical, flowing manner. Great picture with a good description and referencing (impressed you drew it).

-"making connections between...." what do the stages mean? Why does it start at stage 23 instead of stage 1?

-touch/touch receptors is good but where are the references?

-pain and pressure sections also good but needs paragraphs and the formatting of citations is incorrect

-bullet points in pressure section need a brief sentence introducing their purpose. Papers listed at bottom of section should be correctly cited instead of having hyperlinks

-interesting info in temperature

-current research- maybe you could put the name of the paper and authors and explain how they conducted their study? That would help with understanding the nice picture

-Glossary is incomplete

-Needs more pictures

-minor grammatical and spelling errors throughout but overall very good and well sequenced.

==Search==

Hi, the pressure section has some overlap with touch. Can we merge pressure with Touch? Let me know what you think.
--[[User:Z3332863|Z3332863]] 11:49, 3 October 2012 (EST)

Hey, people writing the pressure and thermoceptor section, can you please add some images or tables in your section? You can use the code for the tables in the touch or pain section. If the copyright won't allow you to put images directly from journal articles, can you please draw some images to put up? I don't understand your sections as well as you do. I can put some pictures in your section if you are really stuck - let me know if that is the case. --[[User:Z3332863|Z3332863]] 22:38, 2 October 2012 (EST)

Finally worked all the kinks out for formatting, hence why the table is now on our page. Still uploading the final touches and sections. If there are any problems or questions with the section now, please feel free to contact me, either by this discussion forum, email or message. Thanks --[[User:Z3330539|Z3330539]] 22:18, 1 October 2012 (EST)--

Hey guys, don't mind me, I'm just going to be doing some table mock-ups n the discussion page, just before i upload it onto the main page. I know I could be doing this on the actual page, but I'd rther be safe than sorry, cause our page is coming along really well :)

Cheers --[[User:Z3330539|Z3330539]] 12:10, 1 October 2012 (EST)--

Hi, whoever wrote the history section, can you include some dates as to when the discoveries were made. I was thinking of putting that info into a table but we need the dates to do that. Thank you. --[[User:Z3332863|Z3332863]] 14:50, 15 September 2012 (EST)

[http://www.ncbi.nlm.nih.gov/sites/gquery?term=golgi+tendon+organ+development search pubmed GTO development]

'''Development of Nociceptors, Thermoceptors,and Pruriceptors'''

Lopes C, Liu Z, Xu Y, Ma Q. '''Tlx3 and runx1 act in combination to coordinate the development of a cohort of nociceptors, thermoceptors, and pruriceptors.''' J Neurosci. 2012 Jul 11;32(28):9706-15. <pubmed>22787056</pubmed>

'''Review for general Somatosensory development''' - just for background knowledge:

<pubmed>7812142</pubmed>
--[[User:Z3332863|Z3332863]] 14:53, 23 August 2012 (EST)

'''Central sensory Neuron development:'''

<pubmed>2918087</pubmed>
--[[User:Z3332863|Z3332863]] 14:53, 23 August 2012 (EST)

'''Article on Pain Development:'''

<pubmed>16446141</pubmed>

--[[User:Z3332863|Z3332863]] 10:05, 22 August 2012 (EST)

I think it would be cool to do an organ, but i'll be just as happy to do one of the senses. Does anyone have a specific organ they were thinking of?

My preference was '''Sensory''', but if we get organ that's fine also. If we did do organ I still want to look into some of the topics before I give my opinion, depending on the research and information behind it. If we got sensory, sight could be cool? - ==[[User:Z3330539|Z3330539]] 08:26, 10 August 2012 (EST)==

I'd prefer '''Sensory'''.

I agree; if we got Sensory, I would be happy to do '''Sight'''. But if we got Organ, I want to do the Heart but I'd be just as as happy to do another organ if anyone's keen.
--[[User:Z3332863|Z3332863]] 09:14, 10 August 2012 (EST)

Hi all,

I started with; and have mainly been looking into development relating to "Touch" and the receptors involved and time at which this occurs. I am happy to keep going or do research on the other categories as well? I will share what I found when we meet next. --[[User:Z3330539|Z3330539]] 22:02, 20 August 2012 (EST)--

File:Increased innervation by nociceptors.JPG

2012-10-03T01:37:09Z

Z3332863: uploaded a new version of "File:Increased innervation by nociceptors.JPG": Innervation of peripheral tissue by nociceptors is increased in response to local neurotrophins. This is a student drawn diagram by z3332863, based on information fr

2012 Group Project 2

2012-10-03T01:34:34Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two gens that have been considered in recent findings are c-Maf transcription factor and Shox-2.

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
|'''E11-13''' in Mouse
|'''Days 30-42'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|''' E14.5''' in Mouse
|'''Day 52'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E17''' in Rat
|'''Day 55'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''NA'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E18-20''' in Mouse
|'''NA'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|''' NA'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
|'''P4-10''' in Rat
|'''NA'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Increased innervation by nociceptors.JPG|500px|Increased Innervation of peripheral Tissues by Nociceptors]]

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
[[File:Pressure Receptors in Glabrous Skin.jpg|thumb|alignment|caption]]
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref>

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

File:Increased innervation by nociceptors.JPG

2012-10-03T01:30:52Z

2012 Group Project 2

2012-10-03T01:16:28Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
|'''E11-13''' in Mouse
|'''Days 30-42'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|''' E14.5''' in Mouse
|'''Day 52'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E17''' in Rat
|'''Day 55'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''NA'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E18-20''' in Mouse
|'''NA'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|''' NA'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
|'''P4-10''' in Rat
|'''NA'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==

Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref>

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T01:13:03Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
|'''E11-13''' in Mouse
|'''Days 30-42'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|''' E14.5''' in Mouse
|'''Day 52'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E17''' in Rat
|'''Day 55'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''NA'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E18-20''' in Mouse
|'''NA'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|''' NA'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
|'''P4-10''' in Rat
|'''NA'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Nociceptor Survival]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==

Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref>

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-03T00:45:32Z

Z3332863: /* Details of Nociceptor Development */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

====Shox2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
|'''E11-13''' in Mouse
|'''Days 30-42'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|''' E14.5''' in Mouse
|'''Day 52'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E17''' in Rat
|'''Day 55'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''NA'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E18-20''' in Mouse
|'''NA'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|''' NA'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
|'''P4-10''' in Rat
|'''NA'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Nociceptor Survival]]

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==

Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref>

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

File:Axon growth.JPG

2012-10-03T00:43:23Z

Z3332863: The role of different molecules on the growth of the nociceptor axons. The main neurotrophin stimulating axon growth is Nerve Growth Factor (NGF). After NGF stimulation various downstream molecules are activated to cause axon elongation, branching and thi

The role of different molecules on the growth of the nociceptor axons. The main neurotrophin stimulating axon growth is Nerve Growth Factor (NGF). After NGF stimulation various downstream molecules are activated to cause axon elongation, branching and thickening.

This is a student drawn diagram by z3332863, based on information from:

<pubmed>9920667</pubmed>

<pubmed>12123609</pubmed>

<pubmed>10701827</pubmed>

<pubmed>7175742</pubmed>

<pubmed>14749426</pubmed>

<pubmed>9092599</pubmed>

--------------------------------------------------------------------------------------------------------
Note - This image was originally uploaded as part of an undergraduate science student project and may contain inaccuracies in either description or acknowledgements. Students have been advised in writing concerning the reuse of content and may accidentally have misunderstood the original terms of use. If image reuse on this non-commercial educational site infringes your existing copyright, please contact the site editor for immediate removal.
Copyright: This is a student drawn image and free for non-profit reuse.

2012 Group Project 2

2012-10-03T00:21:08Z

Z3332863: /* Development of Nociceptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
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<table>
{| width=100%
|-bgcolor= "FF9900 "
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
| Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
| Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Genes Involved in Embryonic Development===

====Shox- 2====

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

== Pain ==
With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura & Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease.
On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
|'''E11-13''' in Mouse
|'''Days 30-42'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|''' E14.5''' in Mouse
|'''Day 52'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E17''' in Rat
|'''Day 55'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''NA'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|'''E18-20''' in Mouse
|'''NA'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|''' NA'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
|'''P4-10''' in Rat
|'''NA'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

'''Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

'''Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

'''Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==

Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref>

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

User:Z3332863

2012-10-03T00:08:05Z

Z3332863: /* Lab Attendance */

== Lab Attendance ==

'''Lab 1''' --[[User:Z3332863|Z3332863]] 11:47, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3332863|Z3332863]] 10:20, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3332863|Z3332863]] 10:05, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3332863|Z3332863]] 10:18, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3332863|Z3332863]] 10:01, 22 August 2012 (EST)

'''lab 6''' --[[User:Z3332863|Z3332863]] 10:04, 29 August 2012 (EST)

'''Lab 7'''--[[User:Z3332863|Z3332863]] 09:59, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3332863|Z3332863]] 10:10, 19 September 2012 (EST)

'''Lab 9'''--[[User:Z3332863|Z3332863]] 10:04, 26 September 2012 (EST)

'''Lab 10''' --[[User:Z3332863|Z3332863]] 10:07, 3 October 2012 (EST)

== Individual Assessments and Practical work ==

==== Lab1 ====

'''Assessment:'''

'''Origin of Nobel Prize & Discoverer'''

In 2010, Robert G. Edwards won the Nobel Prize for developing In vitro Fertilisation. IVF originated in 1950s when Edwards began fertilizing human eggs in cell culture dishes as a way of treating infertility. In 1978, Edward's IVF technology gave the world's first IVF baby. Over the next few years, Edwards and his team fine-tuned the technique of IVF.

[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]

'''Research paper on fertilisation:'''

<pubmed>22317970</pubmed>

'''What does this paper tell us about fertilisation?'''

This article looks at the rise of aneuploidies in IVF embryos from women around 40yrs of age. To do this Handyside et al, used 'microarray comparative genomic hybridisation' technology to study the chromosome copy number in the zygote, the 1st and 2nd polar bodies in older women receiving IVF treatment. Handyside et al found that:

* Most of the aneuploidies of IVF embryos arose from the 2nd meiotic division of the oocyte. This is surprising because most aneuploidies in naturally fertilized embryos arise from Meiosis I of the oocyte.
* Aneuploidies in IVF zygotes were not due to non-disjunction of chromosomes in the oocyte. Instead, these Aneuploidies were due to predivision of the chromatids in the oocyte.
* In IVF zygotes made from aged oocytes, often there were multiple aneuploidies in 1 zygote.

By looking at the origin of aneuploidies in IVF zygotes, these scientists are trying to find a way to reduce these aneuploidies.

==== Lab 2 Prac work ====

'''Prac class work (not the assessment - see section after this for assessment'''

'''Genes that display significant strain by stage variation fall into four main categories'''

[[File:Genes that display strain variation.png]]

'''Genes that display significant strain by stage variation fall into four main categories.'''
The genes that show significant variation due to strain by stage interaction were clustered hierarchically. Four distinct patterns appear in the clustered data, identified by the letters A–D. CB4856 (H) are on the left, from the egg to the young adult, while N2 (N) are on the right, from the egg to the young adult. Missing values were imputed using KNN-impute and expression values represent the average from four replicates.

'''Further Description'''

Capra et al were studying the variation in gene expression during the different stages of Development of different isolates of C. elegans. This image is a microarray result, showing genes that are expressed in different amounts in different strains of C. elegans during development. This Micrarray shows allow these differentially expressed genes to be classified into 4 groups. It’s likely the genes in the same cluster are regulated in the same way.

'''Reference'''
<pubmed>19116648</pubmed>

'''Copyright'''
2008 Capra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

==== lab 2 Assessment ====

'''Q1. Paper & Image Related to Fertilization'''

'''Detection and Localisation of HPV in Sperms'''

[[File:Detection and Localisation of HPV in Sperms.png]]
Detection and localization of HPV in human sperm.

a. Fluorescence in situ hybridization (fluorescence microscope) for HPV DNA on sperm from a patient with HPV16 in semen. Infected and noninfected sperm are shown. Red: HPV DNA (Texas red); blue: nuclear staining (DAPI). b. Immunofluorescence (confocal fluorescence microscope) for HPV16 capsid protein L1 on sperm from a control (left) and a patient with HPV16 in semen (right). Upper panel, L1 antibody; central panel, L1 antibody and Pisum Sativum (acrosome); lower panel, L1 antibody and Pisum Sativum after induction of the acrosome reaction. Red: HPV16 L1; green: Pisum Sativum; blue: nuclear staining (DAPI). c. PCR for HPV E7 gene from sperm DNA. Lane M: DNA marker (100 bp); 1: negative control (no template); 2: positive control (sperm transfected with recombinant plasmid pIRES2-AcGFP1-E6E7); 3: sperm from a patient with HPV16 in semen; 4: sperm from a control subject.

'''Outline of the Research:'''

The results of Foresta et al show that Human Papilloma Virus (HPV) can infect sperm through interactions between the virus’ capsid proteins and Syndecan-1 of the sperm. They also found these infected sperm can fertilize the egg and pass the virus into the oocyte

'''Reference:'''

<Pubmed>21408100</pubmed>

'''Copyright'''

2011 Carlo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
{{Template:Student Image}}

''''''Q2. Protein Involved in Implantation''''''

Protein: '''WNT4'''

Franco et al discovered that WNT4 plays a crucial role inregulating uterine development, Progesterone signalling and decidualization during Embryo Implantation. They used a WNT4 deficient mouse model to show that without WNT4, there were:
* Defects in Endometrial stromal cell survival
* reduction in uterine glands
* reduced responsiveness of endometrial cells to progesterone.

Franco et al used a mouse with fully functional Wnt4 as a control and these abnormalities were not seen in the Wnt4 expressing mouse. These researchers studied the Implantation sites of WNT4 deficient versus the control mice. They discovered, while all of the control mice showed implantation sites, only 25% of the WNT4 deficient mice had evidence of implantation. This means without WNT4, implantation cannot take place in most mice. The area of the implantation site in WNT4 deficient mice was smaller than control.

In WNT4 deficient mice, there was also a reduction in Decidualization. Franco et al induced an artificial decidualization in these mice and found the WNT4 deficient mice had a smaller decidual horn (uterine horn) than the control mice with functional WNT4. They found Wnt4 drives decidualization by enhancing the survival and differentiation of the stromal cells in the endometrium.

They noticed that in the WNT4 deficient mouse, another protein Foxa2 was reduced, in comparison to WNT4 expressing mouse. Foxa2 is expressed in uterine glands and is important in their development. Furthermore, leukemia inhibitory factor (Lif), a protein secreted by uterine glands, was also reduced in WNT4 deficient mice but not the control.

<pubmed>21163860</pubmed>

==== Lab 3 Assessment ====

Q1. Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

* Gestational age is the age of the Conceptus or Pregnancy. Gestational age is timed from the first day of the woman's last Menstrual Cycle. However, Post-fertilisation age is the time lapsed since fertilisation of the oocyte.

* Gestational age is used clinically because it is hard to pinpoint the exact day of Fertilisation. Ostetricians can ask the woman when was the first day of her last menstruation to work out the gestation age.

Reference:

[http://medical-dictionary.thefreedictionary.com/gestational+age]

Q2. Identify using histological descriptions at least 3 different types of tissues formed from somites.

* Skeletal Muscle - Formed from the Myotome of the somites. Skeletal muscle is made up of contractile units called Sarcomeres. Components of sarcomeres can be seen using electron microscopes. The sarcomere has a Lightly coloured H band in the middle. This H band consists of actin filaments and myosin tails. The myosin heads interact with actin in the A band (just beside the H band). This gives the Dark band seen under the miscroscope. On the sides of each sarcomere is the Z disc where actin filaments of adjacent sarcomeres are attached.

* Dermis - formed from the Dermatome of the somites. dermis is the deep layer of skin, under the epidermis. Dermis is divided into 2 layers - Papillary layer and Reticular layer. Papillary layer has very fine collagen fibres and lots of cells and blood vessels. It is made up of loose connective tissue. Reticular layer is a dense connective tissue layer, made up of bundles of interlacing collagen fibres.

* Bone - Vertebral body and Intervertebral disc are formed from the Sclerotome of the Somites. Histologically, bone form 2 types of organisations - Compact bone and Trabecular bone. Vertebrae are made up of mainly trabecular bone. Trabecular bone is deposited in the form of lamellae but the lamellae do not form Haversian systems. Trabecular bone is made up of tiny bony bars with intervening spaces. A fully developed vertebral column is made up of 7 cervical, 12 thoracic, 5 lumbar, 5 (fused together) sacral and 1 coccygeal vertebrae. The Invertebral discs are made up of a gelatinous nucleus pulposus, enclosed in a fibrous annulus fibrosis. The annulus is made up of concentric rings of collagen fibres. These fibres fuse with the longitudinal ligaments. reference: <pubmed>16595436</pubmed>

Reference: Blue Histology [http://www.lab.anhb.uwa.edu.au/mb140/]

==== Lab 4 Assessment ====

1. Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

'''Chorionic Villus Sampling (CVS)'''

Catheter is passed into the uterus to collect cells from the placental Chorionic Villi. Ultrasound is used to guide the catheter to the chorionic villi. CVS identifies the karyotype of fetus. CVS identifies chromosomal diseases like:
* Down’s Syndrome
* Tay-Sachs
* Cystic Fibrosis
* sickle cell anaemia

Reference: [http://www.thewomens.org.au/ChorionicVillusSamplingCVS]

'''Cordocentesis:'''

Fetal blood is taken from the Umbilical vein, at the placental end of the vein. Ultrasound imaging is used to guide the needle to the umbilical vein. Blood cells are analyzed in the lab. Cordocentesis looks for the following abnormalities:

* Infections like toxoplasmosis, Cytomeglovirus and rubella
* fetal Anaemia
* isoimmunisation
* Down's Syndrome

Reference: [http://www.womens-health.co.uk/pregnancy/cordo.html]

2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

<pubmed>16223852</pubmed>

This paper investigates the therapeutic value of Umbilical Matrix Stem Cells (UMSC) which is found in Wharton’s Jelly of the umbilical cord. UMSC may be used to treat Parkinson’s disease. Rats with Parkinson’s disease (PD model rats) were given human UMSC as a transplant. One of their preliminary experiments showed there is no rejection of the transplanted cells. Severity of Parkinson’s disease in rats is measured by rotational behaviour of the rats – the more rotations, the worse the disease. Rats with UMSC implant showed a significant reduction in the number of rotations compared to those without UMSC transplant.

Weiss et al also found an increase in the number of Dopaminergic (DA) neurons in PD model rats that were given the UMSC transplant. Weiss et al found UMSC secrete large amounts of GDNF that can stimulate DA neuron growth and fibroblast growth factor 20 which can increase the survival of DA neurons. These factors secreted by UMSC may be responsible for the increased number of DA neurons seen in the rat’s brains after UMSC transplant. Low DA neurons, especially in the ventral tegmental area, are responsible for Parkinson’s disease. Thus by increasing the number of DA neurons UMSC may treat Parkinson’s disease in people.

==== Lab 7 Assessment ====

'''1. (a) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

* A muscle satellite cell is stem cell located in skeletal muscle that promotes regeneration, growth and repair of skeletal muscle fibers. [http://www.thefreedictionary.com/satellite+cell]

* Satellite cells can be activated after extreme exercise. A study was done by Darr et al where mice were vigorously exercised and the level of activated satellite cells were measured before and after their exercise. [1] This study showed exercise can increase the level of satellite cell proliferation which is needed to repair necrotic muscle fibers as a result of extreme exercise. [1] Exercising skeletal muscles may release mitogenic factors that increase satellite cell activation and proliferation. [1] Insulin-like Growth Factor I (IGF-1) can induce skeletal muscle hypertrophy. [2] This hypertrophy may be caused by activation satellite cells. [2] Activated satellite cells increases protein synthesis in muscle fibers to cause muscle hypertrophy. [2] Thus another example of satellite cell action is in IGF-1 induced muscle hypertrophy. [2] Satellite cells are aslo activated in Duchene's Muscular Dystrophy (DMD). [3] In DMD, fibres are lost due to a deficiency in Dystrophin which causes tearing in the cell membrane and activated satellite cells proliferate to replace these lost cells. [3] as the age of the DMD patients increase, the replicative potential of the satellite cells reduce, more so than the control (children without DMD). [3]

'''2. In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

In mice, cutting the spinal cord results in severe atrophy of the muscle fibers. [4] This is where muscle fibers reduce their size and cross-sectional fiber area. [4] Muscle fibers also seem to switch to a 'fast' phenotype, instead of slow fibers. [4]Sustained motor neuron injury also increases the amount of Myosin Heavy chain 2b in skeletal muscle fibers. [4]

'''Reference:'''

[1]
<pubmed>3693217</pubmed>

[2]
<pubmed>10632630</pubmed>

[3]
<pubmed>2267630</pubmed>

[4]
<pubmed>9755066</pubmed>

====Lab 8 Assessment: Peer Review of Group Projects ====

'''Hearing'''

Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:35, 25 September 2012 (EST)

'''Vision:'''

Great eye image at the start to capture attention. It's nice to see that it has the correct referencing and copyright.

The introduction is very clear and simple to read. Overall the written content is easy to understand and provides sufficient detail to cover the developmental stages of the eye and associated structures like the optic nerve and lacrimal glands.

The images throughout the project were very useful because they complement the text nicely. The student drawn diagrams made the optic vesicle formation easier to understand. However, I think the labels are a bit small - you can really only read them if you click on them and see the larger version. If you can put some labels on the orientation (such as the ventral side, posterior side, etc), that would be great too. Can you also put a reference as to where you got the information to draw these images from?

The images you got from the 'Atlas of development of man volume 2', can you put the copyright up? Not many textbooks allow using their images but if it is allowed for this book, you should definitely include the copyright there.

Sections that seemed incomplete are history and current research. with the current research information you uploaded, can you add a bit more text just to summarize what the study found out? There's a picture there with some description but it would be good if you can put into dot points what the significant findings are.

It would also be good if you can write something on the visual cortex of the brain. I think it links in with the section on Optic nerve. Maybe mention some of the genes related to the various stages of eye development. It doesn't have to be a lot of detail - just suggest what stage of development the genes are responsible for.

It would be good if you used more research papers instead of using the textbooks. If you are using the textbooks, it's good to track down the references the textbook used. This means you can put the relevant research papers as reference instead.

--[[User:Z3332863|Z3332863]] 16:09, 23 September 2012 (EST)

'''Taste Development'''

The introduction seemed to go into a lot of detail. for example, the information on Type II receptors should be placed in the same section as neural pathways, not the introduction. Can you also include in your introduction, an overview of what you are going to talk about in your project? That would give your project more structure.

With the neural pathway section, can you draw or find a diagram for that section? I find it hard to understand without one. The taste map section goes into a lot of detail which I think is unnecessary because this is a development project.

Current research section is very interesting. I don't think you need to add any more content on that section - that section to me looks complete, besides a few formatting and referencing issues with the images.

Overall, I felt there wasn't enough written on the development of taste, either the receptors (taste buds) or the neural pathways. Your project seem to focus on the anatomy and physiology or function of the taste system. This is alright to keep but the focus should be on development. You do have a Time-line of taste development that summarizes the development of the Gustatory system which is great to see. I think use that as a starting point and expand on each stage in text form, below the table. In week 12 development in this time-line, you mention 'epithelial types I and II', what are they? Are they similar to skin cells?

Overall, the balance between images and text is great. The colourful images work wonders in breaking up the text. Having said that, Many of your images did not have the correct PMID referencing. These images include:
* images of taste being revoked by visualizing ATP release
* CVP of WT and DKO mouse with H & E and SEM
* histology - can you give a more relevant title for this image? We know it's histology; we can see that. What is this image about?
* Abnormal of Tongue - it should say abnormality of tongue

The history section is excellent because it spans over such a long time - 350BC to 2010. The layout of a coloured table for history is beautiful, clear and concise.

--[[User:Z3332863|Z3332863]] 16:35, 23 September 2012 (EST)

'''Olfactory'''

The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

'''Abnormal vision development'''

Introduction gives an overview of your project. This gives structure to your project. The introduction is a little too brief. It would be nice to add some detail about the significance of eye abnormalities:
* how important is vision to humans
* how does vision abnormalities affect people
* how many people are suffering from major eye abnormalities, etc.

Great images. They highlight the severity of abnormalities associated with vision. It would be nice if you can make the images a little bigger or add more images. it just seem there's too much text and not enough images to break it up.

The normal development section is succinct and give sufficient background information so readers can understand the abnormalities section. It would be good if you can put this normal function part into point form or table. for example, 'stage...development'

The gene mutations section is very complicated. Maybe talk about the FOX genes and Pax6 genes in abnormal lens development and not as a separate section. This is so readers can associate the mutation with the disease immediately, without having to scroll to the bottom to find the consequences of such mutation. The layout makes the disease and gene section hard to understand. Maybe set it out as:
* Genetic mutation
* diseases from this mutation
* clinical symptoms of diseases
* treatments for the diseases

Most of the images are well referenced, except Albino Fundus image. for this image, you need the PMID reference style.

References 45-48 should be placed as one reference.

--[[User:Z3332863|Z3332863]] 17:26, 23 September 2012 (EST)

====Lab 9 Assessment====

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

<pubmed>20600146</pubmed>

This article looks at the senstivity of the melatonin secretion by the pineal gland in response to blood insulin levels. Previous studies have shown that insulin increases the amount of Norepinephrine (NE) stimulated melatonin relase. In this study, it was found that insulin potentiates the melatonin secretion at the beginning and the end of night time. many protiens of the insulin signalling pathway were observed in the pineal gland. This molecules include:
* IRbeta
* IGF-1R
* IRS-1
* IRS-2
* PI3K(p85)
When these researchers blocked PI3K with a kinase inhibitor LY 294002, melatonin production by the pineal gland was reduced. So this pper showed tat melatonin release is stimulated by insulin during certain periods in the day and there is crosstalk between the pathways of insulin signalling and melatonin production.

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Embryonic Layers and tissues contributing to developing teeth:

* ectoderm of the first pharyngeal arch
* neural crest cells
* ectomesenchymal cells

These 3 embryonic tissues/layers give rise to:

* Ameloblasts:
** produce enamel
** comes from differentiation of pre-ameloblasts that rose from inner enamel epithelium

* Neural Crest - derived mesenchymal cells or odontoblasts:
** secrete predentin which calcifies into denti

* Periodontal Ligament:
** is the connective tissue that that surrounds the tooth root
** acts as a shock absorber and sensory apparatus
----

== Group Project notes and Articles ==

Article on Pain Development:

<pubmed>16446141</pubmed>

Talk:2012 Group Project 2

2012-10-02T12:38:45Z

Z3332863: /* Search */

{{2012GroupDiscussion}}

--[[User:Z8600021|Mark Hill]] 09:57, 18 September 2012 (EST) This is a recent review on touch. http://jcb.rupress.org/content/191/2/237.full JCB content allows reuse.

==Group evaluation==

The introduction is ok, there is an imbalance between text and pictures. Particularly there is a sentence which reads “The following picture shows the general organization of the somatosensory system” however there is no picture. Also in terms of sentence structure, there are four sentences in a row which begin with “the somatosensory system...” or “the system...” Try to alternate how different ideas are expressed as at the moment the paragraph reads as a disjunct of ideas.

As a whole the page’s visual appeal needs ameliorating. There is far too much text and only two pictures, one of which is very large and appears to be compensating for a lack of smaller relevant diagrams within the body of each section. Having said this, the neural development section was very well done. It was detailed without being verbose and showed it was well researched. The hand drawn diagram is excellent. The cell biology part was also very well written and well structured however again, it simply need some visuals to aid in some descriptions of molecular processes.

There appears not to be a continuous referencing style on the page. The introduction has in-text referencing whilst the rest of the page contains endnotes. A minor problem which could be fixed easily, though quite important nonetheless.

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I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

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Initial impression is it’s too textual for a wiki. The lack of consistent referencing styles is hard to follow.
Relates the developing somatosensation to the nervous system, which was good and very interesting.
Tables and mind maps/flow carts would be beneficial in sections 1.3.1-1.3.3.
And a section on abnormalities of touch would be nice and/or methods of detecting touch and pain etc (ie: clinical methods) and maybe sensitivity to touch.

However, the way this project was divided was logical and easy to follow. But more defined and succinct paragraphs need to be made as it tends to go on for a bit, but that is a sign of good research into the project.

In the section of thermoreceptors it would be better if there was an image from the article for graphical representation.

Summary: MORE IMAGES!!! Be more succinct.

Good luck with the rest ☺

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"The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!"

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- The introduction is small yet detailed --- I like how its an overview of the development. You do need to fix up the references though.

- You have in the intro section “the following picture….” But there is no picture there….if the picture is further ahead maybe write Fig 1 shows….and also label the picture.

- History section needs a bit work on – you should start with the earliest data and proceed in a chronological order so everyone can see the advancement in development of somatosensory organs.

- In the section of “Development of the primary somatosensory cortex” you have mentioned that there are intrinsic and extrinsic mechanisms --- you should mention what those signalling mechanisms are. Also if you are using the one ref for the whole paragraph do not put the ref after each line. Just put it in the end. Also it would be good to give the origin of the neurons like ecto, endo or meso.

- Its good how your description is divided into stages – it might help to give the weeks as well.

- For the touch section you have a lot of detail on what the receptors are which is fine but there is nothing about their development (which is what the project is about). The same thing is noted with “Pain” section – there is nothing on development. I’m sure you can put some genes or signalling molecules that are important for differentiation of cells into the different receptors.

At the moment your project is focused on what the different somatosensory receptors do but very little detail on how they develop, which is what you need to focus on.

More pictures are needed to break up the text.

Good luck!

--[[User:Z3333794|Z3333794]] 09:51, 23 September 2012 (EST)

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Overall, the key points relating to the topic area are being addressed. The use of current research to develop ideas and provide detail to the separate sub-headings is helpful. However, I would suggest better collaboration amongst team members about what is going to be addressed under each sub-heading because some repetition has taken place, particularly between touch and pressure where overlaps are expected occur.

Additionally, there is clear imbalance between text and images and there are some areas where dot points, tables, images or videos will be better received by the audience than paragraphs of information.

More specifically, the history of discoveries can be tabulated and should include more historic events that may have taken place before Weber and possibly led to his research.
In the section on pain, the bulk of the information can look more easy to read if the different fibres are bolded and put on separate lines with their accompanied descriptions or images or videos are used to replace the text.

A diagram or flow chart may be used in the hot/cold section accompanying or replacing the description on the sensation of temperature.

The section on pressure has all information cramped up in one paragraph which presents different ideas. I suggest each idea being put under a different heading or paragraph. For example, a paragraph on development, one on different structures and their functions (if needed since already addressed), one on research and applications. Images could be helpful!

So far current research looks promising and with the inclusions of more projects, would be interesting. I would suggest only including images in the research section when they can be simply understood and impact on the reader’s understanding or interpretation of the project.

The student diagram used in describing the somatosensory pathway is well done and makes a big difference to the page. The layout of this section is also organised and easy to follow and comprehend.

The references, although extremely extensive, is inconsistent between sections and a consensus should be met amongst team members, additionally, the glossary needs to be built upon. The inclusions of more definitions may help in limiting the text in each section.

Overall, there is no critique on the information presented on the page, it is all very interesting and current, however, a change in organisation of information will help bring this to the attention of the reader.
Good luck!

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Your introduction is quite expansive and the first paragraph gives an excellent overview of what the somatosensory system actually is. At the end of the first paragraph you do refer to a picture; however, there is no picture. Please add this to show the somatosensory organisation within the body. In the second paragraph you mention some key timepoints related to the somatosensory development, which is good. After this (“Development of the system entails…lemniscal system.”) the text is probably too specific for the introduction. This can be used as an introduction for your development subheading. Please make sure that you edit the in-text references to proper references which we can access via your reference list. Also make sure you start adding terms to the glossary, eg. dorsal column-medial lemniscal system (I do not know what this means!)

You have started on your history section, but it would be more interesting and easier to read if you put this in a table. For instance: date – description – significant person. Also try to add a few more important discoveries. Again, please provide proper references. See the ‘editing basics’ section on this embryology website.

The central somatosensory differentiation is good and I can see that a lot of effort has been put into this section. The picture is very helpful and complements the text. To some extend it does seem like the sensory neurons only come from the dorsal aspect (going into the dorsal root ganglion), so maybe put a note in there that the dorsal and ventral rami are mixed nerves and both of them will contain sensory neurons that go to the dorsal root ganglion. With this image, you also have to include the student template. Text and references are good in this section and I particularly found the ‘making connections’ section very clear, organised and enjoyable to read. Do make sure that you add to the glossary – in particular terms from the ‘development of the primary cortex section’, and if possible add more images.

The touch section has a fair amount of text, but no images to complement it. This made it a bit boring to read. Make sure the subheadings stand out by making them bold. Most of the text has not been references at all, which is concerning and could potentially indicate plagiarism. I also did not read anything about the development of the various receptors (or hypotheses it no distinct evidence has been provided yet). Keep in mind we are looking at the development of the system, not the physiology. You did put in some interesting facts, such as that cell abnormalities can lead to Merkel-cell carcinoma.

Pain and hot/cold are similar to touch: good description of the physiology, but no development included. References are only provided as in-text citations or listed below, which will need to be edited to include them into the reference list. Include images to complement your text and engage the reader – this also concerns the touch section.

The pressure section has limited information regarding the development. Please include how this develops – what factors are included etc. In my opinion there is too much focus on the adult physiology. We are studying embryology… As mentioned above, please edit references and include appropriate images.

Current research looks good with an interesting image and the appropriate references, copyright and student template. The description helps to understand the image. Maybe add another research project to this section.

Add to the glossary, references and actually name the external links listed as 1) 2) and 3).

Hope this helps!
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The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?

The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

Group Assessment Criteria:
# ''The key points relating to the topic that your group was allocated are clearly described.'' The introduction outlines the importance of the somatosensory system and provides a good summary of the developmental stages. More emphasis could be made on the key points of the project page.
# ''The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'' The content shows an understanding of the topic area, however the layout makes the text difficult to follow. There is not a clear connection between the ‘Central Somatosensory Differentiation’ and the somatosensory system. There is a lack of diagrams, tables and graphs to explain the written content.
# ''Content is correctly cited and referenced.'' Some sections are correctly referenced whilst others are completely lacking. This area needs working on.
# ''The wiki has an element of teaching at a peer level using the student’s own innovative diagrams, tables or figures and/or using interesting examples or explanations.'' The information is broken down well by headings and subheadings, however there is a lack of relating images to compliment the information. The one student drawn image is very useful.
# ''Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'' The information provided is well researched and satisfies the aims of the project in terms of developmental stages, however in order to go ‘beyond the formal teaching activities’ it needs to include sections such as abnormal development and more on the history, current and future research.
# ''Relates the topics and content of the Wiki entry to learning aims of embryology.'' The topics and content relate to the learning aims of embryology by describing the developmental stages if the somatosensory cortex.
# ''The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.'' There has been a fair amount of research into the topic, however a bulk of the information is focused on descriptions of each of the senses. More emphasis should be placed on the development of each of these sense as that is the key topic area.

Additional points:
* The Introduction and Central Somatosensory Differentiation sections were well written and the accompanying diagram was very useful.
* The layout of the page could be improved with the use of tables and diagrams to reduce/replace the amount of text
* The project seems largely incomplete; more research needs to go into the History and research sections and there is a lack of images

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Somatosensory review:

The key points are clearly presented at the top of the page efficiently formatted allowing viewer a perfect insight to the entire pages content. There is a severe lack of visual stimuli; this makes the page present as boring and text heavy.
Image citation is commendable although throughout the text there is unacceptable links to external sites that are not explained with a messy reference section. The information presented is quite detailed and promotes a significant amount of research and understanding, it is put forward in an excellent matter, sections that could easily be expanded are glossary, and perhaps a section specifically on development.
Attempt to relate to the learning aims of embryology are apparent. There is a large amount of information presented in a fantastic way although the lack of visual stimuli takes away from the final product, perhaps a more summarised presentation matter would be appropriate to break up large amount of text; this along with the tidy up of referencing needs to be addressed.

--[[User:Z3330795|Z3330795]] 10:36, 24 September 2012 (EST)

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The introduction provides a good overview however using the wiki in-text citation system will make it neater.

The history section has made a good start but this can be elaborated on further. Once again, referencing can be improved here.

The central somatosensory section has been well researched and the referencing is good. It would be preferable to label figures as "figure 1" etc as this makes it easy to refer to. The drawing is good and has a good explanation however the "student template" should be added.

The touch/pain/hot and cold/pressure sections have a lot of information on their function but not so much information relating to embryological development. Some sections are well referenced, other bits are referenced without the wiki format, and other sections aren't really referenced at all. This can be improved. Adding pictures to these sections to illustrate points will also be helpful.

The current research section, although small, is very good, well referenced, good inclusion of the figure however this could be given a name such as "figure 2". Adding more current research with variation in the topics covered will make this section even more interesting.

The glossary and external links are good - keep adding to these throughout the project.

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This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

----------------------
The introduction for somatosensory is very informative and the overview of its development is great. The information is also great, however i do notice a bit of overlap throughout the page. It is important to go through the information and remove information that is repeated.

At times it feels like there is far too much information and not enough images, tables and diagrams. Dot points would be an alternative way to present your information as organisation is necessary. Including some tables and breaking up the texts into more subheadings would make the information easier to absorb.

The history section requires some attention, and it is important to put it in a chronological order.
A number of references were not cited correctly and this needs to be corrected. It is important that you refer back to the tutorial on referencing as the citations are very important. Your glossary needs to be worked on and extended, it simply does not cover enough words within your project.

Where is the development section? This is one of the most important topics in the project in addition to function which need to cover signalling molecules and genes. The section on pressure however, is great, but the information needs to be put into tables or under more subheadings to make the information easier to read. At the moment information seems to be all over the place.

The current research section is great and should be expanded upon. The self drawn diagram about the somatosensory pathway is very informative and easy to understand. The references are great but some are included more than once and these need to be organised at the end of the page.
Beside the limited diagrams, images, tables and organisation this page looks very promising. Good luck

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'''Somatosensory'''

Sectioning off the touch, pain, hot/cold and pressure was a very well thought out idea, but wouldn't hot/cold come under a temperature? Just an idea to change the heading to something a bit more formal. Overall the content was very well written. And most sections were referenced properly. Other sections were not, such as the introduction and pressure. The content in these paragraphs is so well written, I fell it is left down by the referencing problem. I found that there were only a few references used in some sections, and sometimes being only one. That may be because there is not enough information out there, I'm just not entirely satisfied with the amount of references. I feel there's more out there.
The hand drawn picture was very well done and I like it.
The Touch section was well done but had no developmental development, current research is lacking and as is the glossary.
There needs to more pictures also.

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The introduction is thorough and explains what your topic is about. The history of discoveries part if that is all the info you can find, why not put it in a table it would format the section so the reader can get an overview on how our understanding on somatosensory began.

Your page could do with adding some more pictures in relation to the different sections of somatosensory. for e.g. you mention Meissner's corpuscles in the touch section, you could add a picture with labels so that people could have a visual to understand, as you state where they are located but lay people would not understand what dermal papillae are.

I see you have an embryology and development part with no information, hopefully this will be added to in the near future otherwise don't forget to delete it.

You should also add more to the glossary and have a part called external links and place your links there.
--[[User:Z3220343|Z3220343]] 21:30, 25 September 2012 (EST)

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Your introductory paragraph is very detailed and has appropriate references. It would be nice to add an image to complement it somehow. Because it’s not very easy to read a big block of text without any image supporting the text. It would look more balanced that way. Also, providing clickable links to the references would be better and make it easier for users to find the original references by clicking on the citation rather than scrolling down and manually looking for the citation in the references.

History of discoveries section is somewhat lacking in content, you need to add more information. It would be nice to do a timeline format to make it easier to see the transition of new discoveries over the past years. Again, adding some images to support this section would make it more interesting to read. Again, providing clickable links to the references would be better and make it easier for users to find the original references by clicking on the citation rather than scrolling down and manually looking for the citation in the references.
“Central Somatosensory Differentiation” is the best section so far. It is very well detailed with appropriate references and has an image to support the text. It even has clickable reference links which is good, as it makes it easier to find the references. It would be good to add a little bit more information to describe the image. And perhaps add a few more images to support this section.
Overall, you only have one image on your entire page. It would be good if you add some more images to support your text.

Current Research section needs more articles about current research. One article doesn’t seem sufficient. It is good that your image from the article has the appropriate reference.
Glossary section needs more words and definitions, there is not enough so far.
Some of the external links needs to be fixed. You need to change the format of the links and explain where the links would take you or what those web pages are about.

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Group 2- Somatosensory

-Great introduction. Really puts the project in context and justifies the importance of your research. Citations need to be formatted like the rest of the page

-History of discoveries-very poor syntax, word repetition and no paragraphs. What is Weber's full name? This is entitled "history of discoveries" when it is actually just a very brief, nonspecific summary of "Weber". What about the other interesting discoveries from various scientists over decades?

-Adult Central Somatosensory systems- ascending in what? Position? Importance? Activity? Sensitivity? This needs a more informative opening sentence.

-Trigeminal system and Development of the Primary Somatosensory Cortex- are well explained and ideas are presented in a logical, flowing manner. Great picture with a good description and referencing (impressed you drew it).

-"making connections between...." what do the stages mean? Why does it start at stage 23 instead of stage 1?

-touch/touch receptors is good but where are the references?

-pain and pressure sections also good but needs paragraphs and the formatting of citations is incorrect

-bullet points in pressure section need a brief sentence introducing their purpose. Papers listed at bottom of section should be correctly cited instead of having hyperlinks

-interesting info in temperature

-current research- maybe you could put the name of the paper and authors and explain how they conducted their study? That would help with understanding the nice picture

-Glossary is incomplete

-Needs more pictures

-minor grammatical and spelling errors throughout but overall very good and well sequenced.

==Search==
Hey, people writing the pressure and thermoceptor section, can you please add some images or tables in your section? You can use the code for the tables in the touch or pain section. If the copyright won't allow you to put images directly from journal articles, can you please draw some images to put up? I don't understand your sections as well as you do. I can put some pictures in your section if you are really stuck - let me know if that is the case. --[[User:Z3332863|Z3332863]] 22:38, 2 October 2012 (EST)

Finally worked all the kinks out for formatting, hence why the table is now on our page. Still uploading the final touches and sections. If there are any problems or questions with the section now, please feel free to contact me, either by this discussion forum, email or message. Thanks --[[User:Z3330539|Z3330539]] 22:18, 1 October 2012 (EST)--

Hey guys, don't mind me, I'm just going to be doing some table mock-ups n the discussion page, just before i upload it onto the main page. I know I could be doing this on the actual page, but I'd rther be safe than sorry, cause our page is coming along really well :)

Cheers --[[User:Z3330539|Z3330539]] 12:10, 1 October 2012 (EST)--

Hi, whoever wrote the history section, can you include some dates as to when the discoveries were made. I was thinking of putting that info into a table but we need the dates to do that. Thank you. --[[User:Z3332863|Z3332863]] 14:50, 15 September 2012 (EST)

[http://www.ncbi.nlm.nih.gov/sites/gquery?term=golgi+tendon+organ+development search pubmed GTO development]

'''Development of Nociceptors, Thermoceptors,and Pruriceptors'''

Lopes C, Liu Z, Xu Y, Ma Q. '''Tlx3 and runx1 act in combination to coordinate the development of a cohort of nociceptors, thermoceptors, and pruriceptors.''' J Neurosci. 2012 Jul 11;32(28):9706-15. <pubmed>22787056</pubmed>

'''Review for general Somatosensory development''' - just for background knowledge:

<pubmed>7812142</pubmed>
--[[User:Z3332863|Z3332863]] 14:53, 23 August 2012 (EST)

'''Central sensory Neuron development:'''

<pubmed>2918087</pubmed>
--[[User:Z3332863|Z3332863]] 14:53, 23 August 2012 (EST)

'''Article on Pain Development:'''

<pubmed>16446141</pubmed>

--[[User:Z3332863|Z3332863]] 10:05, 22 August 2012 (EST)

I think it would be cool to do an organ, but i'll be just as happy to do one of the senses. Does anyone have a specific organ they were thinking of?

My preference was '''Sensory''', but if we get organ that's fine also. If we did do organ I still want to look into some of the topics before I give my opinion, depending on the research and information behind it. If we got sensory, sight could be cool? - ==[[User:Z3330539|Z3330539]] 08:26, 10 August 2012 (EST)==

I'd prefer '''Sensory'''.

I agree; if we got Sensory, I would be happy to do '''Sight'''. But if we got Organ, I want to do the Heart but I'd be just as as happy to do another organ if anyone's keen.
--[[User:Z3332863|Z3332863]] 09:14, 10 August 2012 (EST)

Hi all,

I started with; and have mainly been looking into development relating to "Touch" and the receptors involved and time at which this occurs. I am happy to keep going or do research on the other categories as well? I will share what I found when we meet next. --[[User:Z3330539|Z3330539]] 22:02, 20 August 2012 (EST)--