2017-10-13T05:14:22Z

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=Cerebellum=
The cerebellum is a large portion of the brain that functions in coordination, balance and control, and its development occurs both prenatally and postnatally. The cerebellum underlies the occipital and temporal lobes of the cerebral cortex and constitutes to about 10% of the brains weight however contains around 50% of the neurons.

=Introduction=
This page will highlight the anatomy of the cerebellum, its developmental process, current research on the structure, animal models and abnormalities associated with it. The anatomy will discuss the distinguishable lobes and zones of the cerebellum. The anatomy of the cerebellum cannot be completely discussed without explaining the vasculature of the structure and hence this page will provide a brief overview of it. The development of the cerebellum discusses the neural development and where the cerebellum forms on the neural tube. The development will highlight how the circuitry of the post-natal cerebellum came to be from neurons. Hence purkinje cells, granule cells, deep nuclei cells, glia cells and cerebellar nuclei will be highlighted to discuss the developmental process. A developmental timeline of the formation of the cerebellum is also included on this page. The cerebellum is a topic of continuous research and past findings would not have been done without the use of animal models, hence current research and animal models will be discussed. The abnormalities that could happen if the cerebellum were to be affected is also highlighted.

=Basic Anatomy of the Cerebellum=

The cerebellum has 3 distinguishable lobes; flocculonodular lobe, anterior lobe and the posterior lobe. The anterior and posterior lobe can be further divided in a midline cerebellar vermis and lateral cerebellar hemispheres (Figure 1)
<ref name=”PMID9735944”><pubmed> 9735944</pubmed></ref>. In a superior cerebellar view, the cerebellum contains a vermis that runs through the middle of the organ and 2 intermediate zones located laterally from the vermis (Figure 2).

[[File:Anatomical-Lobes-of-the-Cerebellum.jpg|500px]]

'''Figure 1:''' Anatomical lobes observed in the cerebellum; anterior lobe, posterior lobe and flocculonodular lobe, which is divided by two fissures – the primary fissure and posterolateral fissure <ref>http://teachmeanatomy.info/neuro/structures/cerebellum</ref>

[[File:Cerebellum anatomical subdivisions.png|500px]]

'''Figure 2:''' Superior view of the 3 cerebellar zones. The middle is the vermis. Either side of the vermis is the intermediate zone. Lateral to the intermediate zone is the lateral hemispheres. There is no difference in gross structure between the lateral hemispheres and intermediate zones. <ref>https://commons.wikimedia.org/wiki/File:CerebellumDiv.png</ref>

[[File:Arteries of the cerebellum.jpeg|thumb|'''Figure 3:''' Diagram of the main arteries of the cerebellum <ref>http://teachmeanatomy.info/neuro/structures/cerebellum/</ref>]]

==Vasculature==
The cerebellum contains 3 bilateral paired arteries which supplies this organ with oxygenated blood. These arteries all originate from the vertebrobasilar system; Superior Cerebellar Artery (SCA), Anterior Inferior Cerebellar Artery (AICA) and the Posterior inferior cerebellar artery (PICA). The SCA and AICA are branches of the basilar artery, which wraps around the anterior aspect of the pons before reaching the cerebellum. The PICA arises from the left and right vertebral artery, which form the basilar artery <ref>https://www.ncbi.nlm.nih.gov/books/NBK11042/</ref>. The PICA and AICA combine to supply the inferior half of the cerebellum, while the SCA supplies the majority of the superior half. The PICA and SCA combine to supply the vermis<ref name=”PMID2535662”><pubmed> 2535662</pubmed></ref>. Blood is then drained by superior and inferior cerebellar veins into the superior petrosal and then straight dural venous sinuses. (Figure 3) <ref name=”PMID27766499”><pubmed> 27766499</pubmed></ref>

==Ectoderm==

There are 3 germ layers present in the early embryo; ectoderm (most distal layer), mesoderm (middle layer) and endoderm (most proximal layer). The ectoderm differentiates into the nervous system, forming the spine, peripheral nerves, cerebrum and cerebellum. It also differentiates to form tooth enamel, epidermis, and the linings of the mouth, anus, sweat glands and nostrils<ref name=”PMID14550785”><pubmed> 14550785</pubmed></ref>.

==Microanatomy==
===Cortical Layers===
There are 3 major cortical layers of the cerebellum: the molecular layer, the purkinje cell layer, and the granule cell layer. The molecular layer contains basket cells, stellate cells and the purkinje cell and Golgi cell dendrites. The purkinje cell layer contains purkinje cell bodies and Bergmann glia. The granule cell layer contains granule cells, mossy fibers, and Golgi cell bodies. <ref>http://neurotransporter.org/Cerebellum.html</ref>

===Purkinje/Pyramidal Cells===
Discovered by Jan Evangelista Purkinje in 1837, purkinje cells are inhibitory neurons found in the outside layer of the cerebellum. They receive signals from the granule cell parallel fibers and the superior olive and send inhibitory signals to the deep nuclei in the white matter region via GABA signaling. Purkinje cells have a large branching network of dendrites which allows them to be identified by their morphology.

===Granule Cells===
Named for their small cell body, cerebellar granule cells of were discovered by Camillo Golgi and Ramon y Cajal in 1899. Cerebellar granule cells are the most numerous cell type in the human brain. They receive signals from mossy fibers of the pons and synapse on the fast network of dendrites of the pyramidal cells. Cerebellar granule cells are glutamatergic and the only excitatory neurons found in the cerebellum.
<ref>https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-1333-8_31</ref>

===Deep Nuclei===
There are four different deep nuclei of the cerebellum: the dentate, interpositus, fastigial, and vestibular nuclei. The dentate nucleus receives signals from the lateral purkinje cells, the interpositus nucleus receives signals from the intermediate purkinje cells, the fastigial nucleus receives signals from the medial purkinje cells, and the vestibular nucleus receives signals from the flocculonodular purkinje cells. The deep nuclei integrate the inhibitory signals from the purkinje cells and the excitatory signals from the mossy and climbing fibers to determine their output signals. <ref>http://www.neuroanatomy.wisc.edu/cere/text/P5/intro.htm</ref> The dentate nucleus in particular is thought to be implicated in higher level cognitive processing. It is enlarged in primates and humans and not observed in non-mammalian species.<ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref>

===Bergmann Glia===
Glial cells of the cerebellum were described by Ramon y Cajal in 1911. He divided them into 3 main categories: the glia of the white matter, the astrocytes of the granule cell layer, and the Bergmann glia of the Purkinje cell layer. Also known as Goligi epithelial cells, Bergmann glia are unipolar astrocytes that have cell bodies located in the Purkinje cell layer and long processes projecting into the molecular layer. The Bergmann glia's processes interact with the dendrites of Purkinje cells at synapses with parallel and climbing fibers. Bergmann first characterized the long processes of cells he saw in the cerebellum of cats, dogs, and humans in 1857. Ramon y Cajal later described these cells as "epithelial cells with Bergmann fibers," giving the glia their name. <ref>https://link.springer.com/content/pdf/10.1046%2Fj.0022-7722.2002.00021.x.pdf</ref>

===Cerebellar Nuclei===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Cerebellar Nuclei'''</center>
| width="600" |<center>'''Description''' </center>

|-
| width="40" |<center>'''Fastigial Nucleus'''</center>
| width="65" |<center> Most medially located of the cerebellar nuclei. Receives input from the vermis and cerebellar afferents that carry vestibular, proximal somatosensory, auditory and visual information. </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Interposed Nuclei'''</center>
| width="65" |<center> Consists of emboliform nucleus and globose nucleus. Interposed nuclei are situated laterally with respect to the fastigial nucleus. Receives input from intermediate zone and cerebellar afferents that carry spinal, proximal somatosensory, auditory and visual information. </center>

|-
| width="40" |<center>'''Dentate Nucleus'''</center>
| width="65" |<center> Largest of the cerebellar nuclei. Lateral to interposed nuclei. Receives input from lateral hemisphere and cerebellar afferents that carry information from cerebral cortex. </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Vestibular Nuclei'''</center>
| width="65" |<center> Located outside cerebellum in the medulla. Considered to be cerebellar nuclei as their connectivity patterns are identical to those of cerebellar nuclei. Receive input from flocculonodular lobe and from the vestibular labyrinth. </center>
|}

<ref>Knierim, J. (n.d.). Chapter 5: Cerebellum. Retrieved 10 3, 2017, from Neuroscience: http://neuroscience.uth.tmc.edu/s3/chapter05.html</ref>.

==Early Brain Vesicles==

===Primary Brain Vesicles===
[[File:Primary Brain Vesicles.jpeg]]

(Week 4) 3 primary brain vesicles are formed; forebrain (prosencephalon) midbrain (mesencephalon), and hindbrain (rhombencephalon) <ref>https://www.karger.com/Article/FullText/334842</ref>

===Secondary===
[[File:Secondary brain vesicle.jpeg|700px]]

(Week 5) 3 primary vesicles develop into 5 secondary vesicles <ref>http://onlinelibrary.wiley.com/doi/10.1111/j.1447-0756.2008.00964.x/full</ref>;

*Prosencephalon develops into telencephalon (which includes the endbrain and cerebral hemispheres) and diencephalon (located between the brain and forms an optic outgrowth)

*Mesencephalon does not further develop into a secondary brain vesicle

*Rhombencephalon develops into the metencephalon (behind the brain), and myelencephalon (contains medulla)

==Metencephalon==
The metencephalon refers to the embryonic neural structure that eventually gives rise dorsally, to the cerebellum and ventrally, to the pons. The metencephalon is the anterior part of the rhombencephalon (hindbrain) and differentiates from the posterior part of the rhombencephalon (myencephalon) at week 5 of development.

The dorsal surface is characterised by its highly folded folia separated by grooves termed sulci. The median area is referred to as the vermis, which eventually becomes the most superior aspect of the cerebellum. <ref>Gerardo De Iuliis PhD, Dino Pulerà MScBMC, CMI, in The Dissection of Vertebrates (Second Edition), 2011</ref> The first structure that belies the future cerebellum are the rhombic lips that appear on the metencephalon of a 5-6 week old embryo. The rhombic lips are aptly rhombus-shaped and denote the perimeter between the roof plate and the main body of the rhombencephalon. The anterior pair of lips mark the site at which the cerebellum will develop. <ref>Bruce M. Carlson MD, PhD, in Human Embryology and Developmental Biology (Fifth Edition), 2014</ref>

=Cerebellum Developmental Weeks=

===First Trimester===
{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Week 3'''</center>
| width="65" |<center> ''Neurulation'': Notochord and somites are formed under the ectoderm. The ectoderm then forms the neural plate which then forms the neural tube and then the brain and spinal chord. </center>
| width="65" | [[File:Stage9 dorsal.jpg|200px|thumb|Early stage of neurulation]] [[File:Stage10 bf5.jpg|200px|thumb|Late stages of neurulation]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Week 4'''</center>
| width="65" |<center> Prosencephalon, mesencephalon and rhombencephalon is developed.</center>
| width="65" | [[File:Human Stage13 sagittal upper half01.jpg|200px|thumb| Sagittal view of superior end of embryo <ref> Hill, M.A. 2017 Embryology Human Stage13 sagittal upper half01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage13_sagittal_upper_half01.jpg</ref>]]

|-
| width="40" |<center>'''Week 5'''</center>
| width="65" |<center> Prosencephalon develops into telencephalon and diencephalon. The rhombencephalon differentiates into metencephalon and myelencephalon. The metencephalon will later develop the pons and cerebellum. </center>
| width="65" |<center> [[File:Human Stage14 neural01.jpg|200px|thumb|Lateral view of embryo central nervous system at 5 weeks <ref>M.A. 2017 Embryology Human Stage14 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage14_neural01.jpg</ref>]] </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''week 6'''</center>
| width="65" |<center> A pair of thickenings on the lateral side of the alar plate is formed. This is called the rhombic lip. </center>
| width="65" |<center> </center>

|-
| width="40" |<center>'''Weeks 7-9'''</center>
| width="65" |<center> The rhombic lip is fused medially to the midbrain. The primitive choroid plexus is fused with the cerebellar hemisphere to form the centrally located eosinophilic matrix. During this process, the inferior olive develops into a thick medulla forming a 'bulbo-pontine extension' <ref><pubmed>21380713</pubmed></ref>. Development of cerebellum cell layer (future Purkinje cells) and choroid plexuses of the fourth and lateral ventricles <ref><pubmed> 2252222</pubmed></ref>. </center>
| width="65" |<center> [[File:Human Stage21 neural01.jpg|200px|thumb|Left lateral view of embryonic CNS<ref>Hill, M.A. 2017 Embryology Human Stage21 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural01.jpg</ref>]] [[File:Human Stage21 neural02.jpg|200px|thumb|Left medial view of lateral embryonic CNS <ref>Hill, M.A. 2017 Embryology Human Stage21 neural02.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural02.jpg</ref>]] </center>
|}

===Second Trimester===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''weeks 11-12'''</center>
| width="65" |<center> Cerebellar hemisphere grows in size and thickness. Laminar configuration becomes present and vermis fissures start to develop. Mechanical stress such as shear and rotation can be detected by the cerebellum, causing several deep fissures to be developed <ref><pubmed>21380713</pubmed></ref> </center>

|-
| width="40" |<center>'''Weeks 15-16'''</center>
| width="65" |<center> Nodule and flocculus is developed. Several deep fissures are formed in the vermis which has increased in thickness similar to the hemispheres <ref><pubmed>21380713</pubmed></ref>. </center>
|}

==Neural Development==

[[File:2 day old embryo diagram.jpeg|200px|thumb|Diagram of a 2 Day Old
Embryo Illustrating the Beginnings of Neural Development <ref>Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Neural Development.</ref>]]

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the neural groove fusing to form the neural tube, which then folds to form the cranial and caudal region of the embryo, and ultimately form the cerebellum <ref>https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'</ref> . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

==Cerebellum Development==

[[File:Neural Circuit in the Cerebellum.jpg|thumb|'''Figure 4:''' Cerebellar neuronal circuits (A): Representation of zebrafish cerebellar neurons (B): Sagittal section of the adult zebrafish cerebellum (C): Zebrafish cerebellar structure schematic representation <ref><pubmed>21309081</pubmed></ref>]]
[[File:Screen Shot 2017-10-05 at 3.29.59 pm.png|thumb|'''Figure 5:''' Cerebellum cell development: A 7 day old rat cerebellum that has been sectioned to show the 3 layers of cells - external granule layer, purkinje cells and internal granular layer (a). Showing granule cell precursors proliferating to differentiate into granule neurons (b). Cell organisation (c) <ref><pubmed>4061865</pubmed></ref>]]

As the neural tube folds, the anterior portion develops the three brain vesicles; prosencephalon, mesencephalon and rhombencephalon. The rhombencephalon then further divides into the mesencephalic and myelincephalic vesicles on embryonic day 9. The neural tube failure to close then creates a gap along the dorsal sides and this produces a mouth-like structure as the tube bends to establish the pontine flexure. The pontine flexure further deepens bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brain stem) fold underneath developing the cerebellum plate <ref><pubmed>7605067</pubmed></ref>
Further development of the cerebellum begins between days 40 and 45 and it arises mostly from the metencephalon however the rhombic lips also contributes. The roof plate which is derived from the dorsal part of the alar plate thickens during development to become the cerebellum. The regulation of patterning involved when he primary fissure deepens by the end of the third month and divides the vermis shows to be particularly important for development. The two lateral bulges are separated into the cranial anterior lob and caudal middle lobe. As the lobes divide further into lobules, fissures are formed and this continues throughout embryonic, fetal and postnatal life, thus increasing the surface area of the cerebellar cortex. The most primitive part of the cerebellum to form is the flocculonodular lobe, which is derived from separation of the first transverse fissure and this functions to keep connections with the vestibular system and it is also concerned with subconsciously controlling equilibrium. The flocculonodular lobe is separated from another crucial part of the cerebellum, corpus cerebelli, by the posterolateral fissure.

The cerebellum is connected to the brain stem via three pairs of peduncles and this allows the afferent and efferent pathways to enter and exit the cerebellum. Cerebellum afferent fibers can be grouped into two major types: mossy fibers and climbing fibres. Mossy fibres contribute to most of the afferent fibres in the cerebellum and they communicate with the cerebellar nuclei neurons and with Purkinje cells through granule cells embryonically, however postnatally they displace from Purkinje cells and synapse with their adult targets, the granule cell dendrites. Whilst mossy fibres originate from numerous sites in the nervous system, climbing fibers originate exclusively from the inferior olivary nucleus. Climbing fibers directly synapse with the cerebellar nuclei and Purkinje cells, relaying information to the cerebellum from several regions. The direction of these afferent fibres to their target neurons early in development are controlled by genes and molecules <ref><pubmed>4552263</pubmed></ref>.

The cerebellum has a very basic structure consisting 2 principal classes of neurons and 3 layers, the first is a single layer of inhibitory Purkinje cells which are sandwiched between a dense layer of excitatory granule cells, and another molecular layer of granular cell axons and purkinje cell dendritic fibres. The granule cells receive inputs from outside the cerebellum and project these inputs to purkinje cells where the majority of these inputs are further projected to a variety of cerebellar nuclei in the white matter <ref><pubmed>25336734</pubmed></ref>. Within the layers there are some other main neuronal cell types, the stellate and basket cells are located in the molecular layer, whilst granule, golgi and unipolar brush cells are located in the granular layer (Figure 4) <ref><pubmed>4552263</pubmed></ref>. Among these principal neurons, there is a diverse set of interneurons which are responsible for coordinating the output of the Purkinje cells to the cerebellar nuclei.

The nuclei from the cerebellum are formed by a complex process of neurogenesis and neuronal migration. There are two types of grey matter in the cerebellum, the deep cerebellar nuclei and an external cerebellar cortex. There are 4 deep nuclei formed and the output of the cerebellar cortex are relayed through these nuclei, the ventricular layer produces 4 types of neurons that migrate to the cortex.
The adjacent rhombic lips gives rise to cerebellar granule cells. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H., 2014. Larsen's Human Embryology E-Book. Elsevier Health Sciences.</ref>. Granule cells function in coordinating afferent input to and motor output from the cerebellum through excitatory connections with the Purkinje cells.
Proper cerebellum function requires well-organised neuronal connections and the integration of afferent and efferent fibres throughout the cerebellar circuit <ref><pubmed>4552263</pubmed></ref>. The cerebellum functions in sensorimotor, balance control and vestibular ocular reflex, however recent studies have come out and shown that the cerebellum has a wide range of cognitive functions which include speech, memory and cognitive functions <ref><pubmed>3213765</pubmed></ref>.

==Cellular Migration==

===Granule Cells===
Granule cells migrate tangentially from the rhombic lip to form the transient structure, the external germinal layer (EGL). The EGL consists of an outer and inner layer that is sandwiched between the pia mater and the purkinje cell layer. During this tangential migration, granule cells extend two horizontal processes. Granule cells move from the outer layer of the EGL to differentiate in the inner layer of the EGL. Differentiated cells continue to move radially to the granule cell layer on the inner surface of the purkinje cell layer<ref>http://dev.biologists.org/content/141/21/4031</ref> During radial migration, granule cells extend vertical processes and move through the purkinje cell layer on the radial processes of Bergmann glia.<ref>https://www.researchgate.net/publication/6977220_d-Serine_signalling_in_the_brain_friend_and_foe/figures?lo=1</ref>

===Purkinje Cells===
Purkinje cells originate from the ventricular neuroepithelium and migrate radially towards the pial surface. Many studies have shown that purkinje cells use radial glia processes as a scaffold in this migration. The movement results in a 3 to 4 cell thick layer of purkinje cells beneath the EGL. This layer becomes 1 cell thick 1 week after birth.<ref>https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-1333-8_9</ref>

[[File:Granule Cell and Purkinje Cell Migration.png]]

Figure 6: Granule cell (yellow) and purkinje cell (green) migration timetable in mouse cerebellum. Top shows sagittal sections of entire cerebellum. Bottom shows movement of individual cells at interface of EGL and purkinje cell layer.<ref><pubmed>26475605</pubmed></ref>

==Cell Signaling in Cerebellar Development==
Many different cell signaling pathways are involved with cell migration, proliferation, and differentiation in the cerebellum. Sonic hedgehog (SHH) is particularly important in the proliferation of granule cells in the external germinal layer. The external germinal layer (EGL) is the area of transit amplification of granule cell precursors. This layer is transient and lies on the external surface of the cerebellum until the cells differentiate and migrate radially to their final destination in the internal granule cell layer. SHH is secreted by the purkinje cells and acts locally, causing the granule cell precursors to undergo mitosis and Bergmann glia to differentiate. The autocrine function of SHH on the purkinje cells is unknown. <ref><pubmed>3263706</pubmed></ref> Proliferating cells in the EGL must also be positive for Atoh1, a transcription factor that represses differentiation and promotes division via SHH signaling. In a similar manner to SHH and Atoh1, the pia mater secretes Sdf1 which interacts with the receptor Cxcr4 to maintain proliferation in the EGL. Notch2 signaling and its stimulation of Atoh1 and repression of Bone Morphogenetic Protein (BMP). BMPs are involved in arresting granule cell proliferation in the EGL and stimulating differentiation.<ref><pubmed>3051031</pubmed></ref> Cells exit proliferation and move to the inner EGL where they differentiate upon expression of Neurod1 and interaction with the extracellular matrix components of the inner EGL, vitronectin, F3, and contactin. <ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref> Granule cell migration is stimulated by D-serine secreted by the Bergmann glia. This can be inhibited by DAAO or SR.<ref>Magalie Martineau, Gérard Baux, Jean-Pierre Mothet D-serine signalling in the brain: friend and foe. Trends Neurosci.: 2006, 29(8);481-91 PubMed 16806506</ref>

Fibroblast Growth Factor (FGF) plays a role in allocating the isthmus area of the cerebellum. FGF8 is found in high concentrations in the rostral region of rhombomere 1 and decreased concentrations near the caudal region of rhombomere 1. It is necessary for the formation of the vermis of the cerebellum but the cerebellar hemispheres form independently of FGF8.<ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref>

Reelin is an important signaling molecule that plays a role in many different in the developing brain. Reelin is a glycoprotein secreted by cells in the EGL and rhombic lip and affects purkinje cells through a signal transduction pathway involving receptors VLDLR and ApoER2, adaptor protein Dab1, and many other further downstream intracellular signaling molecules. Reelin has shown to play a role in formation of the monolayer of purkinje cells and detachment of purkinje cells from radial glia. It may also affect other cell morphology and migration in the cerebellum.<ref>Hevner R. F. (2008) Reelin and the Cerebellum. In: Fatemi S. H. (eds) Reelin Glycoprotein. Springer, New York, NY</ref>

The region of rhombomere 1, a segment of the metencephalon that forms the cerebellum, is bound by the expression of the transcription factors Hoxa2 and Otx2. Otx2 is expressed in the midbrain and the lack of Otx2 marks the rostral border of the cerebellar primordium. Hoxa2 is expressed in the hindbrain region and lack of Hoxa2 marks the caudal border of the cerebellar primordium.<ref><pubmed>3051031</pubmed></ref>

==Key Historical Discoveries==
Human interest in the cerebellum has persisted since even the early 1500's, where Galen, Vesalius and Varolio gave the first few attempts to fully describe the macroscopic anatomy of the cerebellum. However, it was not until the late 1700's that advances were made to gain experimental evidence for the function of the cerebellum. Luigi Rolando identified a specifically motor impact after cerebellar lesions developed, as opposed to an intellectual or sensory effect. This led to the conclusion that the cerebellum incited and managed movement. Pierre Flourens and Luigi Luciani were able to use this albeit crude experimentation to further define that the cerebellum coordinated movement instead of creating it, and also to differentiate between the short-term and long-term effects of cerebellar lesions, respectively. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ernesto Lugaro first defined "plasticity" as we know it in neuroscience, and also discovered the specific cells in the cerebellum that are named after him. He also furthered research into the functions of glia and defined "nervous conduction and transmission" in its current meaning. <ref name=”12481483”><pubmed>12481483</pubmed></ref>Joseph Babinski and Gordon Holmes further defined the exact nature of the effect of cerebellar lesions on motor control, and found loss of coordination in antagonistic muscles and also basic loss of muscle control. It was also found that the side of the cerebellum the lesion developed on, affected the same side of the body. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ramon y Cajal made an especially important contribution to understanding the cerebellum. He refuted Camillo Golgi's previous assertion that axons and dendrites would fuse, and also delineated the differing types of cells, most importantly of which were the mossy and climbing fibers of the cerebellum. However, this contribution could not be fully utilised until further technology was developed.

Olof Larsell is credited for developing a standard nomenclature for cerebellar anatomy that eventually spread world-wide, and for conducting a series of studies that illuminated our understanding of the rhombencephalon. <ref>"In Memoriam: Olof Larsell, 1886-1964." Journal of comparative neurology 123:1-4 (1964).</ref>
With the advent of electron microscopy, John Eccles and Janos Szentágothai in the 1960s managed to piece together the first complete map of the functional anatomy of the cerebellum and define the excitory and inhibitory nature of each cell type provided by Cajal. Further discoveries into the relationships between cell synapses, cell natures, and the minutiae of their structures by Jan Voogd, Olov Oscarsson and David Armstrong around the 1970's defined the organisation of Purkinje cells into "a series of longitudinal parasagittal bands", the specificity of which explains the solely Purkinje-axon-output of the cerebellar cortex. <ref>https://www.ncbi.nlm.nih.gov/pubmed/19272426</ref> The current focus in research now leans towards connecting cerebellar function with learning, emotion and perception of time.

=Animal Models=
The mouse model is a primary model organism in the study of cerebellum development, but organisms such as Drosophila (fruit fly), C. elegans (roundworm), Saccharomyces cerevisiae (Baker's yeast), cats, dogs, and cattle are also used in some types of diseases.<ref><pubmed>19669387</pubmed></ref> Looking at a variety of different of organisms' cerebellar development can elucidate the evolution of the cerebellum and further understanding of cerebellar constituents.<ref><pubmed>25336734</pubmed></ref>

==Isthmic Organiser==
Throughout history there have been many investigations on the cerebellum and how it has developed through research involving chicken embryos and mice. As previously mentioned the neural plate closes to form the neural tubes which have anterior-posterior (AP) and dorsal-ventral (DV) axes. Earlier experiments involving chick-quail chimera suggested that the cerebellum was derived from both midbrain and hindbrain. However, through successive gene expression and fate mapping studies, it was discovered that the anterior-most rhombomere of the hindbrain is where the cerebellum is formed from <ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>. Once the axes are formed the isthmic organiser (IsO) is formed which plays a vital role in establishing the anterior limit of the cerebellar territory. The IsO in other words is the mid-hindbrain boundary <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. However, the IsO does not position itself without the help of transcription factors. Studies of mouse and chicken embryos have shown that two homeo domain-containing transcription factors Otx2 and Gbx2 have an important role in positioning the isthmic organiser <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. Surgical movement of the isthmic tissue to more anterior or posterior regions of the neural tube of 10-somite stage chick embryos led to ectopic midbrain and cerebellar structures<ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>, indicating that where the IsO is placed is an important factor in establishing where the cerebellum positions.

=Abnormalities=
Abnormalities found within the posterior fossa of the cranium may affect the functioning and development of the cerebellum. The abnormalities affecting the cerebellum include Dandy-Walker-Malformation, Joubert Syndrome, Tecto-Cerebllar Dysraphism and Rhombencephalosynapsis (RS).
==Dandy-Walker Malformation==
Dandy-Walker-Malformation (DWM) includes the incomplete development of the cerebellar vermis with cystic dilatation of the 4th ventricle and enlargement of the posterior fossa <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The cerebellar vermis (found at the medial, cortico-nuclear zone of the cerebellum<ref name=”PMIDPMC3179064”><pubmed> PMC3179064</pubmed></ref>) may either be elevated or rotated upwards <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The communication of the 4th ventricle with the midline posterior fossa cyst can be seen on MRI scans of DWM <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. Other structures that can be identified on MRI scans include upward displacement of the tentorium and anterolateral shift of cerebellar hemispheres <ref name=”PMID21093738”><pubmed> 21093738</pubmed></ref>.

[[File:DandyWalkerMalformation.jpeg|435px]]

Brain MRIs. Brain imaging of patients with Dandy-Walker malformation (CCM067, CCM095) and patients with normal cerebellum and posterior fossa (CCM001). A: sagittal midline T1-weighted images. B: axial T2-weighted images. <ref name=”PMID PMC3667004”><pubmed> PMC3667004</pubmed></ref>

==Joubert Syndrome==
Joubert syndrome (JS) is described as a rare inherited genetic disorder characterised by lack of muscle coordination, intellectual disability, respiratory disturbances and abnormal eye movement <ref name=”PMIDPMC2913941”><pubmed>PMC2913941</pubmed></ref>. On neuroimaging, the cerebellar vermis is identified to have gone through hypoplasia (underdevelopment) or dysplasia (abnormal development) <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. It is also described as the "molar tooth sign" on brain imaging, which the "molar tooth" shaped is caused by the defects in the midbrain-hindbrain development.

[[File:JoubertSyndrome.jpg|225px]]

Brain Imaging of Joubert Syndrome: Cranial MRI showing “molar tooth sign” (arrows)<ref name=”PMIDPMC3896311”><pubmed>PMC3896311</pubmed></ref>

==Chiari Syndrome I-III==
Chiari Syndrome I-III is when the structures within the posterior cranial fossa protrude into the spinal canal <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref> which can affect the development and functioning of the cerebellum in the long term. Chiari Syndrome can be classified into four types. The downward shift of the cerebellar tonsils to beneath the foramen magnum is type 1 and the downward movement of the vermis, medulla oblongata and pons with the fourth ventricle is type 2 <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>. When majority of the cerebellum lies in the foramen magnum it is type 3 and when it is completely in the foramen magnum (and therefore cannot develop normally) it is type 4<ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>.

[[File:ChiariMalformation.jpg|225px]]

Cerebellar tonsils herniation on magnetic resonance imaging: Chiari malformation type I<ref name=”PMIDPMC4279813”><pubmed>PMC4279813</pubmed></ref>

==Rhombencephalosynapsis==
Rhombencephalosynapsis is a rare cerebellar defect whereby there is dorsal fusion of the cerebral hemispheres, fusion of dentate nuclei and superior cerebellar peduncles as well as the agenesis of the cerebella vermis <ref name=”PMID18155944”><pubmed>18155944</pubmed></ref>. Like other mentioned abnormalities there is development delay because of the underdeveloped cerebellum.

[[File:Rhombencephalosynapsis.jpg|225px]]

Partial Rhombencephalosynapsis with fused upper parts of the cerebellum<ref name=”PMIDPMC3447431”><pubmed>PMC3447431</pubmed></ref>

=Future Questions=

=Glossary=
{{Glossary}}

=References=
<references/>

2017 Group Project 6

2017-10-13T05:13:03Z

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{{ANAT2341Project2017header}}

=<centre>Cerebellum<centre>=
The cerebellum is a large portion of the brain that functions in coordination, balance and control, and its development occurs both prenatally and postnatally. The cerebellum underlies the occipital and temporal lobes of the cerebral cortex and constitutes to about 10% of the brains weight however contains around 50% of the neurons.

=Introduction=
This page will highlight the anatomy of the cerebellum, its developmental process, current research on the structure, animal models and abnormalities associated with it. The anatomy will discuss the distinguishable lobes and zones of the cerebellum. The anatomy of the cerebellum cannot be completely discussed without explaining the vasculature of the structure and hence this page will provide a brief overview of it. The development of the cerebellum discusses the neural development and where the cerebellum forms on the neural tube. The development will highlight how the circuitry of the post-natal cerebellum came to be from neurons. Hence purkinje cells, granule cells, deep nuclei cells, glia cells and cerebellar nuclei will be highlighted to discuss the developmental process. A developmental timeline of the formation of the cerebellum is also included on this page. The cerebellum is a topic of continuous research and past findings would not have been done without the use of animal models, hence current research and animal models will be discussed. The abnormalities that could happen if the cerebellum were to be affected is also highlighted.

=Basic Anatomy of the Cerebellum=

The cerebellum has 3 distinguishable lobes; flocculonodular lobe, anterior lobe and the posterior lobe. The anterior and posterior lobe can be further divided in a midline cerebellar vermis and lateral cerebellar hemispheres (Figure 1)
<ref name=”PMID9735944”><pubmed> 9735944</pubmed></ref>. In a superior cerebellar view, the cerebellum contains a vermis that runs through the middle of the organ and 2 intermediate zones located laterally from the vermis (Figure 2).

[[File:Anatomical-Lobes-of-the-Cerebellum.jpg|500px]]

'''Figure 1:''' Anatomical lobes observed in the cerebellum; anterior lobe, posterior lobe and flocculonodular lobe, which is divided by two fissures – the primary fissure and posterolateral fissure <ref>http://teachmeanatomy.info/neuro/structures/cerebellum</ref>

[[File:Cerebellum anatomical subdivisions.png|500px]]

'''Figure 2:''' Superior view of the 3 cerebellar zones. The middle is the vermis. Either side of the vermis is the intermediate zone. Lateral to the intermediate zone is the lateral hemispheres. There is no difference in gross structure between the lateral hemispheres and intermediate zones. <ref>https://commons.wikimedia.org/wiki/File:CerebellumDiv.png</ref>

[[File:Arteries of the cerebellum.jpeg|thumb|'''Figure 3:''' Diagram of the main arteries of the cerebellum <ref>http://teachmeanatomy.info/neuro/structures/cerebellum/</ref>]]

==Vasculature==
The cerebellum contains 3 bilateral paired arteries which supplies this organ with oxygenated blood. These arteries all originate from the vertebrobasilar system; Superior Cerebellar Artery (SCA), Anterior Inferior Cerebellar Artery (AICA) and the Posterior inferior cerebellar artery (PICA). The SCA and AICA are branches of the basilar artery, which wraps around the anterior aspect of the pons before reaching the cerebellum. The PICA arises from the left and right vertebral artery, which form the basilar artery <ref>https://www.ncbi.nlm.nih.gov/books/NBK11042/</ref>. The PICA and AICA combine to supply the inferior half of the cerebellum, while the SCA supplies the majority of the superior half. The PICA and SCA combine to supply the vermis<ref name=”PMID2535662”><pubmed> 2535662</pubmed></ref>. Blood is then drained by superior and inferior cerebellar veins into the superior petrosal and then straight dural venous sinuses. (Figure 3) <ref name=”PMID27766499”><pubmed> 27766499</pubmed></ref>

==Ectoderm==

There are 3 germ layers present in the early embryo; ectoderm (most distal layer), mesoderm (middle layer) and endoderm (most proximal layer). The ectoderm differentiates into the nervous system, forming the spine, peripheral nerves, cerebrum and cerebellum. It also differentiates to form tooth enamel, epidermis, and the linings of the mouth, anus, sweat glands and nostrils<ref name=”PMID14550785”><pubmed> 14550785</pubmed></ref>.

==Microanatomy==
===Cortical Layers===
There are 3 major cortical layers of the cerebellum: the molecular layer, the purkinje cell layer, and the granule cell layer. The molecular layer contains basket cells, stellate cells and the purkinje cell and Golgi cell dendrites. The purkinje cell layer contains purkinje cell bodies and Bergmann glia. The granule cell layer contains granule cells, mossy fibers, and Golgi cell bodies. <ref>http://neurotransporter.org/Cerebellum.html</ref>

===Purkinje/Pyramidal Cells===
Discovered by Jan Evangelista Purkinje in 1837, purkinje cells are inhibitory neurons found in the outside layer of the cerebellum. They receive signals from the granule cell parallel fibers and the superior olive and send inhibitory signals to the deep nuclei in the white matter region via GABA signaling. Purkinje cells have a large branching network of dendrites which allows them to be identified by their morphology.

===Granule Cells===
Named for their small cell body, cerebellar granule cells of were discovered by Camillo Golgi and Ramon y Cajal in 1899. Cerebellar granule cells are the most numerous cell type in the human brain. They receive signals from mossy fibers of the pons and synapse on the fast network of dendrites of the pyramidal cells. Cerebellar granule cells are glutamatergic and the only excitatory neurons found in the cerebellum.
<ref>https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-1333-8_31</ref>

===Deep Nuclei===
There are four different deep nuclei of the cerebellum: the dentate, interpositus, fastigial, and vestibular nuclei. The dentate nucleus receives signals from the lateral purkinje cells, the interpositus nucleus receives signals from the intermediate purkinje cells, the fastigial nucleus receives signals from the medial purkinje cells, and the vestibular nucleus receives signals from the flocculonodular purkinje cells. The deep nuclei integrate the inhibitory signals from the purkinje cells and the excitatory signals from the mossy and climbing fibers to determine their output signals. <ref>http://www.neuroanatomy.wisc.edu/cere/text/P5/intro.htm</ref> The dentate nucleus in particular is thought to be implicated in higher level cognitive processing. It is enlarged in primates and humans and not observed in non-mammalian species.<ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref>

===Bergmann Glia===
Glial cells of the cerebellum were described by Ramon y Cajal in 1911. He divided them into 3 main categories: the glia of the white matter, the astrocytes of the granule cell layer, and the Bergmann glia of the Purkinje cell layer. Also known as Goligi epithelial cells, Bergmann glia are unipolar astrocytes that have cell bodies located in the Purkinje cell layer and long processes projecting into the molecular layer. The Bergmann glia's processes interact with the dendrites of Purkinje cells at synapses with parallel and climbing fibers. Bergmann first characterized the long processes of cells he saw in the cerebellum of cats, dogs, and humans in 1857. Ramon y Cajal later described these cells as "epithelial cells with Bergmann fibers," giving the glia their name. <ref>https://link.springer.com/content/pdf/10.1046%2Fj.0022-7722.2002.00021.x.pdf</ref>

===Cerebellar Nuclei===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Cerebellar Nuclei'''</center>
| width="600" |<center>'''Description''' </center>

|-
| width="40" |<center>'''Fastigial Nucleus'''</center>
| width="65" |<center> Most medially located of the cerebellar nuclei. Receives input from the vermis and cerebellar afferents that carry vestibular, proximal somatosensory, auditory and visual information. </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Interposed Nuclei'''</center>
| width="65" |<center> Consists of emboliform nucleus and globose nucleus. Interposed nuclei are situated laterally with respect to the fastigial nucleus. Receives input from intermediate zone and cerebellar afferents that carry spinal, proximal somatosensory, auditory and visual information. </center>

|-
| width="40" |<center>'''Dentate Nucleus'''</center>
| width="65" |<center> Largest of the cerebellar nuclei. Lateral to interposed nuclei. Receives input from lateral hemisphere and cerebellar afferents that carry information from cerebral cortex. </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Vestibular Nuclei'''</center>
| width="65" |<center> Located outside cerebellum in the medulla. Considered to be cerebellar nuclei as their connectivity patterns are identical to those of cerebellar nuclei. Receive input from flocculonodular lobe and from the vestibular labyrinth. </center>
|}

<ref>Knierim, J. (n.d.). Chapter 5: Cerebellum. Retrieved 10 3, 2017, from Neuroscience: http://neuroscience.uth.tmc.edu/s3/chapter05.html</ref>.

==Early Brain Vesicles==

===Primary Brain Vesicles===
[[File:Primary Brain Vesicles.jpeg]]

(Week 4) 3 primary brain vesicles are formed; forebrain (prosencephalon) midbrain (mesencephalon), and hindbrain (rhombencephalon) <ref>https://www.karger.com/Article/FullText/334842</ref>

===Secondary===
[[File:Secondary brain vesicle.jpeg|700px]]

(Week 5) 3 primary vesicles develop into 5 secondary vesicles <ref>http://onlinelibrary.wiley.com/doi/10.1111/j.1447-0756.2008.00964.x/full</ref>;

*Prosencephalon develops into telencephalon (which includes the endbrain and cerebral hemispheres) and diencephalon (located between the brain and forms an optic outgrowth)

*Mesencephalon does not further develop into a secondary brain vesicle

*Rhombencephalon develops into the metencephalon (behind the brain), and myelencephalon (contains medulla)

==Metencephalon==
The metencephalon refers to the embryonic neural structure that eventually gives rise dorsally, to the cerebellum and ventrally, to the pons. The metencephalon is the anterior part of the rhombencephalon (hindbrain) and differentiates from the posterior part of the rhombencephalon (myencephalon) at week 5 of development.

The dorsal surface is characterised by its highly folded folia separated by grooves termed sulci. The median area is referred to as the vermis, which eventually becomes the most superior aspect of the cerebellum. <ref>Gerardo De Iuliis PhD, Dino Pulerà MScBMC, CMI, in The Dissection of Vertebrates (Second Edition), 2011</ref> The first structure that belies the future cerebellum are the rhombic lips that appear on the metencephalon of a 5-6 week old embryo. The rhombic lips are aptly rhombus-shaped and denote the perimeter between the roof plate and the main body of the rhombencephalon. The anterior pair of lips mark the site at which the cerebellum will develop. <ref>Bruce M. Carlson MD, PhD, in Human Embryology and Developmental Biology (Fifth Edition), 2014</ref>

=Cerebellum Developmental Weeks=

===First Trimester===
{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Week 3'''</center>
| width="65" |<center> ''Neurulation'': Notochord and somites are formed under the ectoderm. The ectoderm then forms the neural plate which then forms the neural tube and then the brain and spinal chord. </center>
| width="65" | [[File:Stage9 dorsal.jpg|200px|thumb|Early stage of neurulation]] [[File:Stage10 bf5.jpg|200px|thumb|Late stages of neurulation]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Week 4'''</center>
| width="65" |<center> Prosencephalon, mesencephalon and rhombencephalon is developed.</center>
| width="65" | [[File:Human Stage13 sagittal upper half01.jpg|200px|thumb| Sagittal view of superior end of embryo <ref> Hill, M.A. 2017 Embryology Human Stage13 sagittal upper half01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage13_sagittal_upper_half01.jpg</ref>]]

|-
| width="40" |<center>'''Week 5'''</center>
| width="65" |<center> Prosencephalon develops into telencephalon and diencephalon. The rhombencephalon differentiates into metencephalon and myelencephalon. The metencephalon will later develop the pons and cerebellum. </center>
| width="65" |<center> [[File:Human Stage14 neural01.jpg|200px|thumb|Lateral view of embryo central nervous system at 5 weeks <ref>M.A. 2017 Embryology Human Stage14 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage14_neural01.jpg</ref>]] </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''week 6'''</center>
| width="65" |<center> A pair of thickenings on the lateral side of the alar plate is formed. This is called the rhombic lip. </center>
| width="65" |<center> </center>

|-
| width="40" |<center>'''Weeks 7-9'''</center>
| width="65" |<center> The rhombic lip is fused medially to the midbrain. The primitive choroid plexus is fused with the cerebellar hemisphere to form the centrally located eosinophilic matrix. During this process, the inferior olive develops into a thick medulla forming a 'bulbo-pontine extension' <ref><pubmed>21380713</pubmed></ref>. Development of cerebellum cell layer (future Purkinje cells) and choroid plexuses of the fourth and lateral ventricles <ref><pubmed> 2252222</pubmed></ref>. </center>
| width="65" |<center> [[File:Human Stage21 neural01.jpg|200px|thumb|Left lateral view of embryonic CNS<ref>Hill, M.A. 2017 Embryology Human Stage21 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural01.jpg</ref>]] [[File:Human Stage21 neural02.jpg|200px|thumb|Left medial view of lateral embryonic CNS <ref>Hill, M.A. 2017 Embryology Human Stage21 neural02.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural02.jpg</ref>]] </center>
|}

===Second Trimester===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''weeks 11-12'''</center>
| width="65" |<center> Cerebellar hemisphere grows in size and thickness. Laminar configuration becomes present and vermis fissures start to develop. Mechanical stress such as shear and rotation can be detected by the cerebellum, causing several deep fissures to be developed <ref><pubmed>21380713</pubmed></ref> </center>

|-
| width="40" |<center>'''Weeks 15-16'''</center>
| width="65" |<center> Nodule and flocculus is developed. Several deep fissures are formed in the vermis which has increased in thickness similar to the hemispheres <ref><pubmed>21380713</pubmed></ref>. </center>
|}

==Neural Development==

[[File:2 day old embryo diagram.jpeg|200px|thumb|Diagram of a 2 Day Old
Embryo Illustrating the Beginnings of Neural Development <ref>Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Neural Development.</ref>]]

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the neural groove fusing to form the neural tube, which then folds to form the cranial and caudal region of the embryo, and ultimately form the cerebellum <ref>https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'</ref> . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

==Cerebellum Development==

[[File:Neural Circuit in the Cerebellum.jpg|thumb|'''Figure 4:''' Cerebellar neuronal circuits (A): Representation of zebrafish cerebellar neurons (B): Sagittal section of the adult zebrafish cerebellum (C): Zebrafish cerebellar structure schematic representation <ref><pubmed>21309081</pubmed></ref>]]
[[File:Screen Shot 2017-10-05 at 3.29.59 pm.png|thumb|'''Figure 5:''' Cerebellum cell development: A 7 day old rat cerebellum that has been sectioned to show the 3 layers of cells - external granule layer, purkinje cells and internal granular layer (a). Showing granule cell precursors proliferating to differentiate into granule neurons (b). Cell organisation (c) <ref><pubmed>4061865</pubmed></ref>]]

As the neural tube folds, the anterior portion develops the three brain vesicles; prosencephalon, mesencephalon and rhombencephalon. The rhombencephalon then further divides into the mesencephalic and myelincephalic vesicles on embryonic day 9. The neural tube failure to close then creates a gap along the dorsal sides and this produces a mouth-like structure as the tube bends to establish the pontine flexure. The pontine flexure further deepens bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brain stem) fold underneath developing the cerebellum plate <ref><pubmed>7605067</pubmed></ref>
Further development of the cerebellum begins between days 40 and 45 and it arises mostly from the metencephalon however the rhombic lips also contributes. The roof plate which is derived from the dorsal part of the alar plate thickens during development to become the cerebellum. The regulation of patterning involved when he primary fissure deepens by the end of the third month and divides the vermis shows to be particularly important for development. The two lateral bulges are separated into the cranial anterior lob and caudal middle lobe. As the lobes divide further into lobules, fissures are formed and this continues throughout embryonic, fetal and postnatal life, thus increasing the surface area of the cerebellar cortex. The most primitive part of the cerebellum to form is the flocculonodular lobe, which is derived from separation of the first transverse fissure and this functions to keep connections with the vestibular system and it is also concerned with subconsciously controlling equilibrium. The flocculonodular lobe is separated from another crucial part of the cerebellum, corpus cerebelli, by the posterolateral fissure.

The cerebellum is connected to the brain stem via three pairs of peduncles and this allows the afferent and efferent pathways to enter and exit the cerebellum. Cerebellum afferent fibers can be grouped into two major types: mossy fibers and climbing fibres. Mossy fibres contribute to most of the afferent fibres in the cerebellum and they communicate with the cerebellar nuclei neurons and with Purkinje cells through granule cells embryonically, however postnatally they displace from Purkinje cells and synapse with their adult targets, the granule cell dendrites. Whilst mossy fibres originate from numerous sites in the nervous system, climbing fibers originate exclusively from the inferior olivary nucleus. Climbing fibers directly synapse with the cerebellar nuclei and Purkinje cells, relaying information to the cerebellum from several regions. The direction of these afferent fibres to their target neurons early in development are controlled by genes and molecules <ref><pubmed>4552263</pubmed></ref>.

The cerebellum has a very basic structure consisting 2 principal classes of neurons and 3 layers, the first is a single layer of inhibitory Purkinje cells which are sandwiched between a dense layer of excitatory granule cells, and another molecular layer of granular cell axons and purkinje cell dendritic fibres. The granule cells receive inputs from outside the cerebellum and project these inputs to purkinje cells where the majority of these inputs are further projected to a variety of cerebellar nuclei in the white matter <ref><pubmed>25336734</pubmed></ref>. Within the layers there are some other main neuronal cell types, the stellate and basket cells are located in the molecular layer, whilst granule, golgi and unipolar brush cells are located in the granular layer (Figure 4) <ref><pubmed>4552263</pubmed></ref>. Among these principal neurons, there is a diverse set of interneurons which are responsible for coordinating the output of the Purkinje cells to the cerebellar nuclei.

The nuclei from the cerebellum are formed by a complex process of neurogenesis and neuronal migration. There are two types of grey matter in the cerebellum, the deep cerebellar nuclei and an external cerebellar cortex. There are 4 deep nuclei formed and the output of the cerebellar cortex are relayed through these nuclei, the ventricular layer produces 4 types of neurons that migrate to the cortex.
The adjacent rhombic lips gives rise to cerebellar granule cells. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H., 2014. Larsen's Human Embryology E-Book. Elsevier Health Sciences.</ref>. Granule cells function in coordinating afferent input to and motor output from the cerebellum through excitatory connections with the Purkinje cells.
Proper cerebellum function requires well-organised neuronal connections and the integration of afferent and efferent fibres throughout the cerebellar circuit <ref><pubmed>4552263</pubmed></ref>. The cerebellum functions in sensorimotor, balance control and vestibular ocular reflex, however recent studies have come out and shown that the cerebellum has a wide range of cognitive functions which include speech, memory and cognitive functions <ref><pubmed>3213765</pubmed></ref>.

==Cellular Migration==

===Granule Cells===
Granule cells migrate tangentially from the rhombic lip to form the transient structure, the external germinal layer (EGL). The EGL consists of an outer and inner layer that is sandwiched between the pia mater and the purkinje cell layer. During this tangential migration, granule cells extend two horizontal processes. Granule cells move from the outer layer of the EGL to differentiate in the inner layer of the EGL. Differentiated cells continue to move radially to the granule cell layer on the inner surface of the purkinje cell layer<ref>http://dev.biologists.org/content/141/21/4031</ref> During radial migration, granule cells extend vertical processes and move through the purkinje cell layer on the radial processes of Bergmann glia.<ref>https://www.researchgate.net/publication/6977220_d-Serine_signalling_in_the_brain_friend_and_foe/figures?lo=1</ref>

===Purkinje Cells===
Purkinje cells originate from the ventricular neuroepithelium and migrate radially towards the pial surface. Many studies have shown that purkinje cells use radial glia processes as a scaffold in this migration. The movement results in a 3 to 4 cell thick layer of purkinje cells beneath the EGL. This layer becomes 1 cell thick 1 week after birth.<ref>https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-1333-8_9</ref>

[[File:Granule Cell and Purkinje Cell Migration.png]]

Figure 6: Granule cell (yellow) and purkinje cell (green) migration timetable in mouse cerebellum. Top shows sagittal sections of entire cerebellum. Bottom shows movement of individual cells at interface of EGL and purkinje cell layer.<ref><pubmed>26475605</pubmed></ref>

==Cell Signaling in Cerebellar Development==
Many different cell signaling pathways are involved with cell migration, proliferation, and differentiation in the cerebellum. Sonic hedgehog (SHH) is particularly important in the proliferation of granule cells in the external germinal layer. The external germinal layer (EGL) is the area of transit amplification of granule cell precursors. This layer is transient and lies on the external surface of the cerebellum until the cells differentiate and migrate radially to their final destination in the internal granule cell layer. SHH is secreted by the purkinje cells and acts locally, causing the granule cell precursors to undergo mitosis and Bergmann glia to differentiate. The autocrine function of SHH on the purkinje cells is unknown. <ref><pubmed>3263706</pubmed></ref> Proliferating cells in the EGL must also be positive for Atoh1, a transcription factor that represses differentiation and promotes division via SHH signaling. In a similar manner to SHH and Atoh1, the pia mater secretes Sdf1 which interacts with the receptor Cxcr4 to maintain proliferation in the EGL. Notch2 signaling and its stimulation of Atoh1 and repression of Bone Morphogenetic Protein (BMP). BMPs are involved in arresting granule cell proliferation in the EGL and stimulating differentiation.<ref><pubmed>3051031</pubmed></ref> Cells exit proliferation and move to the inner EGL where they differentiate upon expression of Neurod1 and interaction with the extracellular matrix components of the inner EGL, vitronectin, F3, and contactin. <ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref> Granule cell migration is stimulated by D-serine secreted by the Bergmann glia. This can be inhibited by DAAO or SR.<ref>Magalie Martineau, Gérard Baux, Jean-Pierre Mothet D-serine signalling in the brain: friend and foe. Trends Neurosci.: 2006, 29(8);481-91 PubMed 16806506</ref>

Fibroblast Growth Factor (FGF) plays a role in allocating the isthmus area of the cerebellum. FGF8 is found in high concentrations in the rostral region of rhombomere 1 and decreased concentrations near the caudal region of rhombomere 1. It is necessary for the formation of the vermis of the cerebellum but the cerebellar hemispheres form independently of FGF8.<ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref>

Reelin is an important signaling molecule that plays a role in many different in the developing brain. Reelin is a glycoprotein secreted by cells in the EGL and rhombic lip and affects purkinje cells through a signal transduction pathway involving receptors VLDLR and ApoER2, adaptor protein Dab1, and many other further downstream intracellular signaling molecules. Reelin has shown to play a role in formation of the monolayer of purkinje cells and detachment of purkinje cells from radial glia. It may also affect other cell morphology and migration in the cerebellum.<ref>Hevner R. F. (2008) Reelin and the Cerebellum. In: Fatemi S. H. (eds) Reelin Glycoprotein. Springer, New York, NY</ref>

The region of rhombomere 1, a segment of the metencephalon that forms the cerebellum, is bound by the expression of the transcription factors Hoxa2 and Otx2. Otx2 is expressed in the midbrain and the lack of Otx2 marks the rostral border of the cerebellar primordium. Hoxa2 is expressed in the hindbrain region and lack of Hoxa2 marks the caudal border of the cerebellar primordium.<ref><pubmed>3051031</pubmed></ref>

==Key Historical Discoveries==
Human interest in the cerebellum has persisted since even the early 1500's, where Galen, Vesalius and Varolio gave the first few attempts to fully describe the macroscopic anatomy of the cerebellum. However, it was not until the late 1700's that advances were made to gain experimental evidence for the function of the cerebellum. Luigi Rolando identified a specifically motor impact after cerebellar lesions developed, as opposed to an intellectual or sensory effect. This led to the conclusion that the cerebellum incited and managed movement. Pierre Flourens and Luigi Luciani were able to use this albeit crude experimentation to further define that the cerebellum coordinated movement instead of creating it, and also to differentiate between the short-term and long-term effects of cerebellar lesions, respectively. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ernesto Lugaro first defined "plasticity" as we know it in neuroscience, and also discovered the specific cells in the cerebellum that are named after him. He also furthered research into the functions of glia and defined "nervous conduction and transmission" in its current meaning. <ref name=”12481483”><pubmed>12481483</pubmed></ref>Joseph Babinski and Gordon Holmes further defined the exact nature of the effect of cerebellar lesions on motor control, and found loss of coordination in antagonistic muscles and also basic loss of muscle control. It was also found that the side of the cerebellum the lesion developed on, affected the same side of the body. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ramon y Cajal made an especially important contribution to understanding the cerebellum. He refuted Camillo Golgi's previous assertion that axons and dendrites would fuse, and also delineated the differing types of cells, most importantly of which were the mossy and climbing fibers of the cerebellum. However, this contribution could not be fully utilised until further technology was developed.

Olof Larsell is credited for developing a standard nomenclature for cerebellar anatomy that eventually spread world-wide, and for conducting a series of studies that illuminated our understanding of the rhombencephalon. <ref>"In Memoriam: Olof Larsell, 1886-1964." Journal of comparative neurology 123:1-4 (1964).</ref>
With the advent of electron microscopy, John Eccles and Janos Szentágothai in the 1960s managed to piece together the first complete map of the functional anatomy of the cerebellum and define the excitory and inhibitory nature of each cell type provided by Cajal. Further discoveries into the relationships between cell synapses, cell natures, and the minutiae of their structures by Jan Voogd, Olov Oscarsson and David Armstrong around the 1970's defined the organisation of Purkinje cells into "a series of longitudinal parasagittal bands", the specificity of which explains the solely Purkinje-axon-output of the cerebellar cortex. <ref>https://www.ncbi.nlm.nih.gov/pubmed/19272426</ref> The current focus in research now leans towards connecting cerebellar function with learning, emotion and perception of time.

=Animal Models=
The mouse model is a primary model organism in the study of cerebellum development, but organisms such as Drosophila (fruit fly), C. elegans (roundworm), Saccharomyces cerevisiae (Baker's yeast), cats, dogs, and cattle are also used in some types of diseases.<ref><pubmed>19669387</pubmed></ref> Looking at a variety of different of organisms' cerebellar development can elucidate the evolution of the cerebellum and further understanding of cerebellar constituents.<ref><pubmed>25336734</pubmed></ref>

==Isthmic Organiser==
Throughout history there have been many investigations on the cerebellum and how it has developed through research involving chicken embryos and mice. As previously mentioned the neural plate closes to form the neural tubes which have anterior-posterior (AP) and dorsal-ventral (DV) axes. Earlier experiments involving chick-quail chimera suggested that the cerebellum was derived from both midbrain and hindbrain. However, through successive gene expression and fate mapping studies, it was discovered that the anterior-most rhombomere of the hindbrain is where the cerebellum is formed from <ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>. Once the axes are formed the isthmic organiser (IsO) is formed which plays a vital role in establishing the anterior limit of the cerebellar territory. The IsO in other words is the mid-hindbrain boundary <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. However, the IsO does not position itself without the help of transcription factors. Studies of mouse and chicken embryos have shown that two homeo domain-containing transcription factors Otx2 and Gbx2 have an important role in positioning the isthmic organiser <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. Surgical movement of the isthmic tissue to more anterior or posterior regions of the neural tube of 10-somite stage chick embryos led to ectopic midbrain and cerebellar structures<ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>, indicating that where the IsO is placed is an important factor in establishing where the cerebellum positions.

=Abnormalities=
Abnormalities found within the posterior fossa of the cranium may affect the functioning and development of the cerebellum. The abnormalities affecting the cerebellum include Dandy-Walker-Malformation, Joubert Syndrome, Tecto-Cerebllar Dysraphism and Rhombencephalosynapsis (RS).
==Dandy-Walker Malformation==
Dandy-Walker-Malformation (DWM) includes the incomplete development of the cerebellar vermis with cystic dilatation of the 4th ventricle and enlargement of the posterior fossa <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The cerebellar vermis (found at the medial, cortico-nuclear zone of the cerebellum<ref name=”PMIDPMC3179064”><pubmed> PMC3179064</pubmed></ref>) may either be elevated or rotated upwards <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The communication of the 4th ventricle with the midline posterior fossa cyst can be seen on MRI scans of DWM <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. Other structures that can be identified on MRI scans include upward displacement of the tentorium and anterolateral shift of cerebellar hemispheres <ref name=”PMID21093738”><pubmed> 21093738</pubmed></ref>.

[[File:DandyWalkerMalformation.jpeg|435px]]

Brain MRIs. Brain imaging of patients with Dandy-Walker malformation (CCM067, CCM095) and patients with normal cerebellum and posterior fossa (CCM001). A: sagittal midline T1-weighted images. B: axial T2-weighted images. <ref name=”PMID PMC3667004”><pubmed> PMC3667004</pubmed></ref>

==Joubert Syndrome==
Joubert syndrome (JS) is described as a rare inherited genetic disorder characterised by lack of muscle coordination, intellectual disability, respiratory disturbances and abnormal eye movement <ref name=”PMIDPMC2913941”><pubmed>PMC2913941</pubmed></ref>. On neuroimaging, the cerebellar vermis is identified to have gone through hypoplasia (underdevelopment) or dysplasia (abnormal development) <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. It is also described as the "molar tooth sign" on brain imaging, which the "molar tooth" shaped is caused by the defects in the midbrain-hindbrain development.

[[File:JoubertSyndrome.jpg|225px]]

Brain Imaging of Joubert Syndrome: Cranial MRI showing “molar tooth sign” (arrows)<ref name=”PMIDPMC3896311”><pubmed>PMC3896311</pubmed></ref>

==Chiari Syndrome I-III==
Chiari Syndrome I-III is when the structures within the posterior cranial fossa protrude into the spinal canal <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref> which can affect the development and functioning of the cerebellum in the long term. Chiari Syndrome can be classified into four types. The downward shift of the cerebellar tonsils to beneath the foramen magnum is type 1 and the downward movement of the vermis, medulla oblongata and pons with the fourth ventricle is type 2 <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>. When majority of the cerebellum lies in the foramen magnum it is type 3 and when it is completely in the foramen magnum (and therefore cannot develop normally) it is type 4<ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>.

[[File:ChiariMalformation.jpg|225px]]

Cerebellar tonsils herniation on magnetic resonance imaging: Chiari malformation type I<ref name=”PMIDPMC4279813”><pubmed>PMC4279813</pubmed></ref>

==Rhombencephalosynapsis==
Rhombencephalosynapsis is a rare cerebellar defect whereby there is dorsal fusion of the cerebral hemispheres, fusion of dentate nuclei and superior cerebellar peduncles as well as the agenesis of the cerebella vermis <ref name=”PMID18155944”><pubmed>18155944</pubmed></ref>. Like other mentioned abnormalities there is development delay because of the underdeveloped cerebellum.

[[File:Rhombencephalosynapsis.jpg|225px]]

Partial Rhombencephalosynapsis with fused upper parts of the cerebellum<ref name=”PMIDPMC3447431”><pubmed>PMC3447431</pubmed></ref>

=Future Questions=

=Glossary=
{{Glossary}}

=References=
<references/>

Z5114433:

User talk:Z5114433

2017-10-05T05:41:46Z

Z5114433: /* Peer Assessment Page */

=Peer Assessment Page=

-compliment
-feedback on what they can improve on content

Talk:2017 Group Project 6

2017-10-05T05:38:52Z

Z5114433:

{{ANAT2341Project2017discussion}}



=Peer Assessment=

=Project Starting Places=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 6 below are some starting places.

{{Neural Links 2}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebellum+Development ''Cerebellum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebellum+Development ''Cerebellum Development'']

Cerebellum: links between development, developmental disorders and motor learning; [http://journal.frontiersin.org/article/10.3389/fnana.2012.00001/full]

Cellular commitment in the developing cerebellum [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290586/]

Recent papers

<pubmed limit=5>Cerebellum+Development</pubmed>

==Neural Development==
(z5114433)
will fix referencing stuff later #ceebsrn

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the folding of the neural tubes to form the cranial and caudal region of the embryo (''https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'') . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

=z5114433=
structure
time course
functional developing
what cells appear when

glial cells development

4th ventricle

Genes in abnormalities

pathway of development of cere cells
start of as neuroblast

=z5018156=
Things to remember:

Coordinates muscular activities - walking, crawling, writing

Embryo doesnt need the musuclar activities

Prenatal - neurons develop to carry out those activities later on

Postnatal - wiring up

Neural tube

Comes from pontine flexure - 4th ventricle -- the cerebellum develops into this space

Lamination of the cerebellum

https://www.ncbi.nlm.nih.gov/pubmed/19732611

https://www.ncbi.nlm.nih.gov/pubmed/21380713

Development: z5018156 - https://www.ncbi.nlm.nih.gov/pubmed/21295689

=Z5076158=
==Week 7 Work==
What I could add: Paramotal cells, molecular layer, what cerebellum connects to, how they are remodeled postnatally Kahals research
https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-150-the-brainstem-metencephalon-fourth-vesicle-the-cerebellum - good reference
LARSONS HUMAN EMBRYOLOGY TEXTBOOK
The metencephalon gives rise to the pons and the cerebellum, the adjacent rhombic lips also contribute to the development of cerebellum. The pons functions to relay signals that link both the spinal cord and cerebral cortex with the cerebellum and the cerebellum is a centre for postural and balance control. Pontine nuclei relay information from cerebrum to the cerebellum.
The cerebellum is first recognized as a pair of thickened cerebellar plates or cerebellar primordia.
Adjacent rhombic lips gives rise to Cerebellar granule cells
Major portion of the cerebellum consists of a narrow median swelling called the vermis and this grows faster than the flocculonodular which were the primitive part of the cerebellum and therefore becomes the dominant portion of the mature cerebellum.
Folding:
Primary fissure deepens by end of third month and divides vermis and hemispheres into a cranial anterior lobe and caudal middle lobe. Lobes divide further into lobules due to development of transverse fissures. This fissure formation and foliation continues throughout embryonic, fetal and postnatal life and this is done to increase the surface area of the cerebellar cortex.
2 types of grey matter present:
- Internal deep cerebellar nucler
- External cerebellar cortex
4 deep nuclei and all output of the cerebellar cortex is relayed through these nuclei.
These nuclei and cortex are produced by a process called neurogenesis and neuronal migration
1. Dentate
2. Globose
3. Emboliform
4. Fastigular

4th month – germinal layers undergo cell division and this produces populations of cerebellar neurons.
• Ventricular layer – purkinje cells, golgi cells, basket cells, stellate cells
• Granule cells remaining from the cerebellar cortex (these arise from external germinal layer)
• External germinal layer – primitive nuclear neurons these migrate to form deep cerebellar nuclei
==Week 8 Work==
PAPER 1995
Cerebellum – about:
It consists of 3 layers with 2 principal classes of neurons
Granule cells studies of naturally occurring mutations and targeted gene disruption that block discrete steps in development of this region
Development of anterior portion of neural tube involves the formation of 3 brain vesicles:
1. Prosencephalon
2. Mesencephalon
3. Rhombencephalon
Division of rhombencephalon into metencephalic vesicles and myelincephalic vesicles (this forms in day 9)
Failure of neural tube closure creates gap along the dorsal aspect of the neural tube, which bows into a mouth-like structure as the tube bends to establish the pontine flexure.
Further deepening this newly formed pontine flexure, bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brainstem) fold underneath developing the cerebellum plate.

Cells fated for cerebellum are derived from both the mesencephalon and metencephalic vesicles (rhombencephalon). Neuroepithelium of the mesencephalon generated majority of the cells in the cerebellar cortex: V-like area of mediodorsal aspect of the anlarge arose from a caudal movement of cells from the mesencephalon.

PAPER 2014
Cerebellum has a very basic structure:
• Monolayer of inhibitory purkinje cells sandwiched between a dense layer of excitatory granule cells
• Subpiled molecular layer of granular cell axons and purkinje cell dendritic fibres
Granule cells receives inputs from outside the cerebellum and project to the purkinje cells, the majority of which then project to a variety of cerebellar nuclei in the white matter.
The area designated for the cerebellum to reside (anlage) during development was located between hindbrain and midbrain. Regulation of patterning in this early stage (E9) of development shows to be particularly important for development of the uniquely mammalian midline expanded region of the cerebellum, “vermis”.

Specific cell types are allocated along the dorsoventral axis. For glutamatergic cells of cerebellum, remarkably prolonged establishment and an important dynamic process that takes place at most dorsal interface between neural and non-neural roof plate tissue, the rhombic lip. This phase generates the basic dichotomy between GABAergic and glutamatergic cell types that underlies the conserved Purkinje-Granule cell circuit.
Cell type allocation proceeds a third, distinct temporal phase of development that extends into early prenatal (up to 2 years). In this phase, the principal derivative of the rhombic lip, the granule cell precursor, accumulates over the surface of the cerebellum and undergoes further rounds of symmetric division in a process of transit amplification that exponentially expands its numbers.
The anlage of the cerebellum is a product of mechanisms of segmentation that establish iterated rhombomeric subdivision within the hindbrain just after neural tube closure.
All cells of the cerebellum arise from dorsal rhomomere, a region definitively classified by absence of the expression of Otx and Hox genes. Majority of cerebellum arises from metencephalic (rostral) hindbrain.

=z5113034=
Vasculature of cerebellum originates from vertebral arteries and the arteries that arise from it.

Metencephalon; temporary structure that differentiates into pons and cerebellum ventrally and dorsally respectively.

Current Research

Key discoveries during research of cerebellar development

=Topic Selection=
Hi group! I am personally interested in the development of the heart! Also, are you guys happy to exchange details after the lab tomorrow? - z5018156

Hi! Im happy to share details! And yeah heart would be interesting, but I was also thinking maybe the ear? that could be cool

Hey, yeah I was thinking the heart- I did a course on it last semester, but i also feel its quite generic and the other groups would do something similar. Shall we wait until the end of prac and find each other? Call out number 6 LMAO (z5114433)

Hey all! I'm pretty open about topics but I was leaning towards the eye? Unless that's too close to optom, (and it might be a popular subject too?) I'm fine with anything. Let's find each other after prac! -z5113034

The ear sounds good as well as the eye, theres also the lungs as well! We can just make a list and then decide as a group! - z5018156