Difference between revisions of "2017 Group Project 6"
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| width="40" |<center>'''Early 1800s'''</center>
| width="40" |<center>'''Early 1800s'''</center>
| width="40" | <center>Joseph Babinski and Gordon Holmes</center>
| width="40" | <center>Joseph Babinski and Gordon Holmes</center>
| width="80" | 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
| width="80" | 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/>
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| width="80" | [[File:Purkinje Cell Arrangement.png|220px|thumb|right|'''Figure 22:''' Modular organisation of the cerebellum purkinje fibers by Janos Szentágothai<ref><pubmed>23335884 </pubmed></ref>]]
| width="80" | [[File:Purkinje Cell Arrangement.png|220px|thumb|right|'''Figure 22:''' Modular organisation of the cerebellum purkinje fibers by Janos Szentágothai<ref><pubmed>23335884 </pubmed></ref>]]
Pieced together the first complete map of the functional anatomy of the cerebellum and define the excitatory 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 name="PMID19272426
Pieced together the first complete map of the functional anatomy of the cerebellum and define the excitatory 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 name="PMID19272426 The current focus in research now leans towards connecting cerebellar function with learning, emotion and perception of time.
Revision as of 18:20, 26 October 2017
|2017 Student Projects|
- 1 Cerebellum
- 2 Introduction
- 3 Basic Anatomy of the Cerebellum
- 4 Cerebellum Development
- 4.1 Ectoderm
- 4.2 Neural Development
- 4.3 Early Brain Vesicles
- 4.4 Metencephalon
- 4.5 Cerebellum Developmental Weeks
- 4.6 Overview of Development
- 4.7 Overview of Cerebellar Cell Development
- 4.8 Cellular Migration
- 4.9 Cell Signalling in Cerebellar Development
- 5 Key Historical Discoveries
- 6 Abnormalities
- 7 Current Research
- 8 Future Questions
- 9 Terms
- 10 References
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 brain's weight but contains around 50% of the neurons. 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 key historical discoveries, current research and animal models will be discussed. Towards the end of the page there are future questions listed on future investigations involving the cerebellum and the abnormalities from an affected cerebellum are also highlighted. Terms that may be difficult to understand have also been identified and defined.
The following video provides a brief overview on the cerebellum which will be further discussed on this page: 
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) . 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).
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 
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. 
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 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 . 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. Blood is then drained by superior and inferior cerebellar veins into the superior petrosal and then straight dural venous sinuses. (Figure 3) 
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. 
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.
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. 
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.  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.
|Most medially located of the cerebellar nuclei. Receives input from the vermis and cerebellar afferents that carry vestibular, proximal somatosensory, auditory and visual information.|
|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.|
|Largest of the cerebellar nuclei. Lateral to interposed nuclei. Receives input from lateral hemisphere and cerebellar afferents that carry information from cerebral cortex.|
|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.|
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. 
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.
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. 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 tube. Neural tube defects (NTDs) such as spina bifida and anencephaly can arise if the tube does not close effectively.
Early Brain Vesicles
Primary Brain Vesicles
Figure 5: (Week 4) 3 primary brain vesicles are formed; forebrain (prosencephalon) midbrain (mesencephalon), and hindbrain (rhombencephalon) 
Figure 6: (Week 5) 3 primary vesicles develop into 5 secondary vesicles ;
- 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)
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.  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. 
Cerebellum Developmental Weeks
Overview of Development
As the neural tube folds, the anterior portion develops the three brain vesicles:
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 
The cerebellar territory is defined by the expression of Hoxa2 genes (from posterior) and Otx2 (from anterior) genes and these genes are controlled by proteins Wnt and fibroblast growth factor families which regulate the expression of these genes in order to establish the cerebellar territory . 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 the primary fissure deepens by the end of the third month and thus 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.
Overview of Cerebellar Cell Development
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 .
The cerebellum has a very basic structure consisting 2 principal classes of neurons and 3 layers; layers are shown in Figure 15.
- Molecular Layer: consists of excitatory granular cell axons, purkinje cell dendritic fibres. stellate and basket cells.
- Purkinje Cell Layer: consists of a single layer of inhibitory Purkinje cells.
- Granular Cell Layer: Dense layer of excitatory granule cells, golgi cells and unipolar brush cells.
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 . 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 . 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. The dorsomedial ventricular zone of the fourth ventricle gives rise to the principal neuronal output, the Purkinje cell and other neurons within the cerebellum The secondary germinal zone, coming from the adjacent rhombic lip generates the cerebellar granule cells as well as a subpopulation of neurons of cerebellar nuclei and several precerebellar nuclei . Granule cells function in coordinating afferent input to and motor output from the cerebellum through excitatory connections with the Purkinje cell . 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. Proper cerebellum function requires well-organised neuronal connections and the integration of afferent and efferent fibres throughout the cerebellar circuit . 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.
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. During radial migration, granule cells extend vertical processes and move through the purkinje cell layer on the radial processes of Bergmann glia.
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.
Figure 17: 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.
Cell Signalling in Cerebellar Development
Proliferation in the EGL
Many different cell signalling 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.  Proliferating cells in the EGL must also be positive for Atoh1, a transcription factor that represses differentiation and promotes division via SHH signalling. 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 signalling and its stimulation of Atoh1 and repression of Bone Morphogenetic Protein (BMP).
Exit from the EGL
BMPs are involved in arresting granule cell proliferation in the EGL and stimulating differentiation. 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. Granule cell migration is stimulated by D-serine secreted by the Bergmann glia. This can be inhibited by DAAO or SR.
FGF and the Isthmus
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.
Reelin and purkinje cells
Reelin is an important signalling 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 signalling 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.
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.
Key Historical Discoveries
|Described the macroscopic anatomy of the cerebellum|
|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. |
|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. |
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.
|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. |
Pieced together the first complete map of the functional anatomy of the cerebellum and define the excitatory 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. Looking at a variety of different of organisms' cerebellar development can elucidate the evolution of the cerebellum and further understanding of cerebellar constituents.
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 . 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 . 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 . 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, indicating that where the IsO is placed is an important factor in establishing where the cerebellum positions.
The cellular structures in the cerebellum (including Purkinje cells and granule cells) have been investigated in various animal models. One animal model is the zebra fish which is a bony fish (teleosts). Like mammals, the zebrafish cerebellum contains several types of neurons which function as either excitatory or inhibitory neurons . Glutamate is utilised by excitatory neurons as their major neurotransmitter. Excitatory neurons include granule cells, unipolar brush cells and eurydendroid cells. The eurydendoid cells are predicted to be corresponding to the deep cerebellar neurons in mammals. The inhibitory neurons use y-aminobutric acid (GABA) and/or glycine (also known as GABAergic neurons) for neurotransmission. Purkinje cells, Golgi and stellate cells are inhibitory neurons. However, a difference between mammal and teleosts is the lack of basket cells. Basket cells are GABAergic neurons that contribute project their axons to the Purkinje cells . This is important, because as earlier highlighted Purkinje cells (inhibitory neurons) and granule cells (excitatory cells) contribute to the three cortical layers of the cerebellum. This model is important for understanding what structures contribute to the neurotransmission process in the cerebellum.
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) which will be explained in the table below.
Emotional memory in depression
Past investigations have concluded that damage to the posterior lobule of the cerebellum can cause individuals to show changes in manner or emotional instability, similar to a degree of depression or psychosis, without an outward cerebellar motor syndrome. This is highly suggestive of the cerebellum's role in emotional memory despite its involvement with motor control. Patients with Major Depressive Disorder (MDD) display a tendency to only selectively recall aspects of scenarios that match their moods, conforming with the "mood-congruent memory (MCM)" theory . This study was undertaken with that principle in mind, and investigated the depth of cerebellar involvement in emotional memory in depression. A link between the volume and density of cerebellar gray matter with measurements of emotional memory was hypothesised.
The experiment was conducted between patients with Major Depressive Disorder (MDD) and healthy controls (HCs). Patients with MDD displayed an atrophy in both gray matter and white matter, most severely in the posterior lobule. There was a significant impairment in emotional memory and decreased volume of the cerebellum in both anterior and posterior lobules. There was marked abnormalities in cortical density, but only a reduction in volume was found to be associated with decreased emotional memory. The severity of depressive symptoms correlated with both volume and density reduction in the grey matter. The posterior, anterior and flocculonodular lobes of patients with MDD displayed marked structural differences from the healthy controls, and a functional connectivity between lobules VI and VII of the cerebellum and the cerebrum could indicate that the decreased density in the lobules of MDD patients contributes to alterations in this connectivity. The flocculonodular lobe is especially implicated in MDD. The lobe is associated with vestibular regulation; Soza and Aviles (2007) found that patients who experienced vestibular vertigo also experienced depressive symptoms. This study also determined that patients who experienced depression also experienced bouts of dizziness. Thus, an unprecedentedly widespread area of the cerebellum is displayed to be connected with emotional memory, in particular, with positive or negative memory retention and could lead towards a cure for depression.
This investigation into a potential link between dystonia -a disorder where muscles contract involuntarily- and the cerebellum attempts to delineate its pathophysiological role in the disease  . The main concern is that the etiology of dystonia appears to be extremely varied, and as such, unpredictable. There is no significant neural degeneration, but in secondary cases there may be structural lesions present in tissue which could be areas of pathophysiology in dystonia . Dystonia may manifest itself in almost any body part, indicating that the neural area responsible most likely must not be very specific. This in combination with the involuntary nature of dystonia seems to indicate that the cerebellum is the more than likely involved in the disease.
Basal ganglia abnormalities are hinted to be a causative agent in dystonia.. The gap in the knowledge of the true interactions between basal ganglia and the cerebellum with regards to dystonia have led to a hypothesis; that the difference in basal ganglia malfunctioning versus abnormal interaction between the ganglia and the cerebellum could reflect the heterogenous pathophysiology of dystonia; either primary or secondary. Some experimental evidence currently available implies that cerebellar dysfunction could affect the topographic distribution of the symptoms of dystonia, and therefore further research is warranted to investigate the full depth of basal ganglia involvement in the disease.
Adaptation to Delayed Action Effects
Sensory attenuation refers to when individuals filters unnecessary information. When there is a perturbation between actions and the following-sound, the sensory attenuation is reduced . An example of perturbation is when there is a delay when an individual presses a button with sound immediately expected, but instead the sound is delayed. Sensory attenuation can be further described by the forward model theory. The forward model theory suggests that predictions for sensory consequences (for example, sound that is heard) are made simultaneously with the motor movement. Predictions and real sensory input (what really happens), after the sound delay is conducted, are compared in the model. If the prediction and real sensory input do not matchup, sensory attenuation is observed. The prediction errors are then relayed to other brain areas for further processing.
The process of sensory attenuation usually re-emerges after the disruption to the normal mechanism . The re-emerging of this is a process of either correcting previous predictions or updating initial forward models to minimise prediction errors. The cerebellum is currently being researched on how it plays an important role in updating the forward model within the brain. One investigation seeks to find evidence on the involvement of the cerebellum in learning to predict the unexpected delays. This investigation has found that low-frequency activity in the cerebellum, prior to the stimulation, plays a key role in adapting to the delayed stimulus .
The cerebellum has only recently been suspected to be involved in addictive behaviour, as some arguments provided for the initiation of research into the cerebellar role on addiction. The cerebellum is shown to be intrinsically linked with dopamine release and reception; with dopamine being the main hormone on which addiction is predicated, it is likely that the cerebellum could influence the response to the addictive stimuli. It has also been established that addictive drugs cause specific molecular mechanisms, changes in synapse plasticity, and influence intracellular transduction pathways as well as gene expression in the cerebellum. The specificity of the drugs in targeting the cerebellum could highlight the link between the affected organ and addictive behaviour. Addictive drugs such as cocaine have been demonstrated to produce a behavioral sensitivity in mice, and an associated change in cerebellar plasticity. The change of the morphology of Purkinje cells and synaptic terminals in the mice most likely contributed to the difference in reception of the drug. However, this link has not yet been fully investigated.
Although there are numerous articles and ongoing research on the cerebellum, there are still investigations yet to be performed. Some questions that could be answered in future research include: