cerebellum

Brain: Cerebellum
Figure 1a: A human brain, with the cerebellum in purple
Figure 1b: MRI image showing a mid-sagittal view of the human brain, with the cerebellum in purple
Part of	Brain
Artery	SCA, AICA, PICA
Vein	superior, inferior
NeuroLex ID	birnlex_1489

Neuroscience portal

The cerebellum (Latin for little brain) is a region of the brain that plays an important role in the integration of sensory perception, coordination and motor control. In order to coordinate motor control, there are many neural pathways linking the cerebellum with the cerebral motor cortex (which sends information to the muscles causing them to move) and the spinocerebellar tract (which provides proprioceptive feedback on the position of the body in space). The cerebellum integrates these pathways using the constant feedback to fine-tune motor activity.^[1]

Because of this 'updating' function of the cerebellum, lesions within it are not so debilitating as to cause paralysis, but rather present as feedback deficits resulting in disorders in fine movement, equilibrium, posture, and motor learning. Initial observations by physiologists during the 18th century indicated that patients with cerebellar damage show problems with motor coordination and movement. Research into cerebellar function during the early to mid 19th century was done via lesion and ablation studies in animals. Research physiologists noted that such lesions led to animals with strange movements, awkward gait, and muscular weakness. These observations and studies led to the conclusion that the cerebellum was a motor control structure.^[1] However, modern research shows that the cerebellum has a broader role in a number of key cognitive functions, including attention and the processing of language, music, and other sensory temporal stimuli.^[2]

General features

The cerebellum is located in the inferior posterior portion of the head (the hindbrain), directly dorsal to the pons, and inferior to the occipital lobe (Figs. 1 and 3). Because of its large number of tiny granule cells, the cerebellum contains more than 50% of all neurons in the brain, but it only takes up 10% of total brain volume.^[3] The cerebellum receives nearly 200 million input fibers; in contrast, the optic nerve is composed of a mere one million fibers.

The cerebellum is divided into two large hemispheres, much like the cerebrum, and contains ten smaller lobules. The cytoarchitecture (cellular organization) of the cerebellum is highly uniform, with connections organized into a rough, three-dimensional array of perpendicular circuit elements. This organizational uniformity makes the nerve circuitry relatively easy to study. To envision this "perpendicular array", one might imagine a tree-lined street with wires running straight through the branches of one tree to the next.^{[clarification needed]}

Development and evolution

Figure 2: Drawing of the cells in the chicken cerebellum by S. Ramón y Cajal

Phylogenetic

The circuits in the cerebellar cortex look similar across all classes of vertebrates, including fish, reptiles, birds, and mammals (e.g., Fig. 2). There is also an analogous brain structure in cephalopods with well developed brains such as octopuses.^[4][5] This has been taken as evidence that the cerebellum performs functions important to all animal species with a brain.

Embryonic

During the early stages of embryonic development, the brain starts to form in three distinct segments: the prosencephalon, mesencephalon, and rhombencephalon. The rhombencephalon is the most caudal (toward the tail) segment of the embryonic brain; it is from this segment that the cerebellum develops. Along the embryonic rhombencephalic segment develop eight swellings, called rhombomeres. The cerebellum arises from two rhombomeres located in the alar plate of the neural tube, a structure that eventually forms the brain and spinal cord. The specific rhombomeres from which the cerebellum forms are rhombomere 1 (Rh.1) caudally (near the tail) and the "isthmus" rostrally (near the front).^[6]

Two primary regions are thought to give rise to the neurons that make up the cerebellum. The first region is the ventricular zone in the roof of the fourth ventricle. This area produces Purkinje cells and deep cerebellar nuclear neurons. These cells are the primary output neurons of the cerebellar cortex and cerebellum. The second germinal zone (cellular birthplace) is known as the Rhombic lip, neurons then move by embryonic week 27 to the external granular layer. This layer of cells—found on the exterior the cerebellum—produces the granule neurons. The granule neurons migrate from this exterior layer to form an inner layer known as the internal granule layer. The external granular layer ceases to exist in the mature cerebellum, leaving only granule cells in the internal granule layer. The cerebellar white matter may be a third germinal zone in the cerebellum; however, its function as a germinal zone is controversial.

Aging

The human cerebellum changes with age. These changes may be different from those of other parts of the brain, e.g., the gene expression pattern in the human cerebellum shows less age-related alteration than in the human cerebral cortex.^[7]

A stereological study has found that human cerebellar white matter is reduced by 26% with age (over the age range 19–84).^[8] The researchers of the study could detect no global loss of Purkinje or granule cells, however in the anterior lobe there is a significant loss of these cell types as well as a 30% volume loss. With magnetic resonance imaging a moderate volumetric reduction with age in vermis and the cerebellar hemisphere has been observed.^[9]

An autoradiography study of the human cerebellum found an increasing binding of H-3-ketanserin with age.^[10] (ketanserin binds primarily to the 5-HT_2A neuroreceptor) The same research team found no significant correlation with age in their homogenate binding study. Somewhat in line with the autoradiography study a positron emission tomography study with the altanserin 5-HT_2A receptor radioligand found a positive correlation between age and cerebellar nonspecific binding.^[11]

Anatomy

The cerebellum contains similar gray and white matter divisions as the cerebrum. Embedded within the white matter—which is known as the arbor vitae (Tree of Life) in the cerebellum due to its branched, treelike appearance—are four deep cerebellar nuclei. Three gross phylogenetic segments are largely grouped by general function. The three cortical layers contain various cellular types that often create various feedback and feedforward loops. Oxygenated blood is supplied by three arterial branches off the basilar and vertebral arteries.

Divisions

The cerebellum can be divided according to three different criteria: gross anatomical, phyologenetical, and functional.

Gross anatomical divisions

On gross inspection, three lobes can be distinguished in the cerebellum: the flocculonodular lobe, the anterior lobe (rostral to the "primary fissure"), and the posterior lobe (dorsal to the "primary fissure"). The latter two can be further divided in a midline cerebellar vermis and lateral cerebellar hemispheres.

Figure 3: Cerebellum and surrounding regions; sagittal view of one hemisphere. A: Midbrain. B: Pons. C: Medulla. D: Spinal cord. E: Fourth ventricle. F: Arbor vitae. G: Tonsil. H: Anterior lobe. I: Posterior lobe.

Figure 4: Schematic representation of the major anatomical subdivisions of the cerebellum. Superior view of an "unrolled" cerebellum, placing the vermis in one plane.

Phylogenetic and functional divisions

The cerebellum can also be divided in three parts based on both phylogenetic criteria (the evolutionary age of each part) and on functional criteria (the incoming and outgoing connections each part has and the role played in normal cerebellar function). From the phylogenetically oldest to the newest, the three parts are:

Much of what is understood about the functions of the cerebellum stems from careful documentation of the effects of focal lesions in human patients who have suffered from injury or disease or through animal lesion research.

Deep nuclei

The deep nuclei of the cerebellum act as the main centers of communication, and the four different nuclei of the cerebellum (dentate, interpositus, fastigial, and vestibular) receive and send information to specific parts of the brain. In addition, these nuclei receive both inhibitory and excitatory signals from other parts of the brain which in turn affect the nucleus's outgoing signals.^[13]

Cortical layers

Figure 5: Microcircuitry of the cerebellum. Excitatory synapses are denoted by (+) and inhibitory synapses by (-). MF: Mossy fiber. DCN: Deep cerebellar nuclei. IO: Inferior olive. CF: Climbing fiber. GC: Granule cell. PF: Parallel fiber. PC: Purkinje cell. GgC: Golgi cell. SC: Stellate cell. BC: Basket cell.

Figure 6: Confocal micrograph from mouse cerebellum expressing green-fluorescent protein in Purkinje cells

There are three layers to the cerebellar cortex; from outer to inner layer, these are the molecular, Purkinje, and granular layers. The function of the cerebellar cortex is essentially to modulate information flowing through the deep nuclei. The microcircuitry of the cerebellum is schematized in Figure 5. Mossy and climbing fibers carry sensorimotor information into the deep nuclei, which in turn pass it on to various premotor areas, thus regulating the gain and timing of motor actions. Mossy and climbing fibers also feed this information into the cerebellar cortex, which performs various computations, resulting in the regulation of Purkinje cell firing. Purkinje neurons feed back into the deep nuclei via a potent inhibitory synapse. This synapse regulates the extent to which mossy and climbing fibers activate the deep nuclei, and thus control the ultimate effect of the cerebellum on motor function. The synaptic strength of almost every synapse in the cerebellar cortex has been shown to undergo synaptic plasticity. This allows the circuitry of the cerebellar cortex to continuously adjust and fine-tune the output of the cerebellum, forming the basis of some types of motor learning and coordination. Each layer in the cerebellar cortex contains the various cell types that comprise this circuitry.

Granular layer

The innermost layer contains the cell bodies of three types of cells: the numerous and tiny granule cells, a bit larger unipolar brush cells^[14] and the much larger Golgi cells. Mossy fibers enter the granular layer from their main point of origin, the pontine nuclei. These fibers form excitatory synapses with the granule cells and the cells of the deep cerebellar nuclei. The granule cells send their T-shaped axons—known as parallel fibers—up into the superficial molecular layer, where they form hundreds of thousands of synapses with Purkinje cell dendrites. The human cerebellum contains on the order of 60 to 80 billion granule cells, making this single cell type by far the most numerous neuron in the brain (roughly 70% of all neurons in the brain and spinal cord, combined). Golgi cells provide inhibitory feedback to granule cells, forming a synapse with them and projecting an axon into the molecular layer.

Purkinje layer

The middle layer contains only one type of cell body—that of the large Purkinje cell. Purkinje cells are the primary integrative neurons of the cerebellar cortex and provide its sole output. Purkinje cell dendrites are large arbors with hundreds of spiny branches reaching up into the molecular layer (Fig. 6). These dendritic arbors are flat—nearly all of them lie in planes—with neighboring Purkinje arbors in parallel planes. Each parallel fiber from the granule cells runs orthogonally through these arbors, like a wire passing through many layers. Purkinje neurons are GABAergic—meaning they have inhibitory synapses—with the neurons of the deep cerebellar and vestibular nuclei in the brainstem. Each Purkinje cell receives excitatory input from 100,000 to 200,000 parallel fibers. Parallel fibers are said to be responsible for the simple (all or nothing, amplitude invariant) spiking of the Purkinje cell.

Purkinje cells also receive input from the inferior olivary nucleus via climbing fibers. A good mnemonic for this interaction is the phrase "climb the other olive tree", given that climbing fibers originate from the contralateral inferior olive. In striking contrast to the 100,000-plus inputs from parallel fibers, each Purkinje cell receives input from exactly one climbing fiber; but this single fiber "climbs" the dendrites of the Purkinje cell, winding around them and making a large number of synapses as it goes. The net input is so strong that a single action potential from a climbing fiber is capable of producing a "complex spike" in the Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a pause during which simple spikes are suppressed.

Molecular layer

This outermost layer of the cerebellar cortex contains two types of inhibitory interneurons: the stellate and basket cells. It also contains the dendritic arbors of Purkinje neurons and parallel fiber tracts from the granule cells. Both stellate and basket cells form GABAergic synapses onto Purkinje cell dendrites.

Peduncles

Similarly, the cerebellum follows the trend of "threes", with three major input and output peduncles (fiber bundles). These are the superior (brachium conjunctivum), middle (brachium pontis), and inferior (restiform body) cerebellar peduncles.

There are three sources of input to the cerebellum, in two categories consisting of mossy and climbing fibers, respectively. Mossy fibers can originate from the pontine nuclei, which are clusters of neurons located in the pons that carry information from the contralateral cerebral cortex. They may also arise within the spinocerebellar tract whose origin is located in the ipsilateral spinal cord. Most of the output from the cerebellum initially synapses onto the deep cerebellar nuclei before exiting via the three peduncles. The most notable exception is the direct inhibition of the vestibular nuclei by Purkinje cells.

Relationship with cerebral cortex

The local field potentials of the neocortex and cerebellum oscillate coherently at (6–40 Hz) in awake behaving animals.^[15] These appear to be under the control of output from the cerebral cortex.^[16] This output would be mediated by a pathway from layer 5/6 neurons in the neocortex through that project either to the pons or the inferior olive. If through the pon this would go to mossy fibers that synapse with granule and Golgi neurons with the granule cells then targeting Purkinje neurons via their excitatory parallel fibers. If the inferior olive it would go via excitatory climbing fiber inputs to Purkinje neurons.^[16] These return this output back to the cerebral cortex through the ventrolateral thalamus completing the loop.

Blood supply

Figure 7: The three major arteries of the cerebellum: the SCA, AICA, and PICA

Three arteries supply blood to the cerebellum (Fig. 7): the superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), and posterior inferior cerebellar artery (PICA).

The SCA branches off the lateral portion of the basilar artery, just inferior to its bifurcation into the posterior cerebral artery. Here it wraps posteriorly around the pons (to which it also supplies blood) before reaching the cerebellum. The SCA supplies blood to most of the cerebellar cortex, the cerebellar nuclei, and the middle and superior cerebellar peduncles.

The AICA branches off the lateral portion of the basilar artery, just superior to the junction of the vertebral arteries. From its origin, it branches along the inferior portion of the pons at the cerebellopontine angle before reaching the cerebellum. This artery supplies blood to the anterior portion of the inferior cerebellum, and to the facial (CN VII) and vestibulocochlear nerves (CN VIII). Obstruction of the AICA can cause paresis, paralysis, and loss of sensation in the face; it can also cause hearing impairment. Moreover, it could cause an infarct of the cerebellopontine angle. This could lead to hyperacusia (dysfunction of the stapedius muscle, innervated by CN VII) and vertigo (wrong interpretation from the vestibular semi-circular canal's endolymph acceleration caused by alteration of CN VIII).

The PICA branches off the lateral portion of the vertebral arteries just inferior to their junction with the basilar artery. Before reaching the inferior surface of the cerebellum, the PICA sends branches into the medulla, supplying blood to several cranial nerve nuclei. In the cerebellum, the PICA supplies blood to the posterior inferior portion of the cerebellum, the inferior cerebellar peduncle, the nucleus ambiguus, the vagus motor nucleus, the spinal trigeminal nucleus, the solitary nucleus, and the vestibulocochlear nuclei.

Variations among vertebrates

There is considerable variation in the size and shape of the cerebellum in different vertebrate species. It is generally largest in cartilaginous and bony fish, birds, and mammals, but somewhat smaller in reptiles. The large paired and convoluted lobes found in humans are typical of mammals, but the cerebellum is generally a single median lobe in other groups, and is either smooth or only slightly grooved. In mammals, the neocerebellum is the major part of the cerebellum by mass, but in other vertebrates, it is typically the spinocerebellum.^[17]

In amphibians, lampreys, and hagfish the cerebellum is little developed; in the latter two groups it is barely distinguishable from the brain-stem. Although the spinocerebellum is present in these groups, the primary structures are small paired nuclei corresponding to the vestibulocerebellum.^[17]

Function

Functionally, the climbing fiber and the mossy fiber-granule cell-parallel fiber pathways are the two main types of afferents to the cerebellum as a whole and to the Purkinje cells in particular.^[18][19] These afferent systems differ dramatically in their connectivity. The Purkinje cell and its climbing fiber afferent have a one-to-one relationship and the overall projection is organized to produce synchronous activation of specific groupings of Purkinje cells in a rostrocaudal orientation. The relationship between the Purkinje cell and the mossy fiber-parallel fiber system can be characterized as many-to-many, with the directionality being mediolateral orientation within the molecular layer, i.e. at right angles to the Purkinje cell dendrites, which are isoplanar .

The climbing fiber system

Originates from the contralateral inferior olive. There are different views concerning the role of the climbing fibre system. According to a very influential idea first proposed by Marr ^[20] and Albus ^[21] the climbing fibers cause synaptic changes in the cerebellar cortex which underlie motor learning. Evidence from many labs and using different learning paradigms has confirmed this. An alternative view is that, as a result of the electrical coupling between inferior olivary neurons, their dynamic decoupling via return inhibition from the cerebellar nuclei^[22] and the topography of the olivocerebellar projection, this system generates synchronous (on a millisecond time scale) complex spike activation of Purkinje cells, in rostrocaudally oriented bands. These activity bands are about 250 μm wide in the mediolateral direction but can be several millimeters long in the rostrocaudal direction and extend down the walls of the cerebellar folia and across several lobules.^[23] The moment–to–moment synchrony distribution of motor control is dynamically modulated by the inferior olive with the major role of the olivary afferents being to determine the pattern of "effective" electronic coupling between olivary neurons and thereby the distribution of synchronous complex spike activity across the cerebellar cortex. Changes in synchrony patterns are associated with movements made by animals performing a motor task.^[24][25] The olivocerebellar system can be considered an electrically malleable substrate from which unique motor synergies can be sculpted.

The mossy fiber-parallel fiber system

In contrast to the punctate nature of cerebellar activation by the olivocerebellar system, the mossy fiber-parallel fiber system provides a continuous and very delicate regulation of the excitability of the cerebellar nuclei, brought about by the tonic activation of simple spikes in Purkinje cells, which ultimately generates the fine control of movement known as motor coordination. The fact that the mossy fibers inform the cerebellar cortex of both ascending and descending messages to and from the motor centers in the spinal cord and brainstem gives us an idea of the ultimate role of the mossy fiber system: it informs the cortex of the place and rate of movement of limbs and puts the motor intentions generated by the brain into the context of the status of the body at the time the movement is to be executed. Moreover, through its effects on the inhibitory GABAergic cerebellar nuclear cells, which project back to the inferior olive, it helps shape the pattern of coupling among olivary cells and hence the synchrony distribution in the upcoming olivocerebellar discharge.

The cerebellar nuclei

The Purkinje cells are the only output of the cerebellar cortex and are inhibitory in nature.^[26] Their axons contact the cerebellar and Deiters vestibular nucleus as their only target. The activity of the cerebellar nuclei is regulated in three ways: (1) by excitatory input from collaterals of the cerebellar afferent systems, (2) by inhibitory inputs from Purkinje cells activated over the mossy fiber pathways, and (3) by inputs from Purkinje cells activated by the climbing fiber system.

Overall cerebellar function

The output of the cerebellum (the cerebellar nuclei axons) proceeds to generate the background activity that serves to set the overall tone and posture that gives the motor cortex the ability to execute movements on the basis of intention (the strategy of movement). In this context the cerebellum provides the tactics of the multiple muscle activation required to support such definite movements. While the motor brain determines where to move (executive imperative), the cerebellum implements its proper timing and modulates the force given to every motor command, as the coordination of movement is a non-continuous function.^[27]

Cerebellar learning

Several investigators have felt it unlikely that the cerebellum could serve the functions of coordination and fine-tuning of movement unless it had mechanisms for learning. It was proposed by Marr and Albus (see above) that the cerebellar Purkinje cells could learn to change their responses to particular parallel fibre inputs if these were repeatedly paired with simultaneuous inputs from the climbing fibres. In a pioneering study by Gilbert and Thach from 1977, Purkinje cell recordings from monkeys learning a reaching task seemed to be consistent with this suggestion^[28]. The idea of the cerebellum as a site of motor learning has since been pursued by several research groups working with different learning paradigms, such as the vestibulo-ocular reflex and eyeblink conditioning and also with synaptic mechanisms both in vivo and in vitro.

Eyeblink conditioning

In the eyeblink conditioning paradigm, a neutral conditioned stimulus such as a tone or a light is repeatedly paired with an unconditioned stimulus, such as an air puff, that elicits a blink response. After such repeated presentations of the CS and US, the CS will eventually elicit a blink before the US, a conditioned response or CR. It was discovered by McCormick and Thompson in 1984^[29] that lesions to the cerebellum abolished classically conditioned blink responses. The localization of the learning site was further narrowed down to the anterior interpositus nucleus and the hemispheral lobule VI in lesion studies^[30][31]. It was also shown that this area received convergent mossy and climbing fibre input as required by the Marr-Albus hypothesis^[32]. Physiological studies later confirmed this and demonstrated that a number of small cortical areas, most prominently in the C3 zone in HVI, controlled the eyelids ^[33][34]. There was considerable disagreement among researchers about the nature of the cerebellar involvement, but it is now generally accepted that the critical learning mechanisms are located in the cerebellum ^[35][36]. There has remained a disagreement concerning the relative roles of the cerebellar cortex and the deep nuclei, however. It is clear both from lesion studies that the cortex is involved in the learning, but there are also studies suggesting that the deep nuclei have a role^[37]. Crucial evidence for the role of the cortex has recently come from recordings of Purkinje cell behaviour during conditioning. Paired CS-US presentations cause the acquisition of a pause in simple spike firing called a Purkinje cell CR ^[38]. Because of the inhibitory action of Purkinje cells on the deep nuclei, this would be translated into an excitatory output signal the eyelid. Because acquisition of conditioned Purkinje cell responses also occurred when the conditioned and unconditioned stimuli consisted of direct mossy and climbing fibre stimulation, this provides striking confirmation of the original Marr-Albus proposal.

Motor coordination

Head MRI showing deep intracerebral hemorrhage due to bleeding within the cerebellum, approximately 30 hours old.

Two main theories address the function of the cerebellum, both dealing with motor coordination. One claims that the cerebellum functions as a regulator of the "timing of movements". This has emerged from studies of patients whose timed movements are disrupted.^[39] The second, the "Tensor Network Theory", provides a mathematical model of transformation of sensory (covariant) space-time coordinates into motor (contravariant) coordinates by cerebellar neuronal networks.^[40][41] Like many controversies in the physical sciences, there is evidence supporting each of the hypotheses. Studies of motor learning in the vestibulo-ocular reflex and eyeblink conditioning demonstrate that the timing and amplitude of learned movements are encoded by the cerebellum.^[42] Many synaptic plasticity mechanisms have been found throughout the cerebellum. The Marr-Albus model mostly attributes motor learning to a single plasticity mechanism: the long-term depression of parallel fiber synapses. The Tensor Network Theory of sensorimotor transformations by the cerebellum has also been experimentally supported.^[43][44]

Ataxia is a complex of motor symptoms, generally involving a lack of coordination, that is often found in disease processes affecting the cerebellum. To identify cerebellar problems, the neurological examination includes assessment of gait (a broad-based gait being indicative of ataxia), finger-pointing tests and assessment of posture.^[1] Structural abnormalities of the cerebellum (hemorrhage, infarction, neoplasm, degeneration) may be identified on cross-sectional imaging. Magnetic resonance imaging is the modality of choice, as computed tomography is insufficiently sensitive for detecting structural abnormalities of the cerebellum.^[45]

With the advent of more sophisticated neuroimaging techniques such as positron emission tomography (PET)^[46] and fMRI^[47], numerous diverse functions are now at least partially attributed to the cerebellum. What was once thought to be primarily a motor/sensory integration region is now proving to be involved in many diverse cognitive functions.

Cerebellar modeling

There have been many attempts to model the cerebellar function.^[48] The insights provided by the models have also led to extrapolations in the domains of artificial intelligence methodologies, especially neural networks. Some of the notable achievements have been Cerebellatron^[49], Cerebellar Model Associative Memory or CMAC networks, SpikeFORCE for robotic movement control^[50], and the "Tensor Network Theory".^[51]

Additional images

Computed tomography of head, with cerebellum visible at lower part	Lobes	Diencephalon	Scheme showing the connections of the several parts of the brain.
Upper surface of the cerebellum	Under surface of the cerebellum	Sagittal section of the cerebellum, near the junction of the vermis with the hemisphere	Dissection showing the projection fibers of the cerebellum
Scheme of roof of fourth ventricle. The arrow is in the foramen of Majendie.	Dissection showing the course of the cerebrospinal fibers	Diagram showing the positions of the three principal subarachnoid cisternæ	Human cerebellum anterior view
Human brain midsagittal view

References

Further reading

External links

Wikimedia Commons has media related to: Category:Cerebellum

• A worldwide list of laboratories that do research on the cerebellum at the Internet Archive
• Cerebellum and multiple sclerosis at mult-sclerosis.org
• Basal ganglia and cerebellum at Washington University in St. Louis
• Cerebellum - Cell Centered Database
• "The Treasure at the Bottom of the Brain” at newhorizons.org
• Cerebellum images at About.com
• BrainMaps at UCDavis cerebellum

• Histological section of primate cerebellum at University of Birmingham
• Cerebellum and Motor Control, Neurophysiology Lecture Site, Ronald E. Young, Ph.D., University of West Indies, Mona.
• Comparative Neuroscience at Wikiversity
• NIF Search - Cerebellum via the Neuroscience Information Framework