Cerebellum

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Brain: Cerebellum
Figure 1a: A human brain, with the cerebellum coloured 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

The cerebellum (Latin for little brain) is a region of the brain that plays an important role in motor control; there is controversy about whether it has non-movement-related functions as well. The cerebellum does not initiate movement, but it contributes greatly to coordination, precision, and accurate timing. There are neural pathways linking the cerebellum with the motor cortex (the part of the cerebral cortex involved in motor control) and other movement-generating brain areas; it receives input from many sensory systems and many other parts of the brain and spinal cord. The cerebellum integrates these inputs to fine-tune motor activity.^[1]

Because of this 'fine-tuning' function of the cerebellum, damage to it does not cause paralysis, but instead produces disorders in fine movement, equilibrium, posture, and motor learning.^[1] A typical test of cerebellar function is to reach with the tip of the finger for a target at arm's length: where a healthy person will move the fingertip in a rapid straight trajectory, a person with cerebellar damage will reach slowly and erratically, with many mid-course corrections. Deficits in non-motor functions are rarely seen; however numerous recent studies using functional imaging techniques have shown that portions of the cerebellum are frequently activated in ways that have no apparent relationship to movement, suggesting that there are non-motor functions that remain to be clarified, including possible roles in attention, language, and music.^[2]

Anatomically, the cerebellum has the appearance of a separate structure attached to the bottom of the brain, tucked underneath the cerebral hemispheres. The surface of the cerebellum is covered with finely spaced parallel grooves, in striking contrast to the broad irregular convolutions of the cerebral cortex. These parallel grooves conceal the fact that the cerebellum is actually a continuous thin layer of neural tissue (the cerebellar cortex), tightly folded in the style of a Chinese fan, and then refolded again. Within this thin layer are several types of neurons with a highly regular arrangement, the most important being Purkinje cells and granule cells. Purkinje cells have the largest dendritic trees of any neurons in the brain, and in humans receive more than 100,000 synaptic inputs each. Granule cells are tiny and only make a few hundred synapses each, but they are the most numerous neurons in the brain—the human cerebellum has been estimated to contain around 40 billion granule cells. The axons of granule cells, called parallel fibers, travel across the cerebellar layer, all in the same direction, passing through the dendrites of the Purkinje cells, which are flattened into planar nets. This very large and extremely regular network gives rise to a massive signal-processing capability, but almost the entirety of its output is directed to a set of small cerebellar nuclei lying in the brainstem at the base of the cerebellum (a portion also goes to the nearby vestibular nuclei).

In addition to its role in motor control, the cerebellum also is necessary for several types of motor learning, most notably including learning to adjust to changes in sensorimotor relationships. If, for example, a person is fitted with goggles that invert the visual field, hand-eye coordination is severely disrupted at first, but improves over the course of days; the cerebellum has been shown to play an essential role in the improvement. Several theoretical models have been developed to explain sensorimotor calibration in terms of synaptic plasticity within the cerebellum. Most of them derive from early models formulated by David Marr and James Albus, which were motivated by the observation that each cerebellar Purkinje cell receives two dramatically different types of input: on one hand, thousands of inputs from parallel fibers, each individually very weak; on the other hand, input from one single climbing fiber, which is however so strong that a single climbing fiber action potential will reliably cause a target Purkinje cell to fire a burst of action potentials. The basic concept of the Marr-Albus model is that the climbing fiber serves as a "teaching signal", which induces a long-lasting change in the strength of synchronously activated parallel fiber inputs. Observations of long-term depression in parallel fiber inputs have provided broad support for theories of this type, but the details remain controversial.

[edit] Structure

The structure of the cerebellum can be viewed at three levels. At the level of large-scale anatomy, the cerebellum consists of a tightly folded and crumpled layer of cortex, with white matter underneath, several deep nuclei embedded in the white matter, and a fluid-filled ventricle at the base. At the intermediate level, the cerebellum and its auxiliary structures can be decomposed into several hundred or thousand independently functioning modules or "microzones". At the microscopic level, each module consists of the same small set of neuronal elements, laid out with a highly stereotyped geometry. Because the modular structure cannot be understood without knowledge of the microscopic structure, this section describes the three levels in the order macroscopic—microscopic—modular.

[edit] Anatomy

Anterior view of the human cerebellum, with numbers indicating salient landmarks

The cerebellum is located at the bottom of the brain, with the large mass of the cerebral cortex above it and the portion of the brainstem called the pons in front of it. It is separated from the overlying cerebrum by a layer of leathery dura mater; all of its connections with other parts of the brain travel through the pons. Anatomists classify the cerebellum as part of the metencephalon, which also includes the pons; the metencephalon in turn is the upper part of the rhombencephalon or "hindbrain". Like the cerebral cortex, the cerebellum is divided into two hemispheres; it also contains a narrow midline zone called the vermis. A set of large folds are conventionally used to divide the overall structure into ten smaller "lobules". Because of its large number of tiny granule cells, the cerebellum contains more neurons than the rest of the brain put together, but it only takes up 10% of total brain volume.^[3]

Vertical cross-section of the human cerebellum, showing folding pattern of the cortex, and interior structures

The unusual surface appearance of the cerebellum conceals the fact that the bulk of the structure is made up of a very tightly folded layer of gray matter, the cerebellar cortex. It has been estimated that if the human cerebellar cortex were completely unfolded (which could not be done without tearing it in several places), it would give rise to a layer of neural tissue about 1 meter long and averaging 5 centimeters wide—a total surface area of about 500 square cm, packed within a volume of dimensions 6 cm × 5 cm × 10 cm.^[3] Underneath the gray matter of the cortex lies white matter, made up largely of myelinated nerve fibers running to and from the the cortex. Embedded within the white matter—which is sometimes called the arbor vitae (Tree of Life) because of its branched, tree-like appearance—are four deep cerebellar nuclei.

[edit] Subdivisions

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

These structural divisions divide the cerebellum from top to bottom. Functionally, however, there is a more important distinction along the medial-to-lateral dimension. Leaving out the flocculonodular part, which is virtually a separate structure, the cerebellum can be parsed into a medial sector, the spinocerebellum, and a larger lateral sector, the cerebrocerebellum.

The smallest region, the flocculonodular lobe, functionally constitutes the vestibulocerebellum. It is the oldest part in evolutionary terms, and participates mainly in balance and spatial orientation; its primary connections are with the vestibular nuclei, although it also receives visual and other sensory input. Damage to it causes disturbances of balance and gait.

The medial zone of the anterior and posterior lobes constitutes the spinocerebellum, also known as paleocerebellum. This sector of the cerebellum functions mainly to regulate body and limb movements. It receives proprioception input from the dorsal columns of the spinal cord (including the spinocerebellar tract) as well as from the trigeminal nerve, as well as from visual and auditory systems. It sends fibres to deep cerebellar nuclei which in turn project to both the cerebral cortex and the brain stem, thus providing modulation of descending motor systems.

The lateral zone, which in humans is by far the largest part, constitutes the cerebrocerebellum, also known as neocorebellum. This sector is involved in planning movement and evaluating sensory information for action. It receives input exclusively from the cerebral cortex (especially the parietal lobe) via the pontine nuclei (forming cortico-ponto-cerebellar pathways), and sends fibres mainly to the ventrolateral thalamus (in turn connected to motor areas of the premotor cortex and primary motor area of the cerebral cortex) and to the red nucleus. The cerebrocerebellum is involved in planning movement that is about to occur^[4] and may have purely cognitive functions as well.

[edit] Microanatomy

Transverse section of a cerebellar folium, showing principle cell types and connections

As explained in more detail in the Function section, the cerebellum differs from most other brain areas in that the flow of neural signals through it is almost entirely unidirectional: there are virtually no backward connections between its neuronal elements. Two types of neuron play dominant roles in the cerebellar circuit: Purkinje cells and granule cells. Three types of axons also play dominant roles: mossy fibers and climbing fibers (which enter the cerebellum from outside), and parallel fibers (which are the axons of granule cells).

The cerebellar cortex is divided into three layers. At the bottom lies the thick granular layer, densely packed with granule cells, along with much smaller numbers of interneurons, mainly Golgi cells. In the middle lies the Purkinje layer, a narrow zone that contains only the cell bodies of Purkinje cells. At the top lies the molecular layer, which contains the flattened dendritic trees of Purkinje cells, along with the huge array of parallel fibers penetrating the Purkinje cell dendritic trees at right angles. This outermost layer of the cerebellar cortex also contains two types of inhibitory interneurons, stellate cells and basket cells. Both stellate and basket cells form GABAergic synapses onto Purkinje cell dendrites.

[edit] Purkinje cells

Drawing of a Purkinje cell from cat cerebellum

Purkinje cells are among the most distinctive neurons in the brain, and also among the earliest types to be recognized—they were first described by the Czech anatomist Jan Evangelista Purkyně in 1837. What distinguishes them especially is the shape of the dendritic tree: the dendrites branch very profusely, but are severely flattened in a plane perpendicular to the cerebellar folds. Thus, the dendrites of a Purkinje cell form a dense planar net, through which parallel fibers pass at right angles.^[3] The dendrites are covered with dendritic spines, each of which receives synaptic input from a parallel fiber. Purkinje cells receive more synaptic inputs than any other type of cell in the brain—estimates of the number of spines on a single human Purkinje cell run as high as 200,000.^[3] The large, spherical cell bodies of Purkinje cells are packed into a narrow layer (one cell thick) of the cerebellar cortex, called the Purkinje layer. After emitting collaterals that innervate nearby parts of the cortex, their axons travel into the deep cerebellar nuclei, where they make on the order of 1000 contacts each with several types of nuclear cells, all within a small domain. Purkinje cells use GABA as their neurotransmitter, and therefore exert inhibitory effects on their targets.^[3]

[edit] Granule cells

Cerebellar granule cells, in contrast, are among the smallest neurons in the brain. They are also easily the most numerous neurons in the brain: in humans, estimates of their total number average around 50 billion, which means that about 3/4 of the brain's neurons are cerebellar granule cells.^[3] Their cell bodies are packed into a thick layer at the bottom of the cerebellar cortex. A granule cell emits only four to five dendrites, each of which ends in an enlargement called a dendritic claw.^[3] These enlargements are sites of excitatory input from mossy fibers and inhibitory input from Golgi cells.

Granule cells, parallel fibers, and Purkinje cells with flattened dendritic trees

The thin, unmyelinated axons of granule cells rise vertically to the upper (molecular) layer of the cortex, where they split in two, with each branch traveling horizontally to form a parallel fiber; the splitting of the vertical branch into two horizontal branches gives rise to a distinctive "T" shape. A parallel fiber runs for an average of 3 mm in each direction from the split, for a total length of about 6 mm (about 1/10 of the total width of the cortical layer).^[3] As they run along, the parallel fibers pass through the dendritic trees of Purkinje cells, contacting one of every 3-5 that they pass, making a total of 80-100 synaptic connections with Purkinje cell dendritic spines.^[3] Granule cells use glutamate as their neurotransmitter, and therefore exert excitatory effects on their targets.

It is perhaps worth noting that although cerebellar granule cells make up the majority of neurons in the brain, they only generate a minority of synaptic connections. Each granule cell receives about 5 inputs and generates about 100 outputs. A typical cortical pyramidal cell, on the other hand, is thought to have about 10,000 inputs and 10,000 outputs. Thus, even though there may be only 1/5 as many cortical pyramidal cells as cerebellar granule cells, the number of synapses in the cerebral cortex is at least 10 times greater.

[edit] Mossy fibers

Mossy fibers enter the granular layer from their points of origin, many arising from the pontine nuclei, others from the spinal cord, vestibular nuclei, etc. In the human cerebellum, the total number of mossy fibers has been estimated at about 200 million.^[3] These fibers form excitatory synapses with the granule cells and the cells of the deep cerebellar nuclei. Within the granular layer, a mossy fiber generates a series of enlargements called rosettes. The contacts between mossy fibers and granule cell dendrites take place within structures called glomeruli. Each glomerulus has a mossy fiber rosette at its center, and up to 20 granule cell dendritic claws contacting it. Terminals from Golgi cells infiltrate the structure and make inhibitory synapses onto the granule cell dendrites. The entire assemblage is surrounded by a sheath of glial cells.^[3] Each mossy fiber sends collateral branches to several cerebellar folia, generating a total of 20–30 rosettes; thus a single mossy fiber makes contact with an estimated 400–600 granule cells.^[3]

[edit] Climbing fibers

Purkinje cells also receive input from the inferior olivary nucleus (ION) via climbing fibers. Although the ION lies in the pons, and receives input from the spinal cord, brainstem, and cerebral cortex, its output goes entirely to the cerebellum. A climbing fiber gives off collaterals to the deep cerebellar nuclei before entering the cerebellar cortex, where it splits into about 10 terminal branches, each of which innervates a single Purkinje cell.^[3] 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 total of up to 300 synapses as it goes.^[3] The net input is so strong that a single action potential from a climbing fiber is capable of producing an extended "complex spike" in the Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a pause during which activity is suppressed. The climbing fiber synapses cover the cell body and proximal dendrites; this zone is devoid of parallel fiber inputs.^[3]

[edit] Deep nuclei

Cross-section of human cerebellum, showing the dentate nucleus, as well as the pons and inferior olivary nucleus

The deep nuclei of the cerebellum are clusters of gray matter lying within the white matter at the core of the cerebellum. They are, with the minor exception of the nearby vestibular nuclei, the sole sources of output from the cerebellum. These nuclei receive collateral projections from mossy fibers and climbing fibers, as well as inhibitory input from the Purkinje cells of the cerebellar cortex. The three nuclei (dentate, interpositus, and fastigial) each communicate with different parts of the brain and cerebellar cortex. The fastigial and interpositus nuclei belong to the spinocerebellum, whereas the dentate nucleus (which in humans is considerably larger than the others) belongs to the cerebrocerebellum. Output from the vestibulocerebellum (the flocculonodular lobe) goes primarily to the vestibular nuclei.^[3]

[edit] Overview of neuronal components

The following table lists the main neuronal constituents of the human cerebellar system and their primary connections. A number of secondary connections are omitted, perhaps most importantly the mossy fiber and climbing fiber collaterals to the deep nuclei. The numbers are derived from the descriptions above; they are not 100% consistent with each other because there are inconsistencies between different authors.

[edit] Function

The strongest clues to the function of the cerebellum have come from examining the consequences of damage to it. Animals and humans with cerebellar dysfunction show, above all, problems with motor control. They continue to be able to generate motor activity, but it loses precision, producing erratic, uncoordinated, or incorrectly timed movements. Thus, the general conclusion reached decades ago is that the basic function of the cerebellum is not to initiate movements, or to decide which movements to execute, but rather to calibrate the detailed form of a movement.

Prior to the 1990s it was almost universally believed that the function of the cerebellum is purely motor-related, but a diverse array of recent findings have brought that view strongly into question. Functional imaging studies have shown cerebellar activation in relation to language, attention, and mental imagery; correlation studies have shown interactions between the cerebellum and non-motoric areas of the cerebral cortex; and a variety of non-motor symptoms have been recognized in people with damage that appears to be confined to the cerebellum.^[5]

Kenji Doya has argued that the function of the cerebellum is best understood not in terms of what behaviors it is involved in, but rather in terms of what neural computations it performs. The cerebellum, he points out, consists of a large number of more or less independent modules, all with the same geometrically regular internal structure, and therefore all presumably performing the same computation. If the input and output connections of a module are with motor areas (as many are), then the module will be involved in motor behavior; but if the connections are with areas involved in non-motor cognition, the module will show other types of behavioral correlates. The cerebellum, Doya proposes, is best understood as a device for supervised learning, in contrast to the basal ganglia, which perform reinforcement learning, and the cerebral cortex, which performs unsupervised learning.^[5]

The comparative simplicity and regularity of the cerebllear anatomy led to an early hope that it might imply a similar simplicity of computational function, as expressed by the title of one of pioneering books on cerebellar physiology, The Cerebellum as a Neuronal Machine by John C. Eccles, Masao Ito, and Janos Szentágothai.^[6] The problem, however, has turned out to be more difficult than they hoped it would be. Although a full understanding of cerebellar function has remained elusive, at least four features have been identified as clearly important: (1) feedforward processing, (2) divergence and convergence, (3) modularity, and (4) plasticity.

1. Feedforward processing: The cerebellum differs from most other parts of the brain (especially the cerebral cortex) in that the signal processing is almost entirely feedforward—that is, signals move unidirectionally through the system from input to output, with very little recurrent internal transmission. The small amount of recurrence that does exist consists of mutual inhibition; there are no mutually excitatory circuits. This feedforward mode of operation means that the cerebellum, in contrast to the cerebral cortex, cannot generate self-sustaining patterns of neural activity. Signals enter the circuit, are processed by each stage in sequential order, and then leave. As Eccles, Ito, and Szentágothai wrote, "This elimination in the design of all possibility of reverberatory chains of neuronal excitation is undoubtedly a great advantage in the performance of the cerebellum as a computer, because what the rest of the nervous system requires from the cerebellum is presumably not some output expressing the operation of complex reverberatory circuits in the cerebellum, but rather a quick and clear response to the input of any particular set of information."^[7]

2. Divergence and convergence:

3. Modularity: The cerebellar system is functionally divided into more or less independent modules, which probably number in the hundreds to thousands. All modules have a similar internal structure, but different inputs and outputs. A module consists of a small cluster of neurons in the inferior olivary nucleus, a set of long narrow strips of Purkinje cells in the cerebellar cortex ("microzones"), and a small cluster of neurons in one of the deep cerebellar nuclei. Different modules share input from mossy fibers and parallel fibers, but in other respects they appear to function independently—the output of one module does not appear to significantly influence the activity of other modules.

4. Plasticity: The synapses between parallel fibers and Purkinje cells, and the synapses between mossy fibers and deep nuclear cells, are both susceptible to modification of their strength. In a single cerebellar module, input from as many as a billion parallel fibers converges onto a group of perhaps 50 deep nuclear cells, and the influence of each parallel fiber on those nuclear cells is adjustable. This arrangement gives tremendous flexibility for fine-tuning the relationship between cerebellar inputs and outputs.

[edit] Basic circuit

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.

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.^[8][9] 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.

[edit] Granule cells

Granule cells receive all of their input from mossy fibers, but outnumber them 200 to 1 (in humans). Thus, the information in the granule cell population activity state is the same as the information in the mossy fibers, but recoded in a much more expansive way. Because granule cells are so small and so densely packed, it has been very difficult to record their spike activity in behaving animals, so there is little data to use as a basis of theorizing. The most popular concept of their function was proposed by David Marr, who suggested that they could encode combinations of mossy fiber inputs. The idea is that with each granule cell receiving input from only 4–5 mossy fibers, a granule cell would not respond if only a single one of its inputs was active, but would respond if more than one were active. This "combinatorial coding" scheme would potentially allow the cerebellum to make much finer distinctions between input patterns than the mossy fibers alone would permit.

[edit] Climbing fiber system

The climbing fiber input to each side of the cerebellum comes from the inferior olivary nucleus on the contralateral side. This is one of the most unusual projections in the brain: each cerebellar Purkinje cell receives input from a single climbing fiber, but that one climbing fiber winds around the dendrites of the Purkinje cell, making hundreds of synaptic contacts as it climbs. There are different views concerning the functional signficance of this striking arrangement. According to a very influential idea first proposed by Marr^[10] and Albus^[11] 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^[12] 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.^[13] 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.^[14][15] The olivocerebellar system can be considered an electrically malleable substrate from which unique motor synergies can be sculpted.

[edit] 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.

[edit] Cerebellar nuclei

The Purkinje cells are the only output of the cerebellar cortex and are inhibitory in nature.^[16] 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.

[edit] 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 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.^[17] 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.

[edit] 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^[18] 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.^[19] It was also shown that this area received convergent mossy and climbing fibre input as required by the Marr-Albus hypothesis.^[20] 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.^[21][22] 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.^[23][24] 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.^[25] 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.^[26] 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.

[edit] Theories

The large base of knowledge about the anatomical structure and behavioral functions of the cerebellum have made it a fertile ground for theorizing—there are perhaps more theories of the function of the cerebellum than of any other part of the brain. Notable theories include:

• The very influential theory published by David Marr in 1969, which proposed that the cerebellum is a device for learning to associate elemental movements encoded by climbing fibers with mossy fiber inputs that encode the sensory context.^[10]

• The Tensor Network Theory of Pellionisz and Llinás, which provides an advanced mathematical formulation of the idea that the fundamental computation performed by the cerebellum is to transform sensory into motor coordinates.^[27]

[edit] Pathology

Altered walking gait of a woman with cerebellar disease

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.^[28]

[edit] Cerebellar modeling

There have been many attempts to model the cerebellar function.^[29] 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,^[30] Cerebellar Model Associative Memory or CMAC networks, SpikeFORCE for robotic movement control,^[31] and the "Tensor Network Theory".^[32]

[edit] Evolution

Cross-section of the brain of a porbeagle shark, with the cerebellum highlighted

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.^[33] This has been taken as evidence that the cerebellum performs functions important to all animal species with a brain.

There is considerable variation in the size and shape of the cerebellum in different vertebrate species. 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.^[34] The cerebellum is a bit larger in reptiles, considerably larger in birds, and largest in mammals. 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.^[34]

The cerebellum of cartilaginous and bony fishes is extraordinarily large and complex. In at least one important respect it differs in internal structure from the mammalian cerebellum: the fish cerebellum does not contain discrete deep cerebellar nuclei—instead the primary targets of Purkinje cells are a distinct type of cell distributed across the cerebellar cortex, a type of cell not seen in mammals.

As a general principle, species with a large cerebellum are those that are capable of complex and fluid movement: these include fishes, birds, and mammals. The rather rudimentary cerebellum of amphibians and reptiles may in part account for the jerky, somewhat clumsy appearance of much of their behavior.

[edit] Development

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).^[35]

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 human 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.

[edit] 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.^[36]

A stereological study has found that human cerebellar white matter is reduced by 26% with age (over the age range 19—84).^[37] 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.^[38]

[edit] History

Base of the human brain, as drawn by Andreas Vesalius in 1543

The distinctive appearance of the cerebellum caused even the earliest anatomists to recognize it—Aristotle and Galen, however, did not consider it truly part of the brain: they called it the "parencephalon" ("same-as-brain"), as opposed to the "encephalon" or brain proper. Galen was the first to give an extensive description—noting that the cerebellar tissue seemed more solid than the rest of the brain, he speculated that its function is to strengthen the motor nerves.^[39]

Further significant developments did not come until the Renaissance. Vesalius discussed the cerebellum briefly, and the anatomy was described more thoroughly by Thomas Willis in 1664. More anatomical work was done during the 18th century, but it was not until early in the 19th century that the first insights into the function of the cerebellum were obtained. Luigi Rolando in 1809 established the key insight that damage to the cerebellum results in motor disturbances. Jean Pierre Flourens in the first half of the 19th century carried out detailed experimental work, which revealed that animals with cerebellar damage can still move, but with a loss of coordination (strange movements, awkward gait, and muscular weakness); and that recovery after the lesion can be nearly complete unless the lesion is very extensive.^[40] By the dawn of the 20th century it was widely accepted that the primary function of the cerebellum relates to motor control; the first half of the 20th century produced several detailed descriptions of the clinical symptoms associated with cerebellar disease in humans.^[1]

[edit] References

[edit] Further reading

[edit] 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
• Basal ganglia and cerebellum at Washington University in St. Louis
• Cerebellum - Cell Centered Database
• BrainMaps at UCDavis cerebellum

• Histological section of primate cerebellum at University of Birmingham
• NIF Search - Cerebellum via the Neuroscience Information Framework