Give an account of the connections and functions of the cerebellum

March 2003: What does the cerebellum contribute to motor control?

June 2005: What does the circuitry of the cerebellum tell us about cerebellar function?

September 2005: Discuss the role of the cerebellum in postural control.

March 2006: What role does the cerebellum play in postural control?

CONCLUSION!

During the First World War, Gordon Holmes studied patients who sustained
gunshot wounds to the cerebellum and he was the first to describe the signs of cerebellar
damage. He noted that these patients suffered motor control deficits including hypotonia,
ataxia, dysdiadochokinesia and intention tremors. The anatomical organization of the
cerebellum reflects the functions that it performs. The cerebellum receives internal
feedback information about intended movements and external feedback about motor
performance. The neural circuitry of the cerebellum computes errors between intended
movements with actual movements and sends corrective signals to the descending motor
systems. The cerebellum is also involved in motor learning because discrepancy between
intended and actual movements causes long term depression of synapses between parallel
fibres and Purkinje cells which leads to behavioural adaptation. An understanding of the
input-output connections of the different cerebellar subdivisions and the highly organized
connections of neurons in the cerebellar cortex allows us to understand how the
cerebellum performs its functions.

Diagram of cerebellum cortex neural circuitry! Instant notes. p.265

Neural circuitry of cerebellar cortex

The cerebellar cortex consists of five different types of neurons connected in a
highly organized manner. The outermost layer is the molecular layer which contains
parallel fibres (the axons of granule cells) running parallel to the long axis of folium, and
inhibitory interneurons called stellate and basket cells. Beneath the molecule layer is the
Purkinje cell layer which contains Purkinje neurons. Their dendritic trees extend into the
molecular layer and are arranged in a single plane perpendicular to the long axis of
folium. The parallel fibres thus synapses with a row of Purkinje cells and each Purkinje
cell receives inputs from about 200,000 parallel fibres. The innermost layer is the granule
cell layer which contains about 1011 granule cells and Golgi cells in its outer border. The
granule layer also contains cerebellar glomeruli where granule cells synapse with mossy
fibres and Golgi cells.
The major input to the cerebellum is mossy fibres which arise from the
spinocerebellar and corticopontine cerebellar tracts. Mossy fibres synapse with granule
cells in glomeruli which leads to activation of a row of on-beam Purkinje cells. Action
potentials in mossy fibres cause small excitatory postsynaptic potentials in Purkinje cells.
Spatial and temporal summation of mossy fibre inputs may be sufficient to produce a
simple spike, single action potential in Purkinje cells. The excitatory input from mossy
fibre is modulated by climbing fibres which originate from the inferior colliculus nucleus
in the medulla via the olivocerebellar tract. An action potential in climbing fibres causes
a large Ca2+ influx in Purkinje cells and firing of a complex spike, a large action potential
followed by a burst of smaller action potentials. The large Ca2+ influx activates
phosphokinases C and G which downregulate and withdraw AMPA receptor channels
from the postsynaptic membrane. This leads to long term depression of synapses between
parallel fibres and Purkinje cells so Purkinje cells become less responsive to parallel fibre
inputs. This process is important for motor learning as described later.
The activity of Purkinje cells is modulated spatially and temporally by inhibitory
interneurons: stellate and basket cells in the molecular layer and Golgi cells in the granule
cell layer. Stellate cells and basket cells also receive excitatory input from parallel fibres.
The axons of basket cells run perpendicular to the parallel fibres and synapse with
neighbouring Purkinje cells. Thus excitation of parallel fibres excites a row of on-beam
Purkinje cells and, via stellate cells, inhibits off-beam Purkinje cells. Parallel fibre
activity excites Golgi cells which cause them to release GABA onto granule cells, thus
reducing the responsiveness of granule cells to mossy fibre inputs. Golgi cells therefore
produce feedback inhibition leading to temporal focusing of Purkinje cell activity. The
output from the cerebellar cortex is mediated solely via Purkinje cells which project to
deep cerebellar nuclei. Different cerebellar subdivisions send output to different
cerebellar nuclei and thus are involved in different functions.

Vestibulocerebellum
The vestibulocerebellum in the flocculonodular lobe controls axial motor systems
and vestibular reflexes. It receives information about balance transmitted by afferent
nerve fibres from the semicircular canals, the otolith organs, and the vestibular nuclei. It
also receives visual information from the lateral geniculate nucleus, superior colliculi and
striate cortex via the pontine nuclei. Purkinje cells in the vestibulocerebellum project to
the vestibular nuclei. The vestibulocerebellum has several functions: it controls eye
movement, coordinates movements of the head and eyes, and controls axial muscles to
maintain balance. This is supported by clinical studies of patients with damaged
flocculonodular lobe who suffer from nystagmus, disturbances of equilibrium and
incoordinated body and eye movements.

Spinocerebellum
The spinocerebellum, composed of the vermis and the intermediate cerebellar
hemispheres, is involved in planning and cognition. It receives somatosensory
information from spinocerebellar tracts and information from auditory, visual and
vestibular systems. Edgar Adrian and Ray Snider showed that the afferent somatosensory
projections are organized topographically giving rise to somatosensory maps of the body
in the spinocerebellum. The vermis projects its outputs to the fastigial nucleus and
modulate the medial descending system (reticulospinal, vestibulospinal and corticospinal
tracts) to regulate axial and proximal musculature. Lesions of the vermis or fastigial
nuclei therefore disrupt control of axial and truncal muscles resulting in titubation,
truncal tremor, ataxia of gait and loss of facial control. The output of the interemediate
hemisphere is relayed to the interposed nuclei. Neurons in interposed nuclei project via
the superior cerebellar peduncle to the contralateral magnocellular portion of the red
nucleus in the brainstem to modulate activity in the rubrospinal systems. The interposed
nuclei also project to ventral lateral nucleus of thalamus which leads to modulation of
lateral corticospinal tract activity. By modulating the rubrospinal and corticospinal
systems, the intermediate hemispheres control distal limb muscles. Lesions of the
intermediate cerebellum or the interposed nucleus cause ataxia of limb movements and
action tremor.

Cerebrocerebellum
The cerebrocerebellum receives input from the sensory, motor, premotor and
posterior parietal cortices via the pontine nuclei through the middle cerebellar peduncle.
The output from the cerebrocerebellum is projected to the dentate nucleus. Neurons in the
dentate nucleus project via the superior cerebellar peduncle to the ventral lateral nucleus
of the thalamus and so the dentate nucleus regulates the motor and premotor regions of
the cerebral cortex. Animal studies performed by Vernon Brooks showed that the
cerebrocerebellum is involved in initiating movements when he found that, by using a
cooling probe, reversible inactivation of the dentate nucleus caused a delay in the onset of
activity in motor cortex neurons. Furthermore, Jonathan Hore discovered that inactivation
of the dentate nuclei disrupted the timing of agonist and antagonist activation in rapid
movements thus causing terminal tremor (see Vilis and Hore 1977). From these
experimental studies, we now understand that lesions of the cerebrocerebellum or of the
dentate nuclei cause delayed initiation of movement, intention tremor and disrupt
coordination of limb movement. Such disruptions are particularly apparent in multijoint
movements and in the coordination of distal joints such as those in the hand.

Motor learning
As well as contributing to motor and posture control, the cerebellum is also
important for motor learning. Aaron Gonshor and Geoffrey Melville Jones discovered
that when prismatic lenses that reverse left and right visual fields are worn, the vestibulo-
ocular reflex gradually reverses. However, these adaptations are lost if the
vestibulocerebellum is damaged by lesions. Their discovery showed that the cerebellum
contributes to motor learning. The mechanism by which the cerebellum contributes to
motor learning was proposed by David Marr and James Albus when they suggested that
climbing fibre input causes a sustained reduction in the responsiveness of Purkinje
neurons to mossy fibre inputs. Their proposal was supported by Peter Gilbert and Thomas
Thatch who discovered that when monkeys attempt to adapt to an unexpected stimulus,
the number of complex spikes in Purkinje cells increased and the number of simple
spikes dropped. However, the firing pattern of complex and simple spike gradually
returns to normal levels as the monkey adjust.

CONCLUSION!
Experiment: How cerebellum participates in motor learning / Role of cerebellum in
posture

Early 1970s, David Marr and James Albus suggested that cerebellum is necessary for the
learning of motor skills. Proposed that function of climbing fibre input is to modify
response of Purkinje neurons to mossy fibre inputs for prolonged periods of time. Ito had
already suggested that information coming into cerebellum is processed in the deep
nuclei and this processing is regulated by changing levels of Purkinje inhibition. IN the
context of Ito’s idea, Marr suggested that climbing fibre input decreases the effectiveness
of mossy fibres and thereby acts to correct mismatches between intended and actual
movement.
Neural mechanisms whereby cerebellum participates in learning of motor skills. Peter
Gilbert and Thomas Thatch studied activity of lclimbing fibres in monkeys who were
trained to grasp a movable handle and then had to learn to maintain the handle in a new
location using flexors or extensors of writst. By connecting handle to motor, Gilbert and
Thatch could introduce loads that unexpectedly displaced the handle. When the load was
kept constant the trained animal returned the level rapidly and smoothly to required
position from trial to trial. When load was changed unexpectedly animal’s response
became inaccutate but gradually learned to counteract the load with correct force.

Gilbert and Thatch found that when load was constant and predictable, each movement
was accompanied by stereotyped fluctuations in simple spikes from mossy fibres, with an
occasional interspersed complex spike from climbing fibres. When load was changed
suddenly, the pattern of firing of complex spikes increased dramatically and this increase
was paralleled by a gradual decrease in firing frequency of simple spikes. As animals
learned the task and performance became smooth, firing frequency of complex spikes
gradually returned to control levels. Firing of simple spikes remained decreased as if
firing of mossy fibres had been modified so as to be adjusted to the new load. Thus
findings demonstrate that activity of climbing fibre is modulated during motor learning
and suggests that this modulation might serve to reduce by heterosynaptic inhibition, the
strength of mossy fibre input to the Purkinje neurons. Reduction of mossy fibre input
following the perturbing stimulus in turn led to decrease in firing of Purkinje cells and
lead to increase in output, due to disinhibition, of neurons in deep nuclei. Thatch and
colleagues discovered that pharmacological inactivation of cerebellar cortex prevents
behavioural adaptation. Thus results agree with Albus’s idea that climbing fibres
decrease the activity of mossy fibres and that this hetereosynaptic inhibition is designed
to correct any mismatch between intended movement and results achieved.