Chapter 8B - Cerebellar Systems
The cerebellum is a region of the brain that functions largely outside of the realm of conscious awareness. Its best-known functions are involved in coordinating motor activities and learning new motor skills. It is particularly involved in adjusting activities to meet new conditions. However, in addition to these well-known functions, there is a growing awareness that cerebellar systems may be involved in other types of learning and also in emotional reactivity.
The cerebellum, located dorsal to brain stem, is partially hidden by the large occipital lobes of the cortex. The cerebellar cortex is deeply grooved and appears as thin, transverse leaves called folia. There is a deeper transverse fold on the superior aspect of the cerebellum termed the primary fissure. This fissure defines the posterior end of the anterior lobe. The posterolateral fissure divides the small flocculonodular lobe from the remainder of the cerebellum. The portion of the cerebellum in the midline is not as prominent as the lateral hemispheres and is termed the vermis. It is important to note that the cerebellum is connected to ipsilateral body functions. Therefore, whenever the cerebellum connects to portions of the brain that have crossed functions (such as the cerebral cortex), the connection must cross.
There are three functional subdivisions of the cerebellum. The flocculonodular lobe is called the vestibulocerebellum or "archicerebellum." The spinocerebellum (paleocerebellum) includes the anterior lobe and paramedian lobules. The neocerebellum (pontocerebellum) makes up the lateral hemispheres.
The cerebellum is connected to the brain stem by three peduncles. The middle peduncle is, by far, the largest of the peduncles, connecting the pons to the cerebellum. The inferior peduncle connects the medulla to the cerebellum, while the superior peduncle connects the cerebellum to the midbrain. Most input to the cerebellum is through the middle and inferior peduncles and most of the output from the cerebellum is via the superior peduncle.
The deep cerebellar nuclei are within the cerebellum, with the fastigeal nucleus being the most medial, the interposed nuclei, comprised of the small globose and emboliform nuclei, located immediately lateral to the fastigial nucleus and the massive dentate nucleus being the most lateral. The cerebellar cortex is connected to the deep nuclei. The vermal zone of cortex connects to the fastigial nucleus, the paravermal zone connects to the interposed nuclei and the lateral hemispheres connect to the dentate nucleus.
The cerebellar cortex only connects to the deep cerebellar nuclei and to the vestibular nuclei. Neurons in the deep cerebellar nuclei represent virtually all of the output from the cerebellum. The fastigial nuclei are connected to the reticular formation by two pathways. The interposed nuclei are connected through the superior cerebellar peduncle primarily to the red nucleus. The dentate nucleus has a massive connection through the superior peduncle to the ventral lateral nucleus of the thalamus, which relays to the cerebral motor cortex.
Before proceeding with a discussion of the connections of the various regions of the cerebellum it is appropriate to describe the cerebellar cortex (figure 23). The cellular structure of the cerebellar cortex is completely montonous, with every region of the cortex, regardless of its functions or connections, appearing identical. Therefore, the differences in function from one area to another are based entirely on difference in inputs and output from the cortex. It is interesting to note that there are more neurons in the cerebellar cortex than the rest of the brain combined. Furthermore, there are only five different types of neurons in the cortex. These appear in three layers, the granule cell layer is deepest, the Purkinje cell layer is in the middle and a superficial layer is termed the molecular layer. Not surprisingly, granule cells (the most numerous cell type in the human brain) are in the granule cell layer along with Golgi cells. The Purkinje cells appear in a single layer, the Purkinje cell layer. Finally, the molecular layer contains basket and stellate cells. All of these cell types, with the exception of the granule cells, use the inhibitory neurotransmitter, GABA. It is also important to note that the Purkinje cell is the only neuronal type that has an axon that leaves the cerebellar cortex. The remaining cell types make connections only within this thin layer of the cerebellar cortex.
The circuitry of the cerebellar cortex is also quite well understood, and was largely established by Sir John Eccles and colleagues. There are only two types of axons that enter the cerebellum, mossy fibers and climbing fibers. Climbing fibers arise only from the inferior olivary nucleus, while mossy fibers comprise all of the other cerebellar inputs. Both of these fiber types release excitatory neurotransmitter, glutamate in the case of the mossy fibers and aspartate in the case of climbing fibers. As they enter the cerebellum, both the mossy and climbing fibers have collateral branches that synapse on (and excite) the deep cerebellar nucleus neurons. However, these two fiber types have quite different terminations and effects in the cerebellar cortex.
Mossy fibers branch extensively as they enter the cortex. Each mossy fiber terminal synapses on a group of granule cell dendrites, exciting the granule cell. The granule cell axon runs toward the cortical surface, into the molecular layer where it divides in a "T". These granule cell axons run along the axis of the cerebellar folia, crossing the dendritic arbors of many Purkinje cells, with which they make excitatory "en-passant" synapses. There are millions of granule cell axons packed into each folia and they are called "parallel fibers." Several hundred thousand parallel fibers synapse with (and excite) each Purkinje cell. Parallel fiber axons are also the main excitatory input to the Golgi, stellate and basket cells. Each parallel fiber input makes a minute input, but they can summate to activate the Purkinje cell.
The Purkinje cell axons are the only nerve fibers to actually leave the cerebellar cortex and they synapse on deep cerebellar nucleus neurons and on some vestibular neurons, inhibiting them powerfully. Therefore, the excitatory input that entered the cerebellum with the mossy fiber was responsible for exciting the deep nucleus neuron and then for exciting granule cells that stimulate Purkinje cells that "turn off" the deep nucleus neuron. It is critical that the correct amount of inhibition arrive at the deep cerebellar nucleus in order to produce an appropriate output, inhibiting unwanted activity in the deep nuclei. This is a process akin to sculpture, where the unwanted parts of the stone are removed to create a pattern.
The cerebellar climbing fibers synapse directly on the Purkinje cells and powerfully excite them. There is only one climbing fiber per Purkinje cell and each climbing fiber only goes to one to three Purkinje cells. Therefore, there is an intimate connection between the neurons of the inferior olivary nucleus and the Purkinje cells. Current concepts of inferior olivary function place it as an "error detector." When a particular action goes off target, inferior olivary nucleus neurons are activated. This results in powerful activation of the target Purkinje cells through the climbing fibers. This powerful activation of Purkinje cells inhibits the deep cerebellar nucleus neurons, hopefully terminating the unwanted component of the action.
If this is how the cerebellum works, then how does the cerebellum contribute to motor learning, so that the next time the movement is performed, it is performed more accurately from the beginning? This appears to be the result of plasticity of the synapse between the parallel fiber and the Purkinje cell. At the moment of activation of the Purkinje cell by the climbing fiber, all of the parallel fiber synapses that were recently active will undergo a process of long-term depression. This occurs because parallel fiber input activates metabotropic glutamate receptors at the parallel fiber terminal on the Purkinji cell at the same time they are activating the ionotropic AMPA receptors (this is how parallel fibers excite Purkinji cells). The matabotropic glutamate receptors activate phospholipase C, which results in creation of IP3 and DAG. These both contribute directly and indirectly to formation of protein kinase C (PKC). This PKC will phosporylate proteins associated with the AMPA (ionotropic glutamate) receptors. This activation of PKC is massively increased by the extremely high levels of calcium in the dendrite that result from Purkinji cell activation via climbing fibers (aspartate, the neurotransmitter at the the climbing fiber to Purkinji cell synapse, opens calcium channels). This high level of PKC results in internalization of phosphorylated AMPA glutamate channels. This produces a long term depression of subsequent responses to input along the particular parallel fiber that was active immediately before the parallel fiber input.That is, the synapses that were active around the time of climbing fiber input will be weakened, so that the next time the specific parallel fiber is active, it will have less of an excitatory effect on the Purkinje cell. Since our current concept of the climbing fiber function is that they convey an error signal, the granule cell to Purkinje cell synapses that were active at the time of the error will be inhibited. This is appropriate since these synapses were probably at fault in the unwanted activity in the first place. Therefore, each synapse can be adjusted during a process of learning to produce the correct cerebellar output. In the case of motor patterns, this allows for procedural learning, where each time an action is performed, it becomes somewhat more accurate since the "right synapses" are contributing to the response.
Less is known about the activity of the other neurons of the cerebellar cotex. It is noteworthy that all of the other three cell types (Golgi, stellate and basket cells) are inhibitory. Each of these cell types is excited by the parallel fibers and each feeds onto a certain part of the circuit. Golgi cells feedback inhibition to the granule cells. Parallel fiber activation of the stellate cells will feed forward and inhibit Purkinje cells shortly after they, themselves, are excited by the parallel fibers. This inhibition may clear the activity of the Purkinje cells shortly after they have been excited, allowing the Purkinje cell to respond to only to the immediate activity in granule cells and parallel fibers. The basket cells are a special case, since their axons usually go to surrounding Purkinje cells, not the ones to which they are adjacent. This may "turn off" activity in Purkinje cells at a certain distance surrounding the focus of activity. While there are concepts of how these inhibitory neurons of the cerebellar cortex work, suffice it to say that all of the details are not understood and, despite its rather simple architecture, we do not have a working computer model of cerebellar control of any of the complex activities that it so ably regulates. It is clear, however, that damage to the deep cerebellar nuclei or the Purkinje cells have severe and potentially devastating effects.
If the cerebellar cortex is a sea of monotonous circuitry, what distinguishes the different parts of the cerebellum? In a word, these areas are distinguished by their distinct inputs, most dramatically by the particular origins of the mossy fibers that terminate in the cortex. Also, although all of the climbing fibers arise from the inferior olive, there is a very precise topography of origin of climbing fibers within the olive. We will discuss three basic parts of the cerebellum, the vestibulocerebellum, the spinocerebellum and the neocerebellum.
The vestibulocerebellum, or flocculonodular lobe of the cerebellum, receives a substantial amount of its input from the vestibular nerve. This is unique since no other portion of the cerebellum receives direct input from a sensory nerve. Additionally, there are connections from the vestibular nuclei to the vestibulocerebellum. Another unique feature of this portion of the cerebellum is that Purkinje cells here actually leave the cerebellum to synapse in portions of the vestibular nuclear complex in the dorsolateral brain stem. This is the only portion of the cerebellar cortex to have any direct connections other than to deep cerebellar nucleus neurons and suggests that the vestibular complex may have some similarity with deep cerebellar nuclei.
The vestibulocerebellum is an important regulator of the vestibular system. Damage to this region will result in vertigo and nystagmus. However, the most important function of this part of the cerebellum is to allow adaptation to vestibular damage. The effects of damage to the vestibular system, for example by damaging the inner ear, are severe. However, with time, these injuries will be well compensated. This compensation does not happen if the vestibulocerebellum is also injured. The vestibulo-ocular reflex has been the basis for much of the research into cerebellar plasticity since this reflex is very precise in stabilizing the eyes during movement and adjusts to vestibular damage.
The spinocerebellum is important in regulating muscle tone and in adapting the body to changing circumstances. This portion of the cerebellum includes vermal and paravermal zones of the anterior lobe and part of the posterior lobe. Therefore, it receives extensive input from the spinal cord. As described in section VIIa, several direct and indirect spinocerebellar pathways terminate in the spinocerebellum in a topographic manner in two somatotopic maps (one in the anterior lobe and one in the paramedian lobule). The input from muscles and the spinal cord reflex pathways are necessary for proper regulation of muscle tone and movement.
Since the spinocerebellum includes both vermal and paravermal zones of the cerebellum, there are connections with both the fastigeal nuclei and the interposed nuclei. The fastigeal nuclei, in turn, connect to the reticular formation (figure 24), which can affect muscle tone and crude movements via the reticulospinal tracts. The interposed nuclei connect predominantly to the contralateral red nucleus through the superior cerebellar peduncle (figure 24). This nucleus is the origin for the rubrospinal tract that mainly influences limb flexor muscles. Therefore, the spinocerebellum can influence both muscle tone and coordination of the extremities. Additionally, the cerebellum is important in determining the appropriate response to changing situations. For example, when attempting to resist a force on the extremities, a sudden release of force would result in a rebound of the the limb. The ability to rapidly check this motion requires feedback from muscle stretch and tension receptors.
The neocerebellum receives the vast majority of its input from the pontine nuclei. The pontine nuclei receive input from the majority of the cerebral cortex via corticopontine fibers. The pontine nuclei project exclusively through the middle cerebellar peduncles to the cerebellum, where these axons terminate as mossy fibers. It is the largest input to the cerebellum and almost exclusive input to the neocerebellum (which comprises most of the lateral hemispheres of the cerebellum). The neocerebellum connects to the dentate nuclei via its Purkinje cell axons and the dentate nucleus, in turn, projects to the ventral lateral nucleus of the thalamus which relays back to the cerebral cortex (figure 24). Therefore, the lateral hemispheres of the cerebellum are involved in regulating the cerebral cortical motor output. The best-known effect of this is in procedural learning. Activities such as riding a bike or learning to ski involve activity of the cerebellar hemispheres. Damage to the lateral hemispheres results in lack of coordination of limb movement, with overshoot and undershoot (intention tremor).
The discussion to this point has largely focused on control of balance and of skilled voluntary movements. In addition to these functions. the cerebellar vermis receives visual input from the superior colliculus and is involved in coordinating eye movements. It also coordinates speech. Drunken speech, for example, derives from the effect of alcohol on the vermal portions of the cerebellum.
Finally, there has been increasing recognition of the role of the cerebellum in learning and regulating many behaviors at the level of the cerebral cortex. For example, there are abnormalities in the cerebellum in such diverse conditions as schizophrenia and autism, indicating a much broader range of effects than previously appreciated. Of course, the anatomy of the cerebellum does provide a substrate for this interaction, with afferent input to the cerebellar cortex via corticopontine, pontocerebellar fibers from diverse areas of the cerebral cortex. Also, the dentato-thalamo-cortical connection distributes to many regions of the cerebral cortex beyond the classic projections to the ventrolateral thalamic nucleus and motor cortex. However, a full appreciation for these aspects of cerebellar function represents the frontier of research into cerebellar functions.