Michael D. Mauk

The Cerebellum: A Neuronal Learning Machine?

Comparison of two seemingly quite different behaviors yields a surprisingly consistent picture of the role of the cerebellum in motor learning. Behavioral and physiological data about classical conditioning of the eyelid response and motor learning in the vestibulo-ocular reflex suggest that (i) plasticity is distributed between the cerebellar cortex and the deep cerebellar nuclei; (ii) the cerebellar cortex plays a special role in learning the timing of movement; and (iii) the cerebellar cortex guides learning in the deep nuclei, which may allow learning to be transferred from the cortex to the deep nuclei. Because many of the similarities in the data from the two systems typify general features of cerebellar organization, the cerebellar mechanisms of learning in these two systems may represent principles that apply to many motor systems.

Computer simulation of cerebellar information processing.

Although many functions have been ascribed to the cerebellum, the uniformity of its synaptic organization suggests that a single, characteristic computation may be common to all. Computer simulations are useful in examining this cerebellar computation, as they inherently address function at the level of information processing. Progress is facilitated by factors that make the cerebellum particularly amenable to such analysis. We review progress from two contrasting approaches. Top-down simulations begin with hypotheses about computational mechanisms and then ask how such mechanisms might operate within the cerebellum. Bottom-up simulations attempt to build a representation of the cerebellum that reflects known cellular and synaptic components as accurately as possible. We describe recent advances from these two approaches that are leading to an understanding of what information the cerebellum processes and how its neurons and synapses accomplish this task.

Retention of classically conditioned eyelid responses following acute decerebration

We show that classically conditioned eyelid responses are retained in albino rabbits following decerebration. The presence of these responses represents retention rather than reacquisition in that they are present in the initial trials following decerebration. This excludes the possibility that the post-decerebration conditioned responses are mediated by pathways different from those involved in the intact animal. These data indicate that the conditioned response pathway, and sites of plasticity, for eyelid conditioning are spared by decerebration and are contained within the brainstem and cerebellum.

Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses

A fundamental tenet of cerebellar learning theories asserts that climbing fibre afferents from the inferior olive provide a teaching signal that promotes the gradual adaptation of movements. Data from several forms of motor learning provide support for this tenet. In pavlovian eyelid conditioning, for example, where a tone is repeatedly paired with a reinforcing unconditioned stimulus like periorbital stimulation, the unconditioned stimulus promotes acquisition of conditioned eyelid responses by activating climbing fibres. Climbing fibre activity elicited by an unconditioned stimulus is inhibited during the expression of conditioned responses—consistent with the inhibitory projection from the cerebellum to inferior olive. Here, we show that inhibition of climbing fibres serves as a teaching signal for extinction, where learning not to respond is signalled by presenting a tone without the unconditioned stimulus. We used reversible infusion of synaptic receptor antagonists to show that blocking inhibitory input to the climbing fibres prevents extinction of the conditioned response, whereas blocking excitatory input induces extinction. These results, combined with analysis of climbing fibre activity in a computer simulation of the cerebellar–olivary system, suggest that transient inhibition of climbing fibres below their background level is the signal that drives extinction.

What the cerebellum computes

The brain is an organ that processes information. Brain systems such as the cerebellum receive inputs from other systems and generate outputs according to their internal rules of information processing. Thus, our understanding of the cerebellum is ultimately best expressed in terms of the information processing it accomplishes and how cerebellar neurons and synapses produce this processing. We review evidence that indicates how Pavlovian eyelid conditioning reveals cerebellar processing to be an example of feedforward control. Eyelid conditioning demonstrates a capacity for learning in the cerebellum that is error driven, associative and temporally specific--as is required for feedforward control. This computation-centered view is consistent with a variety of proposed functions of the cerebellum, including sensory-motor integration, motor coordination, motor learning and timing. Moreover, feedforward processing could be the common link between motor and non-motor functions of the cerebellum.

Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses

Contradictory results have been reported regarding the effects of cerebellar cortex lesions on the expression of conditioned eyelid responses--either no effect, partial to complete abolition of responses, or disruption of response timing. This uncertainty is increased by debates regarding the region(s) of cerebellar cortex that are involved, by the likelihood that cortex lesions can inadvertently include damage to the interpositus nucleus or other pathways necessary for response expression, and by potential confounds from the degeneration of climbing fibers produced by cerebellar cortex lesions. We have addressed these issues by reversibly blocking cerebellar cortex output via infusion of the GABA antagonist picrotoxin into the interpositus nucleus. After picrotoxin infusion, conditioned responses are spared but their timing is disrupted and their amplitude diminished. In the same animals, conditioned responses were abolished by infusion of the GABA agonist muscimol and were unaffected by infusion of saline vehicle. These results are consistent with the hypothesis that (i) plasticity in the interpositus nucleus contributes to the expression of conditioned responses, as suggested by the responses seen with the cortex disconnected, and (ii) plasticity in the cerebellar cortex also contributes to conditioned response expression, as suggested by disruption of response timing.

Cerebellar function: Coordination, learning or timing?

Theories of cerebellar function have largely involved three ideas: movement coordination, motor learning or timing. New evidence indicates these distinctions are not particularly meaningful, as the cerebellum influences movement execution by feedforward use of sensory information via temporally specific learning.

Mechanisms of cerebellar learning suggested by eyelid conditioning.

Classical eyelid conditioning has been used to great advantage in demonstrating that the cerebellum helps to improve movements through experience, and in identifying the underlying mechanisms. Results from recent studies support the hypotheses that learning occurs in both the cerebellar nucleus and cortex, and that these sites make different contributions. Specifically, results indicate that the cerebellar cortex is responsible for temporally specific learning. A combination of experimental and computational studies has been important for arriving at these conclusions, which seem to be applicable to the broad range of movements to which the cerebellum contributes.

Roles of Cerebellar Cortex and Nuclei in Motor Learning: Contradictions or Clues?

population of granule cells, whose activity is also influThe cerebellum, with its relatively simple and regular enced by the inhibitory Golgi cells. One numeric fact synaptic organization, has yielded much about its contriillustrates these dramatic differences in computing bution to brain function and its internal information propower; each nucleus cell receives around 10 mossy cessing. A central theme that has emerged is the cerefiber synapses (mf→nuc) and is influenced by 10 granbellum’s role in the adaptation or learning of movements. ule cell synapses onto Purkinje cells (gr→Pkj). Ideas about cerebellar-mediated motor learning began Early ideas about cerebellar-mediated motor learning in the 1960s, most notably with the seminal theory prowere based on thesenotable anatomicalcharacteristics. posed by Marr (1969). The basic tenets of this theory In 1969, Marr proposed a theory suggesting how plasticare supported by numerous studies. In particular, analyity in the cerebellar cortex at the gr→Pkj synapses could sis of two forms of motor learning, adaptation of the mediate motor learning. Three basic components of this vestibulo-ocular reflex (VOR) and Pavlovian eyelid contheory were: (i) the mossy fiber/granule cell system enditioning (EC), has revealed much about cerebellar concodes the contexts in which movements occur, with the tributions to motor learning and the cerebellar informaabundance of granule cells providing a rich representation processing involved. tion; (ii) climbing fibers signal that the movement conThe cerebellum is comprised of two anatomical comtrolled by its Purkinje cell should change, and (iii) these ponents, the cerebellar cortex and nuclei. Despite much climbing fiber inputs induce plasticity at coactive gr→Pkj progress, their relative contributions to motor learning synapses, improving subsequent movement perforremain a fundamentally important issue that is largely mance in the context encoded by that pattern of granule

Learning-Induced Plasticity in Deep Cerebellar Nucleus

Evidence that cerebellar learning involves more than one site of plasticity comes from, in part, pavlovian eyelid conditioning, where disconnecting the cerebellar cortex abolishes one component of learning, response timing, but spares the expression of abnormally timed short-latency responses (SLRs). Here, we provide evidence that SLRs unmasked by cerebellar cortex lesions are mediated by an associative form of learning-induced plasticity in the anterior interpositus nucleus (AIN) of the cerebellum. We used pharmacological inactivation and/or electrical microstimulation of various sites afferent and efferent to the AIN to systematically eliminate alternative candidate sites of plasticity upstream or downstream from this structure. Collectively, the results suggest that cerebellar learning is mediated in part by plasticity in target nuclei downstream of the cerebellar cortex. These data demonstrate an instance in which an aspect of associative learning, SLRs, can be used as an index of plasticity at a specific site in the brain.