Tatsuya Ohyama

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.

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.

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.

Interactions between prefrontal cortex and cerebellum revealed by trace eyelid conditioning

Eyelid conditioning has proven useful for analysis of learning and computation in the cerebellum. Two variants, delay and trace conditioning, differ only by the relative timing of the training stimuli. Despite the subtlety of this difference, trace eyelid conditioning is prevented by lesions of the cerebellum, hippocampus, or medial prefrontal cortex (mPFC), whereas delay eyelid conditioning is prevented by cerebellar lesions and is largely unaffected by forebrain lesions. Here we test whether these lesion results can be explained by two assertions: (1) Cerebellar learning requires temporal overlap between the mossy fiber inputs activated by the tone conditioned stimulus (CS) and the climbing fiber inputs activated by the reinforcing unconditioned stimulus (US), and therefore (2) trace conditioning requires activity that outlasts the presentation of the CS in a subset of mossy fibers separate from those activated directly by the CS. By use of electrical stimulation of mossy fibers as a CS, we show that cerebellar learning during trace eyelid conditioning requires an input that persists during the stimulus-free trace interval. By use of reversible inactivation experiments, we provide evidence that this input arises from the mPFC and arrives at the cerebellum via a previously unidentified site in the pontine nuclei. In light of previous PFC recordings in various species, we suggest that trace eyelid conditioning involves an interaction between the persistent activity of delay cells in mPFC-a putative mechanism of working memory-and motor learning in the cerebellum.

Cerebellar cortex contributions to the expression and timing of conditioned eyelid responses.

We used micro-infusions during eyelid conditioning in rabbits to investigate the relative contributions of cerebellar cortex and the underlying deep nuclei (DCN) to the expression of cerebellar learning. These tests were conducted using two forms of cerebellum-dependent eyelid conditioning for which the relative roles of cerebellar cortex and DCN are controversial: delay conditioning, which is largely unaffected by forebrain lesions, and trace conditioning, which involves interactions between forebrain and cerebellum. For rabbits trained with delay conditioning, silencing cerebellar cortex by micro-infusions of the local anesthetic lidocaine unmasked stereotyped short-latency responses. This was also the case after extinction as observed previously with reversible blockade of cerebellar cortex output. Conversely, increasing cerebellar cortex activity by micro-infusions of the GABA(A) antagonist picrotoxin reversibly abolished conditioned responses. Effective cannula placements were clustered around the primary fissure and deeper in lobules hemispheric lobule IV (HIV) and hemispheric lobule V (HV) of anterior lobe. In well-trained trace conditioned rabbits, silencing this same area of cerebellar cortex or reversibly blocking cerebellar cortex output also unmasked short-latency responses. Because Purkinje cells are the sole output of cerebellar cortex, these results provide evidence that the expression of well-timed conditioned responses requires a well-timed decrease in the activity of Purkinje cells in anterior lobe. The parallels between results from delay and trace conditioning suggest similar contributions of plasticity in cerebellar cortex and DCN in both instances.

Temporal Patterns of Inputs to Cerebellum Necessary and Sufficient for Trace Eyelid Conditioning

Trace eyelid conditioning is a form of associative learning that requires several forebrain structures and cerebellum. Previous work suggests that at least two conditioned stimulus (CS)-driven signals are available to the cerebellum via mossy fiber inputs during trace conditioning: one driven by and terminating with the tone and a second driven by medial prefrontal cortex (mPFC) that persists through the stimulus-free trace interval to overlap in time with the unconditioned stimulus (US). We used electric stimulation of mossy fibers to determine whether this pattern of dual inputs is necessary and sufficient for cerebellar learning to express normal trace eyelid responses. We find that presenting the cerebellum with one input that mimics persistent activity observed in mPFC and the lateral pontine nuclei during trace eyelid conditioning and another that mimics tone-elicited mossy fiber activity is sufficient to produce responses whose properties quantitatively match trace eyelid responses using a tone. Probe trials with each input delivered separately provide evidence that the cerebellum learns to respond to the mPFC-like input (that overlaps with the US) and learns to suppress responding to the tone-like input (that does not). This contributes to precisely timed responses and the well-documented influence of tone offset on the timing of trace responses. Computer simulations suggest that the underlying cerebellar mechanisms involve activation of different subsets of granule cells during the tone and during the stimulus-free trace interval. These results indicate that tone-driven and mPFC-like inputs are necessary and sufficient for the cerebellum to learn well-timed trace conditioned responses.

A Subtraction Mechanism of Temporal Coding in Cerebellar Cortex

The temporally specific learning displayed by the cerebellum facilitates mechanistic analysis of neural timing and temporal coding. We report evidence for a subtraction-like mechanism of temporal coding in cerebellar cortex in which activity in a subset of granule cells specifically codes the interval between the offset of two mossy fiber inputs. In a large-scale cerebellar simulation, cessation of one of two ongoing mossy fiber inputs produces a robust temporal code in the population of granule cells. This activity supports simulation learning in response to temporal patterns of stimuli, even when those same stimuli do not support learning when presented individually. Using stimulation of mossy fiber inputs to the cerebellum as training stimuli in rabbits, we confirmed these unusual predictions in a cerebellum-dependent form of learning. Analysis of the simulations reveals a specific working hypothesis for this temporal subtraction process that involves interactions between granule cells and the inhibitory Golgi cells. The results suggest how feedforward inhibition, such as that present in the cerebellar cortex, can contribute to temporal coding.

Trying to understand the cerebellum well enough to build one.

Abstract: The development of an increasingly detailed computer simulation of the cerebellum is briefly described. Specific and relatively direct evaluation of the performance of this simulation is made possible by the straightforward way in which pavlovian eyelid conditioning engages the cerebellum. Inputs to the simulation are based on recordings of mossy fiber and climbing fiber responses to the stimuli used in eyelid conditioning, and the output of the simulation can be evaluated with respect to the extensively characterized behavioral properties of eyelid conditioning. Because construction of the simulation has been guided by a strong aversion to errors of commission, both failures and successes of the simulation have proven informative. The behavior of the simulation related to the inhibitory nucleo‐olivary feedback connection and spontaneous activity of climbing fibers is described. A prediction of the simulation concerning extinction is confirmed by experiment.

A decrementing form of plasticity apparent in cerebellar learning.

Long-term synaptic plasticity is believed to underlie the capacity for learning and memory. In the cerebellum, for example, long-term plasticity contributes to eyelid conditioning and to learning in eye movement systems. We report evidence for a decrementing form of cerebellar plasticity as revealed by the behavioral properties of eyelid conditioning in the rabbit. We find that conditioned eyelid responses exhibit within-session changes that recover by the next day. These changes, which increase with the interstimulus interval, involve decreases in conditioned response magnitude and likelihood as well as increases in latency to onset. Within-subject comparisons show that these changes differ in magnitude depending on the type of training, arguing against motor fatigue or changes in motor pathways downstream of the cerebellum. These phenomena are also observed when stimulation of mossy fibers substitutes for the conditioned stimulus, suggesting that changes take place within the cerebellum or in downstream efferent pathways. Together, these observations suggest a plasticity mechanism in the cerebellum that is induced during training sessions and fades within 23 h. To formalize this hypothesis more specifically, we show that incorporating a short-lasting potentiation at the granule cell to Purkinje cell synapses in a computer simulation of the cerebellum reproduces these behavioral effects. We propose the working hypothesis that the presynaptic form of long-term potentiation observed at these synapses is reversed by time rather than by a corresponding long-term depression. These results demonstrate the utility of eyelid conditioning as a means to identify and characterize the rules that govern input to output transformations in the cerebellum.