Cerebellar dysfunction explains the extinction-like abolition of conditioned eyeblinks after NBQX injections in the inferior olive.

Classical conditioning of the eyeblink response is a form of motor learning that is controlled by the intermediate cerebellum and related brainstem structures. The inferior olive (IO) is commonly thought to provide the cerebellum with a "teaching" unconditioned stimulus (US) signal required for cerebellar learning. Testing this concept has been difficult because the IO, in addition to its putative learning function, also controls tonic activity in the cerebellum. Previously, it was reported that inactivation of AMPA/kainate receptors in the IO produces extinction of conditioned responses (CRs), suggesting that it blocks the transmission of US signals without perturbing the functional state of the cerebellum. However, the electrophysiological support for this critical finding was lacking, mostly because of methodological difficulties in maintaining stable recordings from the same set of single units throughout long drug injection sessions in awake rabbits. To address this critical issue, we used our microwire-based multiple single-unit recording method. The IO in trained rabbits was injected with the AMPA/kainate receptor blocker, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), and its effects on CR expression and neuronal activity in the cerebellar interposed nuclei (IN) were examined. We found that NBQX abolished CR expression and that delayed drug effects were independent of the presentation of the conditioned stimulus and were therefore not related to extinction. In parallel to these behavioral effects, the spontaneous neuronal activity and CR-related neuronal responses in the IN were suppressed, suggesting cerebellar dysfunction. These findings indicate that testing the role of IO in learning requires methods that do not alter the functional state of the cerebellum.

On-line compensation for perturbations of a reaching movement is cerebellar dependent: support for the task dependency hypothesis.

Although the cerebellum has been shown to be critical for the acquisition and retention of adaptive modifications in certain reflex behaviors, this structure's role in the learning of motor skills required to execute complex voluntary goal-directed movements still is unclear. This study explores this issue by analyzing the effects of inactivating the interposed and dentate cerebellar nuclei on the adaptation required to compensate for an external elastic load applied during a reaching movement. We show that cats with these nuclei inactivated can adapt to predictable perturbations of the forelimb during a goal-directed reach by including a compensatory component in the motor plan prior to movement initiation. In contrast, when comparable compensatory modifications must be triggered on-line because the perturbations are applied in randomized trials (i.e., unpredictably), such adaptive responses cannot be executed or reacquired after the interposed and dentate nuclei are inactivated. These findings provide the first demonstration of the condition-dependent nature of the cerebellum's contribution to the learning of a specific volitional task.

Task-dependent role of the cerebellum in motor learning.

This chapter reviews several findings from our laboratory supporting the hypothesis that the cerebellum's role in motor learning is task-dependent. Namely, its contribution is dependent on the specific task being learned. Several studies are reviewed to demonstrate that the effect of temporary or permanent cerebellar lesions on a specific process such as storage varies depending on the behavior. Furthermore, this task-dependency is reflected also in the modulation of Purkinje cells and nuclear neurons recorded during the learning process. The behavioral correlates of this modulation are very paradigm specific. These observations support the above hypothesis and emphasize the importance of paradigm selection in designing experiments focused on elucidating the cerebellum's role in learning a specific motor behavior.