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Cerebellar Function in the Formation of Motor Memories

Christopher H. Yeo
Dept. Anatomy and Developmental Biology, UCL, London , UK

Eyeblink conditioning is a simple form of motor learning that is especially dependent upon the cerebellum in rabbits. Reversible inactivations of cerebellar circuitry have revealed that normal activity in the cerebellar cortex, cerebellar nuclei and inferior olive is necessary for the acquisition of eyeblink conditioning but activity in the cerebellar output pathways is not. So some essential aspects of this motor memory must be stored within cerebellar circuitry. Because each olivo-cortico-nuclear module contains an inhibitory feedback pathway from the nucleus to the olive, reversible inactivations of the olive, cortex or nuclei during eyeblink conditioning training are all equivalent in preventing acquisition because each treatment disturbs function at all nodes in the module. Thus the encoding and storage of this motor memory might be at any or all of the nodes.

Post-training inactivations can disrupt memory consolidation processes and they have dissociated cortical and nuclear functions. Cortical inactivations prevent consolidation of eyeblink conditioning but nuclear inactivations do not, consistent with the suggestion there is memory storage within the cerebellar cortex, though additional memory storage within the nuclei is not ruled out. Cortical inactivations made at different delays after conditioning indicate a time window for the cortical consolidation processes that begin around 1 hour after conditioning and that are nearly complete within 2 hours.

Learning-related changes in gene expression can also give clues to the location and mechanisms of memory storage. There is a significant upregulation of G-substrate (GS) expression in cerebellar cortical lobule HVI during eyeblink/NM conditioning in rabbits. GS is a Purkinje cell specific substrate for PKG and its upregulation suggests an activation of the NO-PKG-GS signalling pathway in conditioning. This pathway is known to be important in parallel fibre LTD and cortical infusions of a PKG inhibitor impair eyeblink NMR conditioning, indicating that LTD and this conditioning may share common mechanisms.

The implications of these findings for models of motor memory formation in the cerebellum will be discussed.