Abstract
The cerebellum is the largest sensorimotor structure in the brain and is crucial for the regulation of movements. It is a key target of damage in many diseases, including chronic alcoholism, fetal alcohol syndrome, a range of genetic disorders, tumours and stroke. Cerebellar damage causes impairment in motor function characterized by ataxia, dysmetria of voluntary movements and an impaired ability to learn new motor skills. How the cerebellum exerts its influence to control movements remains an issue of considerable uncertainty and debate. Because Purkinje cells are the only output of the cerebellar cortex, and their main target is the cerebellar nuclei, the behavioural consequences of cerebellar cortical damage ultimately must result from the abnormal synaptic control of the cerebellar nuclei by altered Purkinje cell activity. Purkinje cells discharge two types of impulse: simple spikes and complex spikes. In pilot experiments we have found that complex spikes can be further subdivided into two distinct waveforms (?spiking? and ?non-spiking?), and the type of complex spike a Purkinje cell discharges at any given time can influence simple spike firing rate of the cell under study. A fundamental gap in our knowledge of cerebellar information processing is the effect of Purkinje cell activity on nuclear output. Using a range of systems level approaches in anaesthetized, decerebrate and awake behaving animals (rats and cats), our overarching aim is therefore to determine how ?spiking? and ?non-spiking? complex spike activity modifies activity in the cerebellar nuclei. Specifically, we will test the hypothesis that ?spiking? and ?non-spiking? complex spikes exert a distinct inhibitory impact on cerebellar output: (i) indirectly, by differentially altering levels of Purkinje cell simple spike activity; and (ii) directly, by transmitting different amounts of information themselves to shape cerebellar nuclear activity. Acute experiments will study mechanisms in detail while chronic recording experiments will study Purkinje cell-cerebellar nuclear interactions during performance of a reach-retrieval task, including motor adaptation. Overall, the results from this project will significantly advance our understanding of how complex spike activity is translated into activity in the cerebellar nuclei and the behavioural significance of this transform. This should lead to an improved understanding of how movement disorders resulting from cerebellar damage occur.