The importance of complex spikes in cerebellar contributions to behaviour.

The cerebellum is a major region of the brain vital for the coordination of movements. When in mammals (including humans) it is damaged ? e.g. due to stroke, genetic disorders, or tumours ? voluntary movements such as reaching to grasp an object become inaccurate and poorly timed; balance is severely disrupted; and our ability to learn new motor skills is impaired. How the internal circuitry of the cerebellum ensures that movements are performed smoothly and accurately remains unknown. Neurones called Purkinje cells are central to this function because they form the only output of the cerebellar cortex. They influence activity in the cerebellar nuclei, which, in turn, provide the output of the cerebellum, so the way in which cerebellar nuclear activity is modified by Purkinje cells is central to understanding how the cerebellum exerts its control over movement. Purkinje cells are exceptional in the mammalian brain in that they discharge two very different types of electrical impulse - simple spikes and complex spikes. The latter are thought to hold the key to cerebellar operation but their role in movement control remains a hotly debated issue. In pilot experiments we have found that complex spikes can be further categorized into two different types: spiking and non-spiking; and that the type of complex spike generated at any given time by a Purkinje cell has an effect on the on-going simple spike activity of the same cell. This has important implications for cerebellar information processing because the two types of complex spike are likely to produce distinct patterns of activity in the cerebellar nuclei, providing powerful timing signals that could underlie cerebellar contributions to coordinating movement. Using neuronal recording techniques we will determine how the two different types of complex spike: i) modify simple spike activity, and ii) influence cerebellar nuclear activity. One of the unique features of our experiments is that the neural recordings will include the natural activity patterns of complex spikes in action in animals performing a skilled reach-to-grasp movement under carefully controlled conditions. The results from this project will therefore shed light on fundamental brain processes underlying our ability to perform coordinated movements.

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.