Project Summary/Abstract (unchanged from parent proposal) Premotor neurons of the cerebellar nuclei (CbN) are spontaneously active neurons that integrate excitatory and inhibitory input, largely from mossy fibers and Purkinje neurons, to generate the output of the cerebellum. The cerebellum facilitates coordinated movement and corrects errors in real time, and also changes to learn new motor patterns over time. These observations raise the question of how synaptic input modulates intrinsic firing in a manner that permits premotor CbN neurons to identify deviations from predicted sensory input and encode appropriate corrective outputs. We are studying the biophysical and synaptic mechanisms that constrain and define patterns of CbN cell firing in response to physiological patterns of synaptic input in vitro and expected or unexpected sensory input during motor behaviors in vivo. Recent work suggests that the degree of inhibitory synchrony from convergent Purkinje cells may dictate cerebellar output in mice in a condition-dependent manner. We will therefore study cerebellar physiology and behavior in mice and in larval zebrafish, to provide a comparative approach, both in vitro and in vivo. Purkinje and CbN cell firing patterns will be monitored both during well-learned, predictable motor behaviors, during unpredicted sensory inputs, and during motor learning such as habituation and associative conditioning. The observations will be related to synaptic studies of the interaction of excitatory with inhibitory inputs, convergence and connectivity, and short- term and long-term plasticity. Such linking of the biophysical and behavioral levels will help explain the mechanisms by which the cerebellar circuit produces adaptive responses to deviations from predictions, thereby facilitating well-executed movement.

Project Narrative (unchanged from parent proposal) The cerebellum receives sensory information, makes short-term predictions, and coordinates movements; its dysfunction can contribute to ataxia, dystonia, dyslexia, and autism spectrum disorders. The sensory input from the environment is received by Purkinje neurons in the cerebellum, which process and transmit it to neurons in the cerebellar nuclei, which further integrate the information with additional sensory signals and then send it to brain regions that control the timing and sequencing of behaviors. In the current application, we propose to study how neural signals are transformed as they are transmitted from Purkinje neurons to neurons in the cerebellar nuclei, and what aspects of signaling change under pathological conditions.