Inhibitory feedback mechanisms that couple circadian clock neurons in mammals

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 DESCRIPTION (provided by applicant): Neuron ensembles display coordinated activity patterns that arise from feedback connections among the constituent neurons; however, the mechanisms that synchronize neural activity in time and space remain poorly understood. This is a fundamental gap in our understanding because neuronal synchronization is critical for normal brain function and its dysfunction is implicated in numerous neurological disorders (e.g., epilepsy, Parkinson's disease, schizophrenia). An excellent model system for studying the principles and mechanisms underlying neuronal synchronization is the suprachiasmatic nucleus (SCN). The SCN is a network of neuronal oscillators that programs circadian rhythms of behavior and physiology in mammals to ensure biological events occur at the appropriate time of day. As a population, SCN neurons display coordinated activity patterns that are integral to circadian clock function; however, the signaling mechanisms that regulate this process remain ill defined. One major obstacle barring progress on this front is the challenge of investigating neuronal interactions while the SCN network is in a functional state. To address this important issue, we have developed a novel analytical assay that quantifies the dynamic process by which SCN neurons interact using an ex vivo slice preparation. In the proposed studies, we will employ this analytical assay together with specific pharmacological tools and innovative genetic manipulations to investigate how different subclasses of SCN neurons interact to control circadian behavior. First, we will test the hypothesis that feedback within the SCN network is necessary for neuronal synchronization in vitro. Second, we will define the intracellular signaling mechanisms that mediate this feedback. Last, we will evaluate whether feedback in the SCN network is required for circadian rhythms in vivo. By defining the functional role of novel signaling pathways that modulate SCN function in vitro and in vivo, our work will significantly advance understanding of the circuit mechanisms that bind SCN neurons into a synchronized network. Greater insight into SCN circuitry is expected to help develop novel therapies to prevent and alleviate the adverse health consequences of disrupted clock function, such as sleep disorders.