The roles of GABA receptor subunits in circadian rhythms in GABA responsiveness in the suprachiasmatic nucleus

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 DESCRIPTION (provided by applicant): Circadian clocks generate endogenous rhythms in nearly all behavior and physiology. Disruption of the entrainment of these clocks to the daily light-dark cycle contributes to a multitude of metabolic, psychiatric, and neurologic disorders. Understanding how the etiology of these disorders is produced by disruptions in entrainment will require understanding the neural mechanisms controlling entrainment in the master circadian clock, which is located in the suprachiasmatic nucleus (SCN). The overall goal of the proposed research is identify neural mechanisms underlying the entrainment of the SCN to the environmental light-dark cycle. Great progress has been made in understanding the translational and transcriptional feedback loops that comprise the molecular clock, yet the specific neurochemical signals that shift the clock during entrainment are not well understood. However, it is clear that GABA is one of these neurochemical signals critical to entrainment of the SCN. The effects of GABA on entrainment of the SCN are phase-specific, however the mechanism underlying this pattern of effects is not known. These studies will test the hypotheses that circadian oscillations in the expression and function between the GABAA2 synaptic receptor and the GABAA extrasynaptic receptor underlie the circadian phase-specific responses of the SCN to GABA during entrainment, and that these receptors differentially mediate induction of the clock gene Period in the SCN. On a larger scale, these studies will provide new information on GABA signaling and the interaction of GABAA receptor subtypes that may be relevant to the action of GABA throughout the CNS. Because many drugs that target the GABA system are used to treat diseases ranging from anxiety disorders to epilepsy, it is clinically important to understand how GABA acts in the brain. Additionally, the training that I will receive in completion of these studies will significantly accelerate my development as a scientist and springboard me to reach my goal as an independent investigator at a research-intensive university.