This project will continue to investigate how neurochemical signals interact within the suprachiasmatic nucleus of the hypothalamus (SCN) to synchronize circadian rhythms in behavior with the day-night cycle. Since disorders of the circadian timing system have been linked to a variety of mental illnesses, understanding the neurobiology of circadian rhythms should lead to the development of new treatments for these disorders. At least three different afferent projection of the SCN are involved in the photic entrainment of circadian rhythms. The retinohypothalamic tract is a direct projection from the retina that is necessary and sufficient for entrainment to photic stimuli. Projections from the raphe and the intergeniculate leaflet to the SCN also influence photic entrainment. In addition, there is evidence that these projections may mediate the phase shifting effects of nonphotic stimuli. The long-term goal of this project is to define the neurochemical basis of the entrainment of circadian rhythms by defining how photic and nonphotic information is communicated to and processed within the SCN. During the next four years we will test the working hypothesis that GABA released within the SCN modulates the capacity of the circadian pacemaker to phase shift at different phases of the circadian cycle. More specifically, we propose that during the day GABA mediates the phase shifts produced by any stimulus (e.g., NPY or 5-HT) by its direct actions on clock cells. During the night, GABA mediates the ability of any stimulus (NPY or 5-HT) to inhibit light-induced phase shifts by its direct action on clock cells. Further, we will also test the hypothesis that GABA regulates the mRNA levels of two clock genes (i.e., Per1 and Per2) that have been hypothesized to regulate phase shifts of circadian rhythms. Existing evidence indicates that Per1 and Per2 mRNA levels are reduced by phase shifting stimuli during the day and increased by light during the night. We therefore propose that GABA released during the day or during the night will reduce Per1 and Per2 mRNA levels.
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