CELLULAR BASIS OF CIRCADIAN RHYTHMS IN MAMMALS

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DESCRIPTION (provided by applicant): The mammalian suprachiasmatic nucleus (SCN) is required for daily cycles in behavior and physiology. Some other brain regions, including the main olfactory bulb (OB), also express intrinsic circadian rhythms. It is not known how or which cells within these regions synchronize and sustain these rhythms or what role they play in behavior. The neuropeptide vasoactive intestinal polypeptide (VIP) is required for circadian synchrony in the SCN and is found in neurons of other circadian tissues. Little is known about how VIP mediates synchrony within the SCN or if it coordinates rhythms in other brain regions. The proposed studies directly address these issues by taking advantage of long-duration recording technologies--multielectrode arrays and bioluminescent reporters of gene activity--and the unique properties of mice with mutations in genes involved in circadian timekeeping or transgenes that allow conditional manipulation of gene expression and cell viability in specific cell types. Aim 1 tests the hypotheses that VIP entrains daily rhythms in variety of brain regions and cell types. The strategy is to compare VIP-induced changes in acute and circadian firing rate and gene expression patterns in real time of neurons and glia within 3 brain regions. In addition, the role of VIP in the OB and in olfaction will be assayed in vivo. Aim 2 tests the hypotheses that VIP neurons in the SCN are required to entrain and sustain circadian locomotor rhythms and that VIP neurons in the OB are required for rhythms in the OB and in olfactory behavior. This Aim also tests whether clock genes in VIP neurons are essential for their rhythmicity and for these rhythms in behavior. Aim 3 uses correlated firing and gene expression patterns and pharmacology to map functional connectivity and the relative roles of glutamate, nitric oxide and VIP in circadian synchrony within the SCN. The recent discoveries of putative circadian oscillators in many mammalian tissues have led to the hypothesis that the circadian system is hierarchically organized and that disruption of this coordination could underlie various neurological disorders including depression. These experiments will, for the first time, identify the mechanisms that coordinate ensemble daily rhythms in the brain and the distinct roles they play in behavior. Daily rhythms in behavior and mood are driven by circadian clocks in the brain. This project examines the role of specific neurons and signaling molecules in the circadian regulation of neural activity and gene expression in and between brain areas and in locomotor and sensory function.