Project Summary Accumulating evidence supports the involvement of circadian rhythm dysfunction in bipolar disorder (BD). There is currently a critical need for identifying the neuropathological correlates of circadian dysfunction in human subjects with BD, and linking these correlates to functional consequences. We focus on the suprachiasmatic nucleus (SCN), the master clock of mammalian organisms, and its major output area the paraventricular nucleus (PVN), a region critically involved in the regulation of stress and anxiety. Our preliminary data showing decreased expression of somatostatin and the clock protein period 2 in the SCN indicate impaired SCN molecular clock rhythms in BD. Furthermore, decreased period 2 along with increased expression of the stress signaling molecule corticotropin releasing factor in the PVN during the morning in subjects with bipolar disorder suggests that weaker SCN rhythms impact downstream stress signaling, coinciding with the established increase in severity of anxiety and depression and increased cortisol at this time of day. Studies in nocturnal rodents have provided insight into how the SCN and PVN are involved in regulating stress and mood, suggesting that disrupted SCN molecular clock rhythms can alter expression rhythms of clock molecules and stress response molecules in regions involved in mood regulation. Our preliminary evidence suggesting weakened molecular clock rhythms in the SCN of subjects with BD supports this hypothesis. There is currently a lack of information regarding the cell specific expression rhythms of neuropeptides and clock molecules, and their association with stress response molecules in these regions in humans. The proposed studies will establish the foundation necessary to test our overarching hypothesis that altered molecular clock rhythms in the SCN in BD are associated with altered clock rhythms and increased expression of stress response molecules in downstream regions involved in stress response and mood regulation. We will test the hypotheses that i) expression of clock molecules, neuropeptides, and corticotropin releasing factor follow diurnal rhythms of expression in the human SCN and PVN ii) SCN and PVN molecular rhythms are disrupted in subjects with BD, associated with altered expression of molecules implicated in genome wide association studies.