Circadian Clock of the Paraventricular Nucleus

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DESCRIPTION (provided by applicant): We now know that mammals have multiple circadian clocks. In addition to the clock in the suprachiasmatic nucleus (SCN), known to regulate daily behavioral activity, mammals have clocks at a number of discrete sites in the central nervous system and in peripheral tissues. In contrast to the SCN clock, little is yet known regarding the importance of circadian clocks outside the SCN. This issue is of importance for our understanding of mammalian physiology. The hypothalamic paraventricular nucleus (PVN) has recently been identified as the site of a circadian clock. The PVN is known to play a vital role in central, endocrine, and autonomic physiological processes, particularly those regulating feeding behavior, energy balance, and glucose homeostasis. As a target of synaptic projections from the SCN, the PVN has been viewed as a passive element within a multi-synaptic pathway by which the SCN confers circadian regulation on endocrine and autonomic signals to viscera. This traditional view is challenged by the demonstration of circadian clocks in the PVN itself and in endocrine glands and visceral organs. The presence of a circadian clock within the PVN raises the possibility that the known functions of the PVN in regulating feeding behavior, energy balance, and glucose homeostasis depend on its intrinsic clock. The general objective of this proposal is to test the hypothesis that the intrinsic circadian clock of the PVN plays a role in the regulation of energy metabolism and/or feeding behavior. Using mouse lines that we have in hand, our experimental strategy will be to generate 1) mice lacking circadian clock function in the PVN but retaining it elsewhere and 2) mice retaining circadian clock function only in the PVN. The specific aims are: 1) to determine if circadian clock function in the PVN is important for regulation of energy balance, glucose homeostasis, and/or feeding behavior; and 2) to determine if the circadian clock in the PVN is sufficient to drive detectable circadian rhythms of feeding behavior or locomotor energy expenditure. PUBLIC HEALTH RELEVANCE Diabetes and obesity are global health hazards, and in recent years there has been a growing realization that these two related conditions are in large part disorders of brain function. The goal of the investigations proposed is to provide new insights into brain and hormonal mechanisms controlling feeding behavior, bodyweight, and blood glucose. Ultimately, the work proposed here could lead to the development of new treatments for diabetes and obesity.