Circadian Clock of the Paraventricular Nucleus

描述(申请人提供)：我们现在知道哺乳动物有多个生物钟。除了已知调节日常行为活动的视交叉上核(SCN)中的时钟外，哺乳动物在中枢神经系统和外周组织中的一些离散位置也有时钟。与SCN时钟不同的是，关于SCN以外的生物钟的重要性还知之甚少。这一问题对我们理解哺乳动物生理学具有重要意义。下丘脑室旁核(PVN)最近被认为是生物钟的位置。众所周知，PVN在中枢、内分泌和自主神经生理过程中发挥着重要作用，特别是那些调节摄食行为、能量平衡和葡萄糖平衡的生理过程。作为SCN突触投射的靶点，PVN一直被视为多突触通路中的被动元件，SCN通过该通路对内分泌和内脏自主神经信号进行昼夜调节。这一传统观点受到了PVN本身以及内分泌腺和内脏器官中昼夜节律的证明的挑战。PVN内生物钟的存在增加了PVN调节摄食行为、能量平衡和葡萄糖动态平衡的已知功能依赖于其内在时钟的可能性。这一建议的总体目标是检验这样一个假设，即室旁核的内在生物钟在能量代谢和/或摄食行为的调节中发挥作用。利用我们手中的小鼠系列，我们的实验策略将是1)在PVN中缺乏生物钟功能但在其他地方保留它的小鼠，以及2)只在PVN中保留生物钟功能的小鼠。其具体目的是：1)确定PVN中的生物钟功能是否对能量平衡、葡萄糖稳态和/或摄食行为的调节至关重要；以及2)确定PVN中的生物钟是否足以驱动可检测到的摄食行为或运动能量消耗的昼夜节律。糖尿病和肥胖是全球性的健康危害，近年来人们越来越认识到这两种相关疾病在很大程度上是大脑功能障碍。这些研究的目的是为大脑和荷尔蒙控制摄食行为、体重和血糖的机制提供新的见解。最终，这里提出的工作可能会导致糖尿病和肥胖症的新疗法的开发。

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.