Neurocircuits that regulate circadian rhythms

项目摘要 虽然调节昼夜节律和能量动态平衡的系统紧密耦合在一起，但 将它们连接在一起的路径还没有被很好地理解。我们最近的发现发现了一部小说， 表达瘦素的下丘脑背内侧部分神经元的生理作用 在昼夜节律控制摄食、运动活动和相关代谢节律的受体。这个 这项建议的首要目标是确定将昼夜节律与DMH控制联系起来的神经回路 瘦素受体(Lepr)神经元及其相关的摄食和代谢反应。建议的目标寻求1) 表征DMH Lepr神经元活动的节律性；2)确定特定的 这些神经元的亚群在摄食行为、新陈代谢和运动的昼夜控制中，以及3) 确定DMH Lepr神经元的上游调节器，这些调节器调节摄食和代谢的昼夜控制。 为了实现这一目标，我们将整合先进的神经科学技术，包括体内纤维光度学， 病毒追踪和化学遗传技术，以及跨部门遗传学方法和 全面的啮齿动物代谢表型。共同努力，这项工作将从根本上提高我们的知识 在行为、进食和新陈代谢的内源性节律下的神经回路，可以 预期将促进制定治疗和预防肥胖症及相关疾病的新战略 人类的疾病。

Project Summary While the systems that regulate circadian rhythms and energy homeostasis are tightly coupled together, the pathways which connect them together are not well understood. Our recent findings have identified a novel, physiological role for a subset of neurons in the dorsomedial hypothalamus (DMH) that express the leptin receptor in the circadian control of feeding, locomotor activity and associated metabolic rhythms. The overarching goal of this proposal is to identify the neurocircuitry linking circadian rhythms to control of DMH leptin receptor (LepR) neurons and associated feeding and metabolic responses. Proposed aims seek to 1) characterize the rhythmicity of DMH LepR neuronal activity; 2) identify the contribution made by specific subsets of these neurons in the circadian control of feeding behavior, metabolism and locomotion, and 3) to identify upstream regulators of DMH LepR neurons that regulate circadian control of feeding and metabolism. To accomplish this, we will integrate advanced neuroscience techniques including in vivo fiber photometry, viral track tracing and chemogenetic techniques, along with an intersectional genetics approach and comprehensive rodent metabolic phenotyping. Together, this work will fundamentally advance our knowledge of the neural circuits underlying endogenous rhythms of behavior, feeding, and metabolism and can be expected to facilitate the development of new strategies for the treatment and prevention of obesity and related disorders in humans.