Decoding brain circuit underlying metabolic regulation of sleep-wake behavior

项目总结/摘要 睡眠障碍和肥胖有着千丝万缕的联系-睡眠质量差和睡眠时间短会增加 肥胖的风险，而肥胖是慢性睡眠中断（CSD）的独立风险因素， 白天过度嗜睡（EDS）。尽管肥胖和肥胖之间存在着明显的双向和有害的联系， 和睡眠障碍，调节这种关联的神经基质在很大程度上仍然未知。我们的研究 该项目旨在确定将代谢改变与CSD和EDS联系起来的关键神经回路。我们的长期 目的是描绘睡眠-觉醒行为代谢调节的神经回路。我们有 最近发现，脂肪细胞衍生的代谢激素，瘦素，促进觉醒和化学发生， 下丘脑外侧区（LHA）中表达瘦素受体的GABA能神经元亚群的激活 （LepR）完全扰乱小鼠的睡眠。这项研究计划的总体目标是阐明瘦素如何 作用于关键的下丘脑神经元，影响正常的睡眠-觉醒周期。基于强大的初步数据， 中心假设是，循环中的瘦素作用于LHA LepR表达GABA能神经元的亚群， 通过投射到腹侧被盖区（VTA）和/或视前区来影响睡眠-觉醒行为 (POA)从而导致通常与肥胖相关的CSD和EDS。我们将测试我们的假设 通过追求以下两个具体目标：1）确定LHA是否是介导瘦素作用的关键位点， 睡眠-觉醒调节和2）确定瘦素是否参与LHA VTA和/或LHA VPOA回路来调节 睡眠-觉醒行为先进的神经科学技术将被用来回答这些问题， 包括Cre/loxP技术、光遗传学/化学遗传学、体内纤维光度学和电生理学 结合自由活动动物的EEG/EMG的慢性无线记录。拟议的研究是 意义重大，因为它不仅有望促进我们对下丘脑调节的理解， 睡眠-觉醒行为，但也揭示了很大程度上未知的机制，连接代谢紊乱， 睡眠-觉醒调节这项研究也是创新的，因为它利用了国家的组合， 艺术神经科学技术加上复杂的生理测量，以解决一个重要的 但在很大程度上研究不足的问题-什么是潜在的神经回路介导的CSD和EDS在 肥胖？这些知识可能最终导致开发一种新的战略，以有效地管理 与肥胖相关的睡眠问题。

Project Summary / Abstract Sleep disorders and obesity are inextricably linked – poor sleep quality and short sleep duration increase the risk of developing obesity, while obesity is an independent risk factor for chronic sleep disruption (CSD) and excessive daytime sleepiness (EDS). Despite a clear bidirectional and pernicious association between obesity and sleep disorders, the neural substrates mediating this association remain largely unknown. Our research program seeks to identify critical neural circuit linking metabolic alterations to CSD and EDS. Our long-term goal is to delineate the neural circuits underlying metabolic regulation of sleep-wake behavior. We have recently found that adipocyte-derived metabolic hormone, leptin, promotes wakefulness and chemogenetic activation of a subset of GABAergic neurons in the lateral hypothalamic area (LHA) expressing leptin receptor (LepR) completely disrupts sleep in mice. The overall objective of this research proposal is to clarify how leptin acts on key hypothalamic neurons to affect normal sleep-wake cycle. Build upon strong preliminary data, the central hypothesis is that circulating leptin acts on a subset of LHA LepR-expressing GABAergic neurons to affect sleep-wake behavior through their projections to the ventral tegmental area (VTA) and/or preoptic area (POA) and thereby contribute to CSD and EDS commonly associated with obesity. We will test our hypothesis by pursuing following two specific aims: 1) determine if the LHA is a key site mediating the action of leptin on sleep-wake regulation and 2) determine if leptin engages LHAVTA and/or LHAPOA circuits to regulate sleep-wake behavior. Advanced neuroscience techniques will be employed to answer these questions, including Cre/loxP technology, optogenetics/chemogenetics, in vivo fiber photometry, and electrophysiology coupled with chronic wireless recording of EEG/EMG in freely moving animals. The proposed research is significant because it is expected to not only advance and our understanding of hypothalamic regulation of sleep-wake behavior but also shed light on largely unknown mechanisms that connect metabolic disorders to sleep-wake regulation. The proposed research is also innovative because it utilizes a combination of state-of- art neuroscience techniques coupled with sophisticated physiological measurements to address an important yet largely under-investigated question – what are the underlying neural circuits mediating CSD and EDS in obesity? Such knowledge may ultimately lead to the development of a novel strategy to effectively manage sleep problems associated with obesity in human patients.