Circadian Regulation of the Dorsomedial Hypothalamic Nucleus and Its Impact on Energy Homeostasis

下丘脑背内侧核的昼夜节律调节及其对能量稳态的影响

• 批准号: 10551723
• 负责人: Chelsea Leigh Faber
• 金额: $ 6.95万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551723
• 关键词: Acceleration; American; Animals; Appetite Stimulants; Area; Behavior; Behavioral; Biological Pacemakers; Body Temperature; Body Weight decreased; Brain; COVID-19 complications; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Complications of Diabetes Mellitus; Consumption; Cues; Darkness; Data; Development; Diet; Diurnal Rhythm; Eating; Electrophysiology (science); Energy Intake; Energy Metabolism; Exhibits; Feedback; Feeding behaviors; Female; Food; Food Patterns; Gene Expression; Genetic Transcription; Health; Histology; Homeostasis; Human; Hypothalamic structure; In Vitro; Indirect Calorimetry; Intake; Light; Lighting; Link; Malignant Neoplasms; Mammals; Maps; Measurement; Metabolic; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modernization; Molecular; Motor Activity; Mus; Neurobiology; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peptides; Periodicals; Periodicity; Persons; Phase; Photoperiod; Physiological; Physiology; Play; Population Dynamics; Prevention; Process; Reporting; Rest; Role; Running; Schedule; Sensory; Signal Transduction; Sleep; Sleep Disorders; Sleep Wake Cycle; Societies; Structure of dorsomedial hypothalamic nucleus; Structure of nucleus infundibularis hypothalami; Synapses; System; Temperature; Testing; Time; Time-restricted feeding; Viral; Wakefulness; Work; cancer complication; circadian; circadian regulation; combat; combinatorial; dietary; disability; feeding; fitness; improved; in vivo; leptin receptor; lifestyle intervention; male; molecular clock; neural; neural network; neurobiological mechanism; novel therapeutics; obesity development; obesity treatment; response; sensory input; shift work; suprachiasmatic nucleus; translation to humans; transmission process; treatment strategy

PROJECT SUMMARY Systems regulating circadian timing and energy homeostasis are tightly integrated, and increasing evidence suggests that circadian disruption (e.g., induced by sleep restriction, or eating during the normal resting period) predisposes to obesity and metabolic syndrome in humans. Thus, an improved understanding of the neurobiological determinants of feeding time has direct translation to human health and may inform novel therapeutic and dietary strategies to combat metabolic dysfunction. In mammals, circadian rhythms of metabolism and behavior are organized by the light-controlled “master clock” located in the hypothalamic suprachiasmatic nucleus (SCN). In harmony with environmental light-dark cycles, this biological pacemaker expresses rhythmic neuronal and molecular activity that encodes and transmits time cues to downstream brain areas and subordinate clocks to align their activity. However, how rhythmic outflow from the SCN is decoded to align diverse physiological and behavioral processes, including feeding, is poorly understood. Among downstream targets of the SCN implicated in feeding is the dorsomedial hypothalamic nucleus (DMH). Our recent findings suggest that the activity of DMH neurons expressing the leptin receptor (DMHLepR) is critical for the consolidation of feeding to the appropriate photoperiod in mice, such that inactivation of DMHLepR neurons promotes obesity and increased light-cycle intake in both male and female mice. Our preliminary data further show that DMHLepR neurons receive input from the subparaventricular zone (SPZ), a critical relay of circadian timing from the SCN, and exhibit diurnal variation in basal and food-evoked activity. Based on these observations, we hypothesize that DMHLepR neurons integrate clock time and sensory inputs regarding food availability to regulate daily feeding time in mice. As a first step to understanding how DMHLepR neurons are regulated, we propose to first identify and characterize neural afferents by both histology and Channelrhodopsin-assisted circuit mapping (CRACM). We will next evaluate whether afferent input from the SPZ, which putatively conveys clock time from the SCN, is required for normal circadian feeding and metabolism in mice. To better understand how DMHLepR activity may regulate feeding behaviors, we will characterize the temporal activity dynamics of this population via both in vitro and in vivo multi-unit electrophysiology approaches. Finally, we will examine how DMHLepR activity is influenced by altered feeding and lighting schedules, and the requirement of SPZ input for these effects. This work is expected to improve our understanding of the neural networks underlying endogenous rhythms in behavior, feeding, and metabolism, and thereby inform the development of new therapeutic and dietary strategies for the treatment of humans with metabolic dysfunction.

项目摘要 制定昼夜节律时机和能量稳态的系统紧密整合，越来越多的证据 表明昼夜节律的破坏（例如，由睡眠限制或在正常休息期间进食） 人类肥胖和代谢综合征的易感性。这是对 喂养时间的神经生物学决定者直接转化为人类健康，并可能为新颖 打击代谢功能障碍的治疗和饮食策略。 在哺乳动物中，光照控制 位于下丘脑上型核（SCN）中的“主时钟”。与环境和谐 浅黑暗循环，这个生物起搏器表达了编码的节奏神经元和分子活性 并将时间提示传输到下游大脑区域并下属时钟以对齐其活动。但是，如何 SCN的节奏插座被解码为对齐潜水员的生理和行为过程，包括 喂食，知之甚少。在喂养中实施的SCN的下游目标之一是背部 下丘脑核（DMH）。我们最近的发现表明表达瘦素的DMH神经元的活性 受体（DMHLEPR）对于在小鼠中添加给适当的光周期的喂养至关重要，这样 DMHLEPR神经元的失活促进肥胖和女性的光周期摄入量增加 老鼠。我们的初步数据进一步表明，DMHLEPR神经元接收到从室内区域的输入 （SPZ），SCN的昼夜节律时间的关键继电器，以及基本和食物诱发的昼夜变化 活动。基于这些观察结果，我们假设DMHLEPR神经元整合了时钟时间和感觉 有关食物可用性的输入，以调节小鼠的日常喂养时间。作为了解如何理解如何 调节DMHLEPR神经元，我们建议首先通过两种组织学识别和表征神经元传入 和通道Ropopsin辅助电路映射（CRACM）。接下来，我们将评估是否来自 正常的昼夜节律喂养和 小鼠的代谢。为了更好地了解DMHLEPR活动如何调节喂养行为，我们将 通过体外和体内多单元来表征该人群的临时活动动态 电生理方法。最后，我们将研究DMHLEPR活动如何受喂养改变的影响 和照明时间表，以及SPZ输入对这些效果的要求。这项工作有望改善我们的 了解行为，喂养和代谢中内源性节奏的神经网络， 从而为治疗人类的新治疗和饮食策略的发展提供了信息 具有代谢功能障碍。