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.

项目概要 调节昼夜节律和能量稳态的系统紧密集成，并且越来越多的证据 表明昼夜节律紊乱（例如，由睡眠限制或正常休息期间进食引起） 易导致人类肥胖和代谢综合征。因此，加深了对 进食时间的神经生物学决定因素对人类健康有直接影响，并可能为新的研究提供信息 对抗代谢功能障碍的治疗和饮食策略。 在哺乳动物中，新陈代谢和行为的昼夜节律是由光控制的 “主时钟”位于下丘脑视交叉上核（SCN）。与环境和谐 光暗循环，这种生物起搏器表达有节律的神经元和分子活动，编码 并将时间线索传输到下游大脑区域和从属时钟以调整它们的活动。然而，如何 SCN 的节律性流出被解码以协调不同的生理和行为过程，包括 喂养，了解甚少。与摄食有关的 SCN 下游目标之一是背内侧 下丘脑核（DMH）。我们最近的研究结果表明，表达瘦素的 DMH 神经元的活性 受体（DMHLepR）对于小鼠巩固进食到适当的光周期至关重要，因此 DMHLepR 神经元失活会促进男性和女性肥胖并增加光周期摄入量 老鼠。我们的初步数据进一步表明 DMHLepR 神经元接收来自室旁区的输入 (SPZ)，SCN 昼夜节律的关键中继，并表现出基础和食物诱发的昼夜变化 活动。基于这些观察，我们假设 DMHLepR 神经元整合了时钟时间和感觉 有关食物供应的输入，以调节小鼠的每日进食时间。作为了解如何进行的第一步 DMHLepR 神经元受到调节，我们建议首先通过组织学来识别和表征神经传入 和视紫红质通道辅助电路测绘（CRACM）。接下来我们将评估传入输入是否来自 SPZ 假定从 SCN 传递时钟时间，是正常昼夜节律喂养所必需的 小鼠的新陈代谢。为了更好地了解 DMHLepR 活性如何调节进食行为，我们将 通过体外和体内多单元表征该群体的时间活动动态 电生理学方法。最后，我们将研究 DMHLepR 活性如何受到喂养改变的影响 和照明时间表，以及这些效果的 SPZ 输入要求。这项工作预计将改善我们的 了解行为、进食和新陈代谢的内源性节律背后的神经网络， 从而为人类治疗新的治疗和饮食策略的开发提供信息 伴有代谢功能障碍。