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: 10387635
• 负责人: Chelsea Leigh Faber
• 金额: $ 6.6万
• 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/10387635
• 关键词: Circadian; Regulation; Dorsomedial; Hypothalamic; Nucleus

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 调节昼夜节律时间和能量稳态的系统是紧密结合的，越来越多的证据表明， 表明昼夜节律紊乱（例如，由睡眠限制或在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，更好地了解 进食时间的神经生物学决定因素直接影响人类健康， 治疗和饮食策略来对抗代谢功能障碍。 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 光暗周期，这种生物起搏器表达有节奏的神经元和分子活动， 并将时间线索传递到下游大脑区域和下属时钟，以调整它们的活动。但如何 SCN的节律性流出被解码，以调整不同的生理和行为过程，包括 饮食，知之甚少。在涉及摄食的SCN的下游靶点中，背内侧核是 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）对于巩固小鼠中适当光周期的喂养至关重要， DMHLepR神经元的失活促进了男性和女性的肥胖和光周期摄入的增加 小鼠我们的初步数据进一步表明DMHLepR神经元接受来自室旁下区的输入 (SPZ)，从SCN的昼夜节律定时的关键中继，并表现出昼夜变化的基础和食物诱发的 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神经元。 关于食物可用性的输入，以调节小鼠的每日喂养时间。作为了解 DMHLepR神经元的调节，我们建议首先确定和表征神经传入的组织学 和视紫红质辅助电路映射（CRACM）。接下来，我们将评估传入输入是否来自 SPZ从SCN传送时钟时间，是正常昼夜节律进食所必需的， 在小鼠体内的代谢。为了更好地了解DMHLepR活性如何调节摄食行为，我们将 通过体外和体内多单位表征该群体的时间活动动力学 电生理学方法。最后，我们将研究DMHLepR活性如何受到改变喂养的影响 和照明时间表，以及这些效果的SPZ输入要求。这项工作有望改善我们的 了解行为、进食和代谢中内源性节律的神经网络， 从而为治疗人类的新的治疗和饮食策略的开发提供信息 代谢紊乱