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

项目总结 调节昼夜节律和能量平衡的系统紧密结合在一起，越来越多的证据表明 提示昼夜节律紊乱(例如，由睡眠限制或在正常休息期间进食引起) 易患肥胖症和代谢综合征。因此，更好地理解 摄食时间的神经生物学决定因素对人类健康有直接的影响，并可能为小说 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 “主钟”位于下丘脑视交叉上核(SCN)。与环境和谐相处 这种生物起搏器表达有节奏的神经元和分子活动，编码 并将时间提示传输到下游的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对齐不同的生理和行为过程，包括 觅食，人们对此知之甚少。与摄食有关的SCN下游靶点之一是背内侧 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)对于巩固小鼠摄食到适当的光周期至关重要，从而 DMHLepR神经元失活促进男性和女性肥胖和光周期摄入量增加 老鼠。我们的初步数据进一步表明，DMHLepR神经元接受来自室旁区的输入 (SPZ)，是来自SCN的昼夜节律的关键继电器，在基础和食物诱发的时间上表现出日变化 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 关于食物可获得性的投入，以调节小鼠的每日进食时间。作为了解如何 DMHLepR神经元是受调控的，我们建议首先通过两种组织学来识别和表征神经传入 和通道视紫红质辅助电路标测(CRACM)。接下来我们将评估传入的输入是否来自 据推测，SPZ从SCN传递时钟时间，是正常昼夜摄食所必需的，并且 小鼠的新陈代谢。为了更好地了解DMHLepR活性如何调节摄食行为，我们将 通过体外和体内多个单位表征这一群体的时间活动动态 电生理学方法。最后，我们将研究改变喂养对DMHLepR活性的影响 和照明时间表，以及这些效果对SPZ输入的要求。这项工作有望提高我们的 了解行为、摄食和新陈代谢的内源性节律背后的神经网络， 从而为人类治疗的新的治疗和饮食策略的发展提供了信息 有代谢功能障碍。

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.