Hypocretinergic integration of circadian rhythms and sleep

昼夜节律和睡眠的低泌尿素整合

• 批准号: 9386665
• 负责人: JEFFREY R JONES
• 金额: $ 5.71万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386665
• 关键词: Action Potentials; Anatomy; Anxiety; Arousal; Behavior; Biology; Brain; Calcium; Cerebrospinal Fluid; Circadian Dysregulation; Circadian Rhythms; Collection; Complex; Development; Disease; Exhibits; FOS gene; Fire - disasters; Functional disorder; Genes; Health; Histology; Human; Hypothalamic structure; Image; Investigation; Lateral; Lead; Lesion; Link; Measures; Mental Depression; Mental Health; Mentors; Molecular; Mood Disorders; Narcolepsy; Neurons; Neurosciences; Pacemakers; Periodicity; Physiology; Polysomnography; Process; Psyche structure; Research; Role; Sleep; Sleep Disorders; System; Testing; Transcript; Viral; Wakefulness; Work; behavior influence; circadian pacemaker; hypocretin; improved; in vivo calcium imaging; insight; neuromechanism; novel; optogenetics; pressure; public health relevance; receptor; relating to nervous system; shift work; suprachiasmatic nucleus

 DESCRIPTION (provided by applicant): Circadian (~24 hr) rhythms influence nearly all aspects of behavior and physiology. Disrupted circadian rhythms contribute to a wide range of human health conditions including sleep disorders such as shift work disorder and affective disorders such as anxiety and depression. However, understanding how circadian rhythms control or influence behavior remains a fundamental problem in neuroscience. While most neurons in the brain contain a "molecular clock", overt circadian rhythms are orchestrated by the master pacemaker, the suprachiasmatic nucleus (SCN). Neurons of the SCN rhythmically fire action potentials and, together as a network, communicate circadian information to other circuits responsible for complex behaviors, perhaps the most obvious of which is sleep. Theoretical work has suggested that circadian drive for sleep (Process C) and homeostatic sleep pressure (Process S) follow distinct, albeit interconnected oscillations. A proposed mechanistic link between these processes lies in the hypocretin/orexin (Hcrt) system, a collection of neurons in the lateral hypothalamus that is essential for the stability of arousal. The loss of Hcrt or its receptors is associated with the disorder narcolepsy, which is characterized by the intrusion of sleep into wakefulness, and the optogenetic stimulation of Hcrt neurons directly promotes sleep-to-wake transitions. Importantly, Hcrt neuron activity (as read out by c-Fos), Hcrt transcript levels, and levels of Hcrt in the cerebrospinal fluid exhibit circadian rhythmicity. As circadian clock genes are ubiquitous throughout the brain and have been shown to influence neural activity and behavior outside the SCN, an intriguing possibility is that the molecular clock within Hcrt neurons regulates their activity independent of, or in concurrence with, input from the SCN. Thus, I hypothesize that SCN neural activity and the molecular clock within Hcrt neurons synergistically exert circadian control over Hcrt neural activity and sleep/wake behavior. To test this hypothesis, I will investigate the link between circadian rhythms, Hcrt neural activity, and sleep using a unique strategy that combines optogenetic manipulation of SCN activity, Hcrt neuron-specific molecular clock disruption, in vivo calcium imaging of Hcrt activity, and polysomnographic recording of sleep state. This proposal will provide novel insight into not only the essential relationship between circadian rhythms and arousal, but also the general neuroscience question of defining the neural mechanisms of complex behaviors that, when disrupted, can cause mental disease. To understand how the dysregulation of circadian rhythms may lead to illnesses such as sleep and affective disorders, it is first necessary to understand how they work in a healthy brain. Thus, this research plan will ultimately improve our understanding of the interplay of vital circadian and sleep circuits whose dysfunction can negatively impact human health.

 描述（由申请人提供）：昼夜节律（约 24 小时）影响行为和生理学的几乎所有方面。昼夜节律紊乱会导致多种人类健康状况，包括睡眠障碍（如轮班工作障碍）和情感障碍（如焦虑和抑郁）。然而，了解昼夜节律如何控制或影响行为仍然是神经科学中的一个基本问题，尽管大脑中的大多数神经元都包含“分子时钟”，但明显的昼夜节律是。由主起搏器、视交叉上核 (SCN) 精心策划，视交叉上核神经元有节奏地激发动作电位，并作为一个网络，将昼夜节律信息传递给负责复杂行为的其他回路，其中最明显的可能是睡眠。研究表明，睡眠的昼夜节律驱动（过程 C）和稳态睡眠压力（过程 S）遵循不同但相互关联的振荡，这些过程之间存在机械联系。下丘脑分泌素/食欲素 (Hcrt) 系统是下丘脑外侧神经元的集合，对觉醒的稳定性至关重要。Hcrt 或其受体的丧失与发作性睡病有关，其特征是睡眠侵入清醒状态。 Hcrt 神经元的光遗传学刺激直接促进睡眠到觉醒的转变。重要的是，Hcrt 神经元活动（由 c-Fos 读出），Hcrt。脑脊液中的转录物水平和 Hcrt 水平表现出昼夜节律性，因为生物钟基因在整个大脑中普遍存在，并且已被证明会影响 SCN 之外的神经活动和行为，因此一个有趣的可能性是，生物钟基因也存在于 SCN 内。 Hcrt 神经元的活动独立于 SCN 的输入，或与 SCN 的输入同时进行。因此，我研究了 SCN 神经活动和 Hcrt 神经元内的分子时钟对 Hcrt 神经活动和睡眠/觉醒行为的昼夜节律协同控制。假设，我将使用一种独特的策略来研究昼夜节律、Hcrt 神经活动和睡眠之间的联系，该策略结合了 SCN 活动的光遗传学操作、Hcrt 神经元特异性分子时钟该提案不仅将为昼夜节律与觉醒之间的基本关系提供新的见解，而且还将为定义复杂行为的神经机制的一般神经科学问题提供新的见解。当昼夜节律失调时，可能会导致精神疾病。要了解昼夜节律失调如何导致睡眠和情感障碍等疾病，首先有必要了解它们如何在健康的大脑中发挥作用。因此，这项研究计划最终将实现这一目标。提高我们对重要昼夜节律和睡眠回路相互作用的理解，这些回路的功能障碍会对人类健康产生负面影响。