Regulation of arousal state by the suprachiasmatic clock

视交叉上时钟对唤醒状态的调节

• 批准号: 10624379
• 负责人: Patrick M Fuller
• 金额: $ 42.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624379
• 关键词: Acute; Alzheimer' s Disease; Anatomy; Animals; Arousal; Attenuated; Behavioral; Brain; Cell Nucleus; Cells; Coupled; Data; Dependence; Disease; Electroencephalography; Exhibits; Fatigue; Functional disorder; Galanin; Genetic Transcription; Goals; Health; Heterogeneity; Human; Hypersomnias; Hypothalamic structure; Image; Individual; Intervention; Knowledge; Link; Mammals; Maps; Medial Dorsal Nucleus; Mental Depression; Mission; Molecular; Molecular Profiling; Neurodegenerative Disorders; Neurons; Outcome; Patients; Pharmaceutical Preparations; Physiological; Physiology; Population; Public Health; Rabies; Regulation; Research; Role; Site; Sleep; Source; Surface; Synapses; Testing; Time; United States National Institutes of Health; Wakefulness; Work; base; burden of illness; cell type; circadian; circadian pacemaker; clinical development; cognitive performance; disability; experience; improved; in vivo; innovation; nervous system disorder; neural circuit; neuropsychiatric disorder; novel; optogenetics; pharmacologic; postsynaptic; preoptic nucleus; pressure; presynaptic; prevent; receptor; single nucleus RNA-sequencing; suprachiasmatic nucleus; therapy development; transcriptome; virtual

Project Summary There is a fundamental gap in understanding the circuit, cellular and synaptic bases by which the circadian pacemaker, located in the hypothalamic suprachiasmatic nucleus (SCN) of mammals, regulates brain arousal. This knowledge gap is an important problem because it not only reduces our ability to treat arousal disorders, such as hypersomnia and fatigue, but also impacts treatment and deeper understanding of many neuropsychiatric, neurodegenerative and neurological disorders that often include severe arousal disruption, including depression and Alzheimer's disease. Our long-term goal is to understand the anatomic, cellular and synaptic outflow bases by which the SCN regulates brain arousal. The objectives of this application are to 1) determine if Neuromedin S-producing SCN (SCNNMS) neurons promote arousal, 2) define their state-dependent firing profile in vivo; 3) establish a functional tri-synaptic circuit spanning SCNNMS->dorsomedial hypothalamus (DMH)->ventrolateral preoptic nucleus (VLPO), 4) define the functional synaptic physiology of the DMH->VLPO interface, including the cellular profile of the targeted neurons, 5) determine presynaptic inputs to SCNNMS neurons, and 6) define the molecular/transcriptional landscape of SCNNMS neurons. The central hypothesis is that SCNNMS neuron are both necessary and sufficient for clock regulation of arousal levels. The rationale for the proposed research is that identifying the anatomic, cellular and synaptic bases by which the SCN can modulate arousal levels is a critical first step towards manipulating them and reducing the dysfunction experienced by individuals with disorders of arousal. Guided by strong preliminary data, this hypothesis will be tested by pursuing four specific aims: 1) Determine in vivo if acute activation/inhibition of SCNNMS neurons can promote/attenuate arousal, respectively, and, via in vivo Ca+2 imaging, if they exhibit a wake-active profile; 2) Demonstrate that SCNNMS neurons are functionally, synaptically connected with sleep-promoting VLPO neurons via a DMH `relay'; 3) Determine the sources of presynaptic inputs to SCNNMS neurons and confirm functional connectivity; and 4) Determine molecular heterogeneity within the SCNNMS cell population. The approach is intellectually and technically innovative because it seeks to reveal the mechanistic basis by which the SCN regulates brain arousal and because it employs a novel combination of newly developed and validated approaches. The proposed research is significant, because it is expected to vertically advance and expand understanding of the cellular and synaptic mechanisms subserving the SCN clock. Ultimately, such knowledge has the potential to inform the development of treatments to reduce the dysfunction and negative health effects experienced by not only the growing number of patients with circadian- and arousal-based disorders, such as hypersomnia and fatigue, but also of those suffering one of the host of neuropsychiatric, neurodegenerative and neurological disorders with severe arousal disruption, such as depression or Alzheimer's disease, including many in which a clock contribution has been implicated or demonstrated.

项目摘要 在理解昼夜节律的电路、细胞和突触基础方面存在着根本性的差距。 位于哺乳动物下丘脑视交叉上核（SCN）的起搏器调节脑唤醒。 这种知识差距是一个重要的问题，因为它不仅降低了我们治疗唤醒障碍的能力， 如嗜睡和疲劳，但也影响治疗和更深入地了解许多 神经精神、神经变性和神经系统疾病，通常包括严重的唤醒中断， 包括抑郁症和老年痴呆症我们的长期目标是了解解剖，细胞和 突触流出基地，通过它SCN调节大脑唤醒。本申请的目的是1） 确定神经介肽S产生SCN（SCNNMS）神经元是否促进唤醒，2）定义它们的状态依赖性 3）建立一个跨越SCNNMS->背内侧下丘脑的功能性三突触回路 （DMH）->腹外侧视前核（VLPO），4）定义DMH->VLPO的功能性突触生理学 接口，包括靶神经元的细胞概况，5）确定对SCNNMS的突触前输入 神经元，和6）定义SCNNMS神经元的分子/转录景观。核心假设是 SCNNMS神经元对于唤醒水平时钟调节是必要的和充分的。的理由 建议的研究是，确定SCN的解剖，细胞和突触基础， 调节唤醒水平是控制它们和减少功能障碍的关键的第一步 都是由性唤起障碍的人所经历的在强有力的初步数据的指导下，这一假设将是 通过追求四个具体目标进行测试：1）在体内确定SCNNMS神经元的急性激活/抑制是否可以 分别促进/减弱唤醒，并且如果它们表现出唤醒活性曲线，则通过体内Ca+2成像; 2） 证明SCNNMS神经元在功能上与促进睡眠的VLPO突触连接 3）确定SCNNMS神经元的突触前输入来源，并确认 功能连接性;和4）确定SCNNMS细胞群内的分子异质性。的 方法是智力和技术创新，因为它试图揭示的机械基础， SCN调节大脑唤醒，因为它采用了新开发的新组合， 有效的方法。拟议的研究是重要的，因为它预计将垂直推进， 扩展对SCN时钟的细胞和突触机制的理解。最终，这样的 知识有可能为治疗的发展提供信息，以减少功能障碍和负面影响。 不仅越来越多的基于昼夜节律和觉醒的患者经历了健康影响， 疾病，如嗜睡和疲劳，但也有那些患有主机之一的神经精神， 神经退行性和神经系统疾病，伴有严重的唤醒中断，如抑郁症或 阿尔茨海默氏病，包括许多与生物钟有关或已被证明的疾病。