Dissection of a novel inhibitory hypothalamic arousal circuit

新型抑制性下丘脑唤醒回路的剖析

• 批准号: 9904769
• 负责人: Patrick M Fuller
• 金额: $ 37.84万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904769
• 关键词: Ally; Alzheimer' s Disease; Anatomy; Animals; Arousal; Behavioral; Brain; Cardiovascular Diseases; Cellular Neurobiology; Cognition; Coupled; Data; Development; Disease; Dissection; Drowsiness; Functional disorder; Galanin; Genes; Genetic; Goals; Health; Human; Hypothalamic structure; In Vitro; Individual; Intervention; Knowledge; Laboratories; Lateral; Lead; Lesion; Link; Mental Depression; Mission; Molecular; Mus; Neurobiology; Neurodegenerative Disorders; Neurons; Outcome; Paper; Patients; Pharmacology; Physiological; Physiology; Play; Population; Post-Traumatic Stress Disorders; Preoptic Areas; Public Health; Publishing; Rabies; Regulation; Research; Role; Scientist; Site; Sleep; Sleeplessness; Source; Synapses; Testing; United States National Institutes of Health; Wakefulness; Work; base; burden of illness; cellular targeting; disability; experience; experimental study; improved; in vivo; innovation; insight; neural circuit; neuropsychiatric disorder; non rapid eye movement; novel; postsynaptic neurons; preoptic nucleus; role model; sleep regulation; therapeutic development

Project Summary/Abstract Recent work by our laboratory has identified a delimited node of VGAT+ (GABAergic) neurons in the ventral lateral hypothalamus (LHVGAT) that are both necessary and sufficient for normal behavioral and electroen- cephalographic (EEG) wakefulness. There is a fundamental gap however in understanding the cellular and synaptic circuit basis by which LHVGAT neurons trigger waking. The long-term goal is to understand the func- tional circuit basis by which LHVGAT neurons generate and regulate behavioral and EEG arousal. The objective in this particular application is to extend our previous findings by defining the functional, synaptic “neurocircuit” basis by which LHVGAT neurons trigger wakefulness. The central hypothesis is that LHVGAT neurons promote wake and fast EEG rhythms through direct inhibition of the sleep-active ventrolateral preoptic (VLPO) nucleus, located within the greater preoptic area. The rationale for the proposed research is that identifying the circuit basis by which LHVGAT neurons promote waking represents a critical first step towards manipulating them and reducing the dysfunction experienced by individuals with arousal-based disorders, including hyperarousal- driven insomnia. Guided by strong preliminary data, our hypotheses will be tested by pursuing three specific aims: 1) determine if LHVGAT neurons promote arousal through direct inhibition of sleep-promoting VLPO neu- rons; 2) define the functional synaptic physiology of the LHVGAT–VLPO interface, including the cellular profile of the targeted neurons; and 3) determine synaptic inputs to the LHVGAT and establish a functional tri-synaptic cir- cuit spanning inputLHVGATVLPO. The approach is intellectually and technically innovative because it rep- resents a new and substantive departure from contemporary models of the role of LH neurons in wake-sleep regulation and because it employs a novel combination of newly developed and validated approaches, includ- ing complimentary in vivo and in vitro opto-genetic based experiments. The proposed research is significant because it is expected to vertically advance and expand understanding of the cellular and circuit (synaptic) mechanisms underlying LHVGAT regulation of wakefulness and fast cortical rhythms associated with cognition. Ultimately, such knowledge has the potential to inform the development of therapeutic and interventional strat- egies to reduce the dysfunction and negative health effects experienced by a growing number of patients worldwide with arousal-based disorders and disorders of arousal and sleep, including hyperarousals of PTSD and insomnia.

项目摘要/摘要 我们实验室最近的工作发现了腹侧VGAT+(GABA能)神经元的一个分隔结节 外侧下丘脑(LHVGAT)是正常行为和电活动的必要条件和充分条件。 头颅定位(EEG)觉醒。然而，在理解细胞和 LHVGAT神经元触发觉醒的突触电路基础。我们的长期目标是了解功能- LHVGAT神经元产生和调节行为和脑电觉醒的神经回路基础。目标是 在这个特殊的应用中是通过定义功能性的、突触的“神经回路”来扩展我们之前的发现 LHVGAT神经元触发觉醒的基础。中心假说是LHVGAT神经元促进 通过直接抑制睡眠活跃的腹外侧视前核(VLPO)来实现觉醒和快速脑电节律， 位于较大的视前区。拟议研究的基本原理是识别电路 LHVGAT神经元促进觉醒的基础是操纵它们的关键第一步 减少有觉醒障碍的人所经历的功能障碍，包括过度唤醒- 被驱使失眠。在强劲的初步数据的指导下，我们的假设将通过追求三个具体的 目的：1)确定LHVGAT神经元是否通过直接抑制促进睡眠的VLPO-neu来促进觉醒 2)定义LHVGAT-VLPO界面的功能性突触生理学，包括 目标神经元；以及3)确定LHVGAT的突触输入，并建立一个功能性的三突触回路。 电路跨越输入LHVGATVLPO.这种方法在智力和技术上都是创新的，因为它代表了- 对当代模型中促黄体生成素神经元在觉醒睡眠中的作用的新的实质性的背离感到不满 法规，因为它采用了新开发和验证的方法的新组合，包括- ING免费提供体内和体外基于光遗传的实验。这项拟议的研究具有重要意义 因为它有望垂直推进和扩大对细胞和回路(突触)的理解 LHVGAT对觉醒和与认知相关的快速皮质节律调节的潜在机制。 最终，这些知识有可能为治疗和干预策略的发展提供信息。 EGES以减少越来越多的患者经历的功能障碍和负面健康影响 世界范围内以唤醒为基础的障碍以及唤醒和睡眠障碍，包括创伤后应激障碍的过度唤醒 还有失眠。