Neuronal and homeostatic regulation of sleep by the preoptic area and tuberomammillary nucleus

视前区和结节乳头核对睡眠的神经元和稳态调节

• 批准号: 10495189
• 负责人: John Maurer
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495189
• 关键词: Address; Animals; Axon; Brain; Brain region; Cardiovascular Diseases; Cell Nucleus; Cells; Fiber; Foundations; Genetic; Glutamates; Health; Histamine; Homeostasis; Hypothalamic structure; Impaired cognition; Label; Mammals; Measurement; Mediating; Metabolic; Modernization; Monitor; Narcolepsy; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Organism; Photometry; Physiological; Play; Population; Preoptic Areas; Regulation; Risk; Role; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Sleeplessness; Societies; Techniques; Wakefulness; cardiovascular disorder risk; cell type; immune system function; improved; in vivo; interdisciplinary approach; mammilloinfundibular nucleus structure; mouse model; nerve supply; non rapid eye movement; novel; optogenetics; patch clamp; pressure; rapid eye movement; relating to nervous system; response; sleep onset; sleep regulation

PROJECT SUMMARY While sleep is evolutionarily conserved across all animals studied, the precise function of sleep remains unknown. It is vital that organisms receive an adequate amount of sleep, as sleep deprivation has profound widespread physiological effects including cognitive impairment, compromised immune system function, increased risk of cardiovascular disease, and in extreme cases can be fatal. In mammals, sleep is characterized by transitions between rapid eye movement (REM) and non-REM (NREM) sleep states. Sleep states and transitions between them are regulated by diverse neuronal populations found throughout the brain and are under the influence of homeostatic pressure. While numerous sleep-active and wake-active brain regions have been identified, it remains unknown how diverse neuronal populations coordinate their actions to regulate sleep and wakefulness. The preoptic area (POA) of the hypothalamus contains sleep-active GABAergic neurons and activation of their axons innervating the tuberomammillary nucleus (TMN) are critical for sleep regulation. However, it is yet understood exactly how the activity of POA GABAergic axonal projections to the TMN changes in response to increased sleep need and whether they are necessary to integrate homeostatic pressure. Conversely, the TMN histaminergic neurons are wake-active and innervate the POA. It is unknown how the activation of axonal projections of TMN histaminergic neurons or other neuronal subtypes to the POA promotes wakefulness. Understanding how these cell-type specific nuclei coordinate as a circuit via axonal projections will help elucidate the mechanism of sleep and wake regulation. The central hypothesis of this proposal is that the POA and TMN contain cell-type specific reciprocal projections that encode homeostatic sleep need and mediate sleep and wakefulness. To address this hypothesis, this proposal will integrate genetic mouse models for specifically labeling specific cell types, in vivo and ex vivo measurements of activity using fiber photometry, optrode and whole-cell patch-clamp recordings, and optogenetic and chemogenetic techniques to modulate neuronal activity. Aim 1 will investigate the role of POA GABAergic axonal projections to the TMN in sleep homeostasis. Aim 2 will define cell-type specific roles of TMN axons innervating the POA in wake regulation. Together, these studies will reveal novel circuit mechanisms by which the POA and TMN coordinate their activity during sleep/wake and periods of homeostatic sleep pressure.

项目总结 虽然睡眠在所有被研究的动物中都是进化保守的，但睡眠的确切功能仍然存在 未知。生物体获得充足的睡眠是至关重要的，因为睡眠剥夺具有严重的 广泛的生理影响，包括认知障碍，免疫系统功能受损， 增加心血管疾病的风险，在极端情况下可能是致命的。在哺乳动物中，睡眠是 以快速眼动(REM)和非快速眼动(NREM)睡眠状态之间的转换为特征。沉睡 它们之间的状态和转换受到遍布大脑的不同神经元群体的调节 并受到动态平衡压力的影响。虽然许多睡眠活跃和清醒活跃的大脑 区域已经确定，但仍不清楚不同的神经元群体如何协调他们的行动 调节睡眠和清醒。下丘脑的视前区(POA)包含睡眠活跃区 GABA能神经元及其支配结节乳头核(TMN)的轴突的激活是至关重要的 用来调节睡眠。然而，目前尚不清楚POA GABA能轴突活动是如何 对TMN的预测随着睡眠需求的增加而变化，以及它们是否有必要 积分动态平衡压力。相反，TMN组胺能神经元是觉醒活跃的，并支配 POA。目前尚不清楚TMN组胺能神经元或其他神经元轴突投射的激活 POA的亚型有助于保持清醒。了解这些细胞类型的特定核是如何作为 通过轴突投射的回路将有助于阐明睡眠和觉醒调节的机制。中环 这一建议的假设是POA和TMN包含细胞类型特定的相互投影， 编码动态平衡睡眠需求，调节睡眠和清醒。为了解决这一假设，这项提议 将整合遗传小鼠模型，用于体内和体外特定细胞类型的特定标记 使用光纤光度法、光电极和全细胞膜片钳记录测量活性，以及 调节神经元活动的光发生和化学发生技术。目标1将调查POA的作用 在睡眠稳态中，GABA能轴突投射到TMN。目标2将定义细胞类型的特定角色 尾波调节中支配POA的TMN轴突。总之，这些研究将揭示新的电路 POA和TMN在睡眠/清醒和睡眠期间协调活动的机制 动态平衡睡眠压力。