Neuronal and homeostatic regulation of sleep and wake by corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus

下丘脑室旁核中促肾上腺皮质激素释放激素神经元对睡眠和觉醒的神经元和稳态调节

• 批准号: 10464942
• 负责人: ALYSSA N WIEST
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464942
• 关键词: Address; Animals; Arousal; Attention; Axon; Behavior; Brain region; CRH gene; CRISPR/Cas technology; Calcium; Cell Nucleus; Chronic; Chronic stress; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Emotional; Genes; Genetic; Health; Homeostasis; Hypothalamic structure; Image; Impairment; In Situ Hybridization; Injections; Label; Lead; Mediating; Mental Health; Mental disorders; Metabolic; Monitor; Neurons; Patients; Pituitary Gland; Play; Population; Preoptic Areas; REM Sleep; Risk; Role; Short-Term Memory; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Stress; Stressful Event; Techniques; Wakefulness; Waste Products; circadian; cognitive function; emotional functioning; improved; in vivo; in vivo calcium imaging; in vivo monitoring; insight; mouse model; neural circuit; neuromechanism; new therapeutic target; non rapid eye movement; optogenetics; paraventricular nucleus; physical conditioning; pressure; receptor; relating to nervous system; response; sleep quality; sleep regulation; social defeat; vigilance

PROJECT SUMMARY Sleep is an evolutionarily conserved behavior that is widely observed across the animal kingdom. It is characterized by transitions between different vigilance states: wake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. These transitions are controlled by interactions between different neuronal populations and are under the influence of homeostatic and circadian mechanisms. As sleep has many beneficial and restorative effects, good quality sleep is important for mental and physical health. It has been well-established that stress and sleep have a bidirectional relationship. Stress is known to be a major cause of disrupted sleep. Chronic sleep disruption can lead to an increased risk of developing psychiatric disorders. The paraventricular nucleus of the hypothalamus (PVN) contains corticotropin-releasing hormone (CRHPVN) neurons that have been shown to be activated by stress. Central and systemic administration of CRH has been found to induce wakefulness. Additional studies have found that central blockade of the CRH receptor 1 (CRHR1) reduces the wake-promoting effects of CRH injection, suggesting this receptor plays a key role in CRH-mediated arousal. However, the neural mechanisms by which CRH neurons regulate wakefulness are not very well understood. Tracing studies have revealed that CRHPVN neurons project to the preoptic area of the hypothalamus (POA), a well-known sleep center containing neurons that are crucial for sleep regulation. In situ hybridization studies have shown that CRHR1 is expressed in the POA. While CRH has been implicated as a regulator of wakefulness, the role that CRHPVN neurons and their projections to the POA (CRHPVN→POA) play in the sleep-wake cycle and sleep homeostasis has not been fully investigated. The central hypothesis of this proposal is that CRHPVN neurons control wakefulness and impair the homeostatic response to sleep pressure following chronic stress. To address this hypothesis, this proposal will use a genetic mouse model, CRH-Cre, to specifically label CRH neurons, in vivo calcium imaging, optogenetic manipulations, CRISPR-Cas9 gene editing techniques, and a chronic social defeat stress paradigm to manipulate these neurons and their projections. Aim 1 will determine the role of CRHPVN→POA projections in regulating sleep and wakefulness. Aim 2 will investigate the role of CRHPVN neurons and CRHPVN→POA projections in sleep homeostasis following chronic stress. Understanding how CRHPVN neurons promote wakefulness and regulate sleep homeostasis in response to chronic stress will further elucidate how the circuits controlling stress are interconnected with those regulating sleep and wakefulness.

项目摘要 睡眠是一种观察的进化论行为。 以不同警惕状态之间的过渡为特征：唤醒，快速眼动（REM）睡眠和 这些过渡由不同的神经元种群之间的相互作用控制 并受到稳态和昼夜节律的影响。 恢复性效果，高质量的睡眠是重要的福特和身体健康。 压力和睡眠有双向关系。 慢性睡眠破坏会导致副疾病的风险增加 下丘脑（PVN）的核中含有皮质激素释放激素（CRHPVN）神经元已 被压力激活。 清醒。 CRH注射的唤醒作用，建议该受体在CRH介导的唤醒中起关键作用。 然而，crons正常觉醒的神经机制并不是很好地理解。 追踪研究揭示了下丘脑（POA）的上型前区域 众所周知的睡眠中心遏制对睡眠调节至关重要的神经元。 表明CRHR1在POA中表示。 THPVN神经元及其对POA的预测（CRHPVN→POA）在睡眠觉醒周期中扮演 睡眠体内平衡尚未得到充分研究。 神经元控制着清醒并损害慢性应激后对睡眠压力的稳态反应。 为了解决这一假设，该提案将使用遗传小鼠模型CRH-CRE来专门标记CRH 神经元，体内钙成像，光遗传操作，CRISPR-CAS9基因编辑技术和A 慢性社会失败压力范式操纵神经元，而AIM 1将决定。 CRHPVN→POA预测在调节睡眠和清醒中的作用。 慢性压力后，神经元和CRHPVN→POA在睡眠稳态中的POA投影。 神经元促进清醒和正常的睡眠体内平衡，以响应慢性压力，并进一步阐明 控制应力的电路如何与调节睡眠和清醒的人相互联系。