Impact of Corticotropin Releasing Factor on Sleep Regulation

促肾上腺皮质激素释放因子对睡眠调节的影响

• 批准号: 9241041
• 负责人: Ronald Szymusiak
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241041
• 关键词: Acute; Address; Adenosine; Adverse effects; Amygdaloid structure; Anxiety Disorders; Architecture; Axon; Behavioral; Biological Preservation; Brain; Brain Stem; CRH gene; Cell Nucleus; Chronic; Chronic stress; Circadian Rhythms; Circadian desynchrony; Clozapine; Cognitive; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Development; Disease; Drug Delivery Systems; Drug usage; Endocrine; FOS gene; Female; Funding; Goals; Health; Homeostasis; Hyperactive behavior; Hypothalamic dysfunction; Hypothalamic structure; Impairment; Infusion procedures; Injection of therapeutic agent; Knock-in Mouse; Laboratories; Light; Link; Maintenance; Mediating; Mental Depression; Mental disorders; Metabolism; Microdialysis; Microinjections; Mood Disorders; Mus; Neurobiology; Neurons; Neuropeptides; Opsin; Outcome; Oxides; Pattern; Phase; Physiologic pulse; Physiological; Population; Post-Traumatic Stress Disorders; Process; Psychological Stress; Rattus; Recovery; Recurrence; Rhodopsin; Risk Factors; Role; Severities; Signal Transduction; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Stress; Structure of terminal stria nuclei of preoptic region; Symptoms; System; Therapeutic Intervention; Training; Veterans; Wakefulness; Work; combat; common symptom; density; design; experimental study; hypothalamic-pituitary-adrenal axis; immunoreactivity; improved outcome; light effects; male; modifiable risk; paraventricular nucleus; prevent; receptor; response; sleep onset; sleep regulation; stress resilience; stressor; suprachiasmatic nucleus; targeted treatment

Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders. Depression and PTSD are associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Brain levels of corticotrophin-releasing factor (CRF), a critical neuropeptide regulator of the HPA axis, are chronically elevated in these disorders. CRF has well characterized wake-promoting/sleep-disruptive effects. Previous work from our laboratory and others has identified GABAergic neurons in the preoptic hypothalamus as critical regulators of sleep onset, sleep maintenance and sleep homeostasis. During the previous funding period, we demonstrated that acute elevations of CRF has sleep disruptive effects mediated, in part, by actions on preoptic neurons. We provide preliminary data that the disruption of sleep homeostasis that accompanies chronic partial sleep restriction can be reversed by administration of CRF receptor antagonists. We hypothesize that activation of CRF neurons occurring in response to the stress of chronic sleep restriction disrupts sleep homeostasis. We further hypothesize that CRF effects on sleep homeostasis are mediated through suppression of the activity of sleep-regulatory GABAergic neurons in the preoptic hypothalamus and in the rostral medulla. We propose four specific aims to address these hypotheses. Aim 1 will determine if CRF disrupts preoptic and medullary sleep-regulatory neuronal activity during chronic sleep restriction in rats. Aim 2 will determine the nuclei of origin of CRF neuronal afferents to GABAergic sleep regulatory neurons in the preoptic hypothalamus and the rostral medulla through targeted microinjections in the hypothalamus and extended amygdala of AAV-DIO-mcherry in CRF-ires- CRE knock-in mice. Aim 3 will identify CRF neuronal populations responsible for the negative modulation of sleep homeostasis by expressing channel rhodopsin-2 and hM3Dq excitatory designer receptor in hypothalamic and extended amygdala nuclei that contain CRH neurons and determining the effects of light-induced and chemogenetic excitation of different CRF neuronal populations on sleep homeostasis. Aim 4 will determine if chemogenetic silencing of CRF neurons restores homeostatic responses to sleep loss during chronic sleep restriction. Insomnia and insufficient sleep are common in psychiatric disorders that are associated with and/or exacerbated by physiological or psychological stress. We propose to examine fundamental mechanisms and circuits that might underlie the negative impact of chronic mild stressors on the homeostatic regulation of sleep, with the goal of identifying critical regulatory nodes that can be targeted for therapy. Chronic sleep disturbance can contribute to maladaptive stress and may be a modifiable risk factor for poor psychiatric and health outcomes in PTSD, depression and other disorders.

失眠和睡眠障碍是情绪和焦虑症的常见症状。抑郁和 PTSD与下丘脑-垂体-肾上腺（HPA）轴功能障碍有关。的脑水平 促肾上腺皮质激素释放因子（CRF）是HPA轴的关键神经肽调节因子， 在这些疾病中升高。CRF具有良好的促醒/睡眠破坏作用。 我们实验室和其他人以前的工作已经确定了视前区的GABA能神经元 下丘脑是睡眠启动、睡眠维持和睡眠稳态的关键调节器。期间 在上一个资助期，我们证明了CRF的急性升高具有睡眠破坏作用 部分是通过对视前神经元的作用来介导的。我们提供的初步数据表明睡眠中断 伴随慢性部分睡眠限制的体内平衡可通过给予CRF逆转 受体拮抗剂我们假设CRF神经元的激活是对应激的反应， 长期睡眠限制会破坏睡眠的平衡。我们进一步假设CRF对睡眠的影响 稳态是通过抑制睡眠调节GABA能神经元的活性来介导的， 视前区下丘脑和头端延髓。我们提出了四个具体目标来解决这些问题 假设目的1将确定CRF是否破坏视前和延髓睡眠调节神经元的活动 在慢性睡眠限制的大鼠。目的2确定CRF神经元传入的起源核团 下丘脑视前区和延髓头端的GABA能睡眠调节神经元 AAV-DIO-mcherry在CRF-IRES-1中的下丘脑和延伸杏仁核中的靶向显微注射， CRE基因敲入小鼠。目的3将确定CRF神经元群体负责负调制 通过表达通道视紫红质-2和hM 3Dq兴奋性设计受体来调节睡眠稳态， 下丘脑和延伸杏仁核，含有CRH神经元和确定的影响， 不同CRF神经元群体的光诱导和化学激发对睡眠稳态的影响。 目的4将确定CRF神经元的化学基因沉默是否恢复对睡眠的稳态反应 慢性睡眠限制期间的损失。失眠和睡眠不足在精神疾病中很常见 与生理或心理压力相关和/或由生理或心理压力加剧。我们建议 研究可能导致慢性轻度抑郁症负面影响的基本机制和电路， 压力源对睡眠稳态调节的影响，目的是确定关键的调节节点， 可以作为治疗的目标。慢性睡眠障碍可能导致适应不良的压力， 在PTSD、抑郁症和其他疾病中，这是一个可改变的精神和健康结果不佳的风险因素。