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.

失眠和睡眠不安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）轴的功能障碍有关。大脑水平 皮质营养素释放因子（CRF）是HPA轴的关键神经肽调节剂，是长期的 这些疾病升高。 CRF具有良好的特征性唤醒/干扰性效应。 我们的实验室和其他人的先前工作已经确定了peroptic的GABA能神经元 下丘脑作为睡眠发作，睡眠维护和睡眠体内平衡的关键调节剂。期间 上一个融资期，我们证明了CRF的急性升高具有睡眠破坏性影响 部分是由对载前神经元的作用进行介导的。我们提供的初步数据使睡眠破坏 伴随慢性部分睡眠限制伴随的稳态可以通过CRF的管理来逆转 受体拮抗剂。我们假设由于应力而发生的CRF神经元的激活 慢性睡眠限制破坏了睡眠体内平衡。我们进一步假设CRF对睡眠的影响 稳态通过抑制睡眠调节性GABA能神经元的活性来介导 前下丘脑和延髓髓质。我们提出了四个特定的目的来解决这些问题 假设。 AIM 1将确定CRF是否会破坏前和髓质睡眠调节性神经元活动 在大鼠的慢性睡眠限制期间。 AIM 2将确定CRF神经元传入的起源核 通过前下丘脑和延髓髓质的GABA能睡眠调节神经元通过 在CRF-IRES-中的下丘脑和AAV-DIO-MCHERRY的杏仁核中的靶向显微注射 CRE敲门小鼠。 AIM 3将确定负责负调制的CRF神经元种群 通过表达通道Rhodopsin-2和HM3DQ兴奋性设计器受体的睡眠体内平衡。 下丘脑和扩展的杏仁核核，其中包含CRH神经元并确定 睡眠体内稳态上不同CRF神经元种群的光引起和化学发生激发。 AIM 4将确定CRF神经元的化学发生沉默是否恢复了对睡眠的稳态反应 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的和/或加剧的。我们建议 检查可能是慢性轻度影响的基本机制和电路 对睡眠体内稳态调节的压力源，目的是确定关键的调节节点 可以针对治疗。慢性睡眠障碍会导致适应不良的压力，可能是 PTSD，抑郁症和其他疾病中精神病和健康成果差的危险因素可改变。