The Role of Hypocretins in the Regulation of Stress and Arousal

下丘脑分泌素在压力和唤醒调节中的作用

• 批准号: 7749000
• 负责人: MATTHEW E CARTER
• 金额: $ 3.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2011-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749000
• 关键词: Acute; Adverse effects; American; Animals; Anxiety Disorders; Arousal; Attenuated; Behavior; Behavioral; Biological; Blood Pressure; Body Temperature; Brain; Cations; Cells; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Disease; Drug Delivery Systems; Drug Design; Endocrine; Environment; Event; Future; Gene Expression; Health; Heart Rate; Homeostasis; Hour; Hypothalamic structure; Immediate-Early Genes; Immune system; In Vitro; Inferior; Injection of therapeutic agent; Intervention; Lateral; Lead; Life; Mammals; Measures; Medical; Mental disorders; Methods; Motor Activity; Mus; Myocardial Infarction; Neurobiology; Neuromodulator; Neurons; Neuropeptides; Obesity; Organism; Peptides; Physiological; Physiological Processes; Physiology; Pituitary Gland; Pituitary-Adrenal System; Plasma; Population; Post-Traumatic Stress Disorders; Regulation; Research; Risk; Role; Series; Stress; Surface; Symptoms; System; Techniques; Technology; Testing; Time; Traumatic Stress Disorders; acute stress; base; biological adaptation to stress; depression; drug development; environmental stressor; gain of function; hypocretin; in vivo; lateral ventricle; millisecond; new therapeutic target; novel; novel therapeutics; paraventricular nucleus; public health relevance; research study; response; stress related disorder; stressor

DESCRIPTION (provided by applicant): In response to a stressor that threatens to disrupt an organism's homeostasis, the brain activates various neuropeptide-secreting systems to attempt to maintain the health of the animal. These adjustments include changes in behavioral state, such as an increase in locomotor activity, as well as changes in physiological state, such as an increase in heart rate, blood pressure, and body temperature. If the stress response is excessive and prolonged, as frequently occurs in the busy lives of Americans, the altered behavioral and physiological states can be deleterious and harmful. An excessive stress response can weaken the immune system and increase the risk of illness, obesity, and heart attacks. The neurobiological basis of the stress response is poorly understood. The most studied stress inducing neuropeptide is corticotropin-releasing factor (CRF), which initiates a series of biological events that stimulate the stress response in mammals. Interestingly, a pair of novel neuropeptides, the Hypocretins (Herts), also causes a heightened arousal in animals. The precise role of Hcrt cells in initiating the stress response is unknown, primarily due to the difficulty in observing and manipulating this relatively small population of neurons in the inferior surface of the brain. However, specific manipulation of Hcrt cells is now possible using the novel technique of photostimulation, a method by which we can specifically excite Hcrt neurons with high temporal precision. The purpose of this proposal is to use photostimulation technology to study a causal role between Hypocretin cell activation and the stress response. Our specific hypothesis is that stimulation of Hcrt neurons induces behaviors and physiological processes associated with the response to acute stressors by stimulating the release of CRF. We will study this hypothesis in three aims: (1) To determine if stimulation of Hcrt neurons is sufficient to promote behaviors associated with acute stress; (2) To determine if stimulation of Hcrt neurons is sufficient to promote autonomic physiological processes associated with stress; (3) To determine if stimulation of Hcrt neurons alters CRF cell activity, gene expression, and peptide release. PUBLIC HEALTH RELEVANCE Research aimed at exploring the neurobiological basis of stress may lead to the development of drugs and other treatments to relieve the negative symptoms of stress disorders. Hypocretins have recently been the target of drug design, and elucidating the role of these neuropeptides in the stress response could lead to novel therapeutics for stress disorders and related illnesses, as well as identify potential side effects for drugs that target the Hcrt system for other disorders.

描述（由申请人提供）：为了响应威胁破坏生物体内平衡的应激源，大脑激活各种神经肽分泌系统以试图维持动物的健康。这些调整包括行为状态的变化，如运动活动的增加，以及生理状态的变化，如心率、血压和体温的增加。如果压力反应过度且持续时间长，就像美国人在忙碌的生活中经常发生的那样，那么改变的行为和生理状态可能是有害的。过度的压力反应会削弱免疫系统，增加患病、肥胖和心脏病发作的风险。压力反应的神经生物学基础知之甚少。促肾上腺皮质激素释放因子（corticotropin-releasing factor，CRF）是目前研究最多的应激诱导神经肽，它能启动一系列刺激哺乳动物应激反应的生物学事件。有趣的是，一对新的神经肽，Hypocretins（Herts），也会引起动物的高度觉醒。Hcrt细胞在启动应激反应中的确切作用尚不清楚，主要是由于难以观察和操纵大脑下表面中相对较小的神经元群体。然而，现在可以使用新的光刺激技术对Hcrt细胞进行特定操作，通过这种方法，我们可以以高的时间精度特异性地激发Hcrt神经元。本研究的目的是利用光刺激技术研究下丘脑分泌素细胞活化与应激反应之间的因果关系。我们的具体假设是，刺激Hcrt神经元诱导的行为和生理过程相关的急性应激反应刺激CRF的释放。我们将从三个方面研究这一假说：（1）确定刺激Hcrt神经元是否足以促进与急性应激相关的行为;（2）确定刺激Hcrt神经元是否足以促进与应激相关的自主生理过程;（3）确定刺激Hcrt神经元是否改变CRF细胞活性、基因表达和肽释放。公共卫生相关性旨在探索压力的神经生物学基础的研究可能会导致药物和其他治疗方法的发展，以缓解压力障碍的负面症状。Hypocretins最近已经成为药物设计的目标，阐明这些神经肽在应激反应中的作用可能会导致应激障碍和相关疾病的新疗法，以及确定靶向Hcrt系统治疗其他疾病的药物的潜在副作用。