The Role of Hypocretins in the Regulation of Stress and Arousal

描述（由申请人提供）：当压力源威胁到生物体的体内平衡时，大脑会激活各种神经肽分泌系统，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，就像美国人在忙碌的生活中经常发生的那样，行为和生理状态的改变可能是有害的。过度的应激反应会削弱免疫系统，增加患病、肥胖和心脏病发作的风险。应激反应的神经生物学基础尚不清楚。研究最多的应激诱导神经肽是促肾上腺皮质激素释放因子（CRF），它在哺乳动物中引发一系列刺激应激反应的生物事件。有趣的是，一对新的神经肽，下丘脑分泌素（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，主要是由于很难观察和操纵大脑下表面相对较小的神经元群。然而，现在可以使用光刺激的新技术对Hcrt细胞进行特定的操作，这种方法可以以高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神经元通过刺激CRF的释放来诱导与急性应激源反应相关的行为和生理过程。我们将从三个方面研究这一假设：(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神经元是否会改变CRF细胞活性、基因表达和肽释放。旨在探索应激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，以减轻应激障碍的负面症状。下丘脑泌素最近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新的治疗应激障碍和相关疾病的方法，以及确定针对Hcrt系统治疗其他疾病的药物的潜在副作用。

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.