Amygdala CRH, Insomnia and Depression

描述（申请人提供）：应激暴露刺激大脑促肾上腺皮质激素释放激素（CRH）的释放，激活下丘脑-垂体-肾上腺（HPA）轴，这是应激调节的关键机制。自1981年首次发现CRH在应激中的作用以来，近40年来对其作用的研究进展迅速（Vale et al., 1981）。虽然CRH依赖的HPA激活是无可争议的，但CRH来自PVN以外来源的作用在很大程度上仍然未知，证据不一致。最近，我们的实验室已经成功地培育了CRHflox小鼠，使我们能够通过Cre重组酶特异性地删除CRH，这为我们阐明CRH在不同区域的作用提供了一个优雅的工具。我们的中心假设是通过评估遗传和环境风险因素，中央杏仁核（CeA） CRH的失调是应激性抑郁症的原因。该假设将通过完成3个具体目标来验证。特异性目标1将验证CeA CRH系统是激活HPA对心因性应激源而非系统性应激源的反应所必需的假设。我们预测，CeA中CRH的丢失会减弱HPA对脏笼暴露的反应，但不会减弱对缺氧应激暴露的反应。特异性目的2将验证应激性失眠是通过CeACRH介导的，并涉及LC中的去甲肾上腺素能通路。我们预测，CeA CRH的缺失将减轻压力情绪相关的失眠。特异性目的3将检验CeA CRH对调节应激性抑郁是必要的假设。本研究旨在评估CeA CRH在急性应激反应（适应）和长期应激相关脆弱性（适应不良）中的作用。这项研究的完成将阐明crh介导的神经回路在抑郁症，特别是失眠，情感性疾病的标志，并引导我们找到潜在的预防或治疗方法来治疗失眠，从而减轻精神障碍。该职业发展奖（K01）将为候选人提供必要的技能，以发展一个独立的研究项目，专注于压力调节的分子机制。培训计划旨在为候选人提供昼夜生物学和睡眠调节，心理生理学和精神病理学以及遗传流行病学方面的技能，这些对我选择的研究领域至关重要。特别是，候选人将获得以下方面的知识和技能：1)进行基因修饰研究，以识别情绪和焦虑障碍背后的神经通路；2)设计、进行和分析与压力相关的失眠研究。这些技能将通过教学培训、指导阅读和指导研究项目的结合来发展。研究结果和培训活动将用于制定R01提案，以进行一项评估遗传和环境风险因素的前瞻性研究，旨在确定与压力相关的疾病状态的潜在分子靶点。

DESCRIPTION (provided by applicant): Stress exposure stimulates the release of corticotropin releasing hormone (CRH) in the brain and activates the hypothalamus-pituitary-adrenal (HPA) axis, which is key mechanism of stress regulation. Research into the role of CRH in stress has advanced rapidly in the past 40 years since it was first characterized in 1981 (Vale et al., 1981). While the CRH-dependent HPA activation is undisputed, the role for CRH derived from sources other than the PVN remains largely unknown with inconsistent evidences. Recently, our lab has successfully generated the CRHflox mice which allow us to site-specifically delete the CRH through Cre recombinase, which provide us an elegant tool to clarify the role of CRH in different area. Our central hypothesis is that dysregulation of central amygdala (CeA) CRH is responsible for the stress-induced Depression by assessing the genetic and environmental risk factors. The hypothesis will be tested by the completion of 3 Specific Aims. Specific Aim 1 will test the hypothesis that CeA CRH system is required for the activation of HPA responsivity to psychogenic stressor but not systemic stressor. We predict that the loss of CRH from the CeA will attenuate the HPA responsivity to dirty cage exposure but not to hypoxia stress exposure. Specific Aim 2 will test the hypothesis that stress-induced insomnia is mediated through the CeACRH and noradrenergic pathway in LC is involved. We predict that deletion of the CeA CRH will attenuate the stress emotion-associated insomnia. Specific Aim 3 will test the hypothesis that CeA CRH is necessary for regulating stress-induced depression. This aim will assess the role of CeA CRH in acute stress responses (adaptation) and prolonged stress-associated vulnerability (maladaptation). The accomplishment of this study will illuminate the CRH-mediated neuronal circuitry underlying the depression, particularly for insomnia, a hallmark for affective diseases, and lead us to find a potential preventive or therapeutic approach to treat insomnia, thus, alleviate mental disorders. This Career Development Award (K01) will provide the candidate with the necessary skills to develop an independent research program focused on molecular mechanism of stress regulation. The training plan is designed to provide the candidate with skills in circadian biology and sleep regulation, psychophysiology and psychopathology, and genetic epidemiology which are critical in my chosen area of study. Specially, the candidate will acquire the knowledge and skills to 1) conduct the gene-modified research to identify the neuropathway underlying the mood and anxiety disorders 2) design, conduct and analyze stress-associated insomnia research. These skills will be developed through a combination of didactic training, guided readings and mentored research projects. Research results and training activities will be used to develop a R01 proposal for a prospective study that assesses both genetic and environmental risk factors and aims to identify the potential molecular targets for stress- related disease states. PUBLIC HEALTH RELEVANCE: Stressful life events often precede anxiety disorders, and the first depressive episode often develops following the occurrence of a major negative life event. The proposed research aims to identify the mechanisms of the genetic and environmental risk factors utilizing corticotropin-releasing hormone that underlying the onset of mood and sleep disorders. Elucidation of these mechanisms, and the role of genetic vulnerability that alter mediating pathways, is critical to development of therapeutic or preventative strategies to combat stress-induced depression. Given that the depression is a serious neuropsychiatric illness and greatest public health burden http://www.nimh.nih.gov/statistics/4COST_AM2006.shtml, undertaking this study represents an important public priority.