Amygdala CRH, Insomnia and Depression

描述（由申请人提供）：应激暴露刺激大脑中促肾上腺皮质激素释放激素（CRH）的释放，并激活下丘脑-垂体-肾上腺（HPA）轴，这是应激调节的关键机制。自1981年首次表征CRH以来，对CRH在应激中的作用的研究在过去40年中进展迅速（Vale等人，1981年）。虽然CRH依赖的HPA激活是无可争议的，但CRH来源于PVN以外的来源的作用在很大程度上仍然未知，证据不一致。最近，我们实验室成功地培育了CRHflox小鼠，使我们能够通过Cre重组酶定点删除CRH，这为我们阐明CRH在不同领域的作用提供了一个优雅的工具。我们的中心假设是，中央杏仁核（CeA）CRH的失调是负责通过评估遗传和环境的危险因素的压力诱导的抑郁症。将通过完成3个特定目标来检验假设。具体目标1将检验以下假设：CeA CRH系统是激活HPA对心因性应激而非全身性应激的反应所必需的。我们预测，从CeA的CRH的损失将减弱HPA的脏笼暴露的反应性，但不缺氧应激暴露。具体目标2将检验这一假设，即应激诱导的失眠是通过CeACRH介导的，LC中的去甲肾上腺素能通路参与其中。我们预测，删除CeA CRH将减轻压力情绪相关的失眠。具体目标3将测试的假设，CeA CRH是必要的调节应激诱导的抑郁症。这一目标将评估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。本研究的完成将阐明抑郁症，特别是失眠症的CRH介导的神经回路，并引导我们找到潜在的预防或治疗方法来治疗失眠症，从而减轻精神障碍。 该职业发展奖（K 01）将为候选人提供必要的技能，以开发专注于压力调节分子机制的独立研究计划。该培训计划旨在为候选人提供昼夜节律生物学和睡眠调节，心理生理学和精神病理学以及遗传流行病学方面的技能，这些技能对我所选择的研究领域至关重要。特别是，候选人将获得知识和技能1）进行基因修饰研究，以确定情绪和焦虑症的神经通路2）设计，进行和分析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相结合的发展。研究结果和培训活动将用于制定前瞻性研究的R 01提案，该研究评估遗传和环境风险因素，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.