Amygdala CRH, Insomnia and Depression

杏仁核 CRH、失眠和抑郁

• 批准号: 8384482
• 负责人: RONG ZHANG
• 金额: $ 13.3万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384482
• 关键词: Acute; Adrenal Glands; Affective; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Area; Attenuated; Behavior; Behavioral; Biology; Brain; Chronic stress; Circadian Rhythms; Corticotropin-Releasing Hormone; Development; Disease; Emotions; Environmental Exposure; Environmental Risk Factor; Etiology; Event; Functional disorder; Future; Gene-Modified; Genes; Genetic Predisposition to Disease; Genetic Risk; Glucocorticoid Receptor; Health; Hormonal; Hormones; Hypothalamic structure; Hypoxia; K-Series Research Career Programs; Knowledge; Lead; Life; Limbic System; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Mentors; Molecular; Molecular Target; Mood Disorders; Mus; Neurons; Neurosecretory Systems; Pathway interactions; Patients; Pituitary Gland; Pituitary-Adrenal System; Preventive; Process; Prospective Studies; Psyche structure; Psychopathology; Psychophysiology; Public Health; REM Sleep; Reading; Regulation; Research; Research Project Grants; Risk; Role; Severities; Site; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Source; Stress; Structure; Symptoms; System; Testing; Therapeutic; Training; Training Activity; Transgenic Animals; Viral; acute stress; adeno-associated viral vector; biological adaptation to stress; clinically relevant; combat; depressive symptoms; design; experience; genetic epidemiology; insight; locus ceruleus structure; male; mouse model; neural circuit; neuronal cell body; neuronal circuitry; neuropsychiatry; non rapid eye movement; noradrenergic; novel; pleasure; programs; psychological stressor; rapid eye movement; receptor; recombinase; relating to nervous system; research study; response; skills; sleep regulation; statistics; stress related disorder; stressor; therapeutic development; tool

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.

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在不同区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。 公共卫生关系：压力性生活事件通常先于焦虑症，第一次抑郁发作通常在发生重大负面生活事件后发生。这项研究的目的是利用促肾上腺皮质激素释放激素来确定情绪和睡眠障碍发病的遗传和环境风险因素的机制。阐明这些机制，以及改变介导途径的遗传脆弱性的作用，对于开发治疗或预防策略以对抗压力诱导的抑郁症至关重要。鉴于抑郁症是一种严重的神经精神疾病，也是最大的公共卫生负担http：//www.nimh.nih.gov/apartics/4COST_AM2006.shtml，开展这项研究是一项重要的公共优先事项。