AMYGDALA GLUCOCORTICOID RECEPTOR FUNCTION IN STRESS

压力下杏仁核糖皮质激素受体的功能

• 批准号: 8011545
• 负责人: Louis J Muglia
• 金额: $ 37.95万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-13 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011545
• 关键词: Adrenal Glands; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological; Bipolar Disorder; Cell Nucleus; Circadian Rhythms; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Development; Disease; Endocrine; Enkephalins; Feedback; Fright; Functional disorder; Gene Expression; Glucocorticoid Receptor; Glucocorticoids; Health; Human; Hyperactive behavior; Hypothalamic structure; Infection; Knock-out; Learning; Major Depressive Disorder; Measures; Mediating; Memory; Mental Depression; Mental disorders; Mineralocorticoid Receptor; Modeling; Motor; Mus; Neurons; Neurosecretory Systems; Nodal; Performance; Pituitary Gland; Process; Production; Prosencephalon; Public Health; Regulation; Reporter; Research; Role; Rosa; Schizophrenia; Signal Transduction; Site; Stress; Structure; Subfamily lentivirinae; Swimming; System; Tail Suspension; Target Populations; Testing; United States; Vasopressins; biological adaptation to stress; brain pathway; conditioned fear; conditioning; genetic manipulation; hypothalamic-pituitary-adrenal axis; indexing; insight; novel; novel therapeutic intervention; receptor function; response

DESCRIPTION (provided by applicant): The long-term objective of our studies is to define the biological role of the hypothalamic-pituitary-adrenal (HPA) axis and signaling through the glucocorticoid receptor (GR) in both the normal stress response and in psychiatric disease. Dysfunction HPA axis, the endocrine stress response, is specifically associated with vulnerability to major depression, bipolar disorder, anxiety disorders, and schizophrenia. The amygdala is a key nodal forebrain structure for integrating neuroendocrine and behavioral responses to stress, and amygdalar hyperactivity occurs in human depression and HPA hypersecretory states. Moreover, glucocorticoid action in the central nucleus of the amygdala (CeA) has been implicated in mediating a positive feedback loop that potentiates activity of the HPA axis, anxiety, and acquisition or expression of emotionally salient memory. The mechanisms by which these processes occur remain poorly understood, in part because of inadequately specific means for genetic manipulation of CeA function. We will test the hypotheses that glucocorticoid receptors in the CeA regulate behavioral and adrenal responses to stress by control of corticotropin-releasing hormone (CRH) gene expression at this site. Our specific aims will seek to establish a novel CeA-specific GR knockout system, determine the phenotypic consequences of loss of GR function in the CeA for HPA axis regulation and behavior, and determine whether alteration in CRH expression contributes to the resulting behavioral and adrenal axis changes by regional replacement of CRH. Ultimately, our efforts aim to further the understanding of neuroendocrine circuits relevant for psychiatric diseases and promote development of novel therapeutic approaches for these major health disorders. PUBLIC HEALTH RELEVANCE An estimated 40 million people in the United States suffer from a psychiatric disorder, generating an enormous societal and public health burden. The results of our planned studies on the role of glucocorticoid receptor function in the amygdala hold promise for new insights into brain pathways regulating the responses to stress and the genesis and treatment of mental illness.

描述（由申请人提供）：我们研究的长期目标是确定下丘脑-垂体-肾上腺（HPA）轴的生物学作用以及通过糖皮质激素受体（GR）在正常应激反应和精神疾病中的信号传导。下丘脑-垂体-肾上腺轴（HPA轴）功能障碍，即内分泌应激反应，与抑郁症、双相情感障碍、焦虑症和精神分裂症的易感性特别相关。杏仁核是整合神经内分泌和应激行为反应的关键节点前脑结构，杏仁核过度活跃发生在人类抑郁和HPA过度分泌状态。此外，杏仁核中央核（CeA）中的糖皮质激素作用涉及介导一个正反馈回路，该正反馈回路增强HPA轴的活性、焦虑和情绪显著记忆的获得或表达。这些过程发生的机制仍然知之甚少，部分原因是没有足够的具体手段进行遗传操作的CeA功能。我们将测试的假设，糖皮质激素受体在CeA调节行为和肾上腺对压力的反应，通过控制促肾上腺皮质激素释放激素（CRH）基因在这个网站的表达。我们的具体目标将寻求建立一种新的CeA特异性GR敲除系统，确定GR功能丧失的表型后果，在CeA HPA轴的调节和行为，并确定是否在CRH表达的改变，从而导致行为和肾上腺轴的变化CRH的区域替代。最终，我们的努力旨在进一步了解与精神疾病相关的神经内分泌回路，并促进这些主要健康疾病的新型治疗方法的发展。 据估计，美国有4000万人患有精神疾病，这给社会和公共卫生带来了巨大的负担。我们计划对杏仁核中糖皮质激素受体功能的作用进行研究，其结果有望对调节应激反应的大脑通路以及精神疾病的发生和治疗提供新的见解。