AMYGDALA GLUCOCORTICOID RECEPTOR FUNCTION IN STRESS

压力下杏仁核糖皮质激素受体的功能

基本信息

批准号：
7769911
负责人：
Louis J Muglia
金额：
$ 38.34万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-13 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7769911
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 public health relevance receptor function response

项目摘要

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定义下丘脑 - 垂体 - 肾上腺（HPA）轴的生物学作用，并通过糖皮质激素受体（GR）在正常应力反应和精神病学中的信号传导疾病。功能障碍HPA轴（内分泌应力反应）特别与易受重大抑郁症，躁郁症，焦虑症和精神分裂症的脆弱性有关。杏仁核是一种关键的淋巴结前脑结构，用于整合神经内分泌和对压力的行为反应，杏仁核多动症发生在人类抑郁症和HPA超分泌状态。此外，杏仁核（CEA）中央核中的糖皮质激素作用已与介导一个正反馈环，从而增强了HPA轴的活性，焦虑，并获得或表达情感显着的记忆。这些过程发生的机制仍然很少理解，部分原因是对CEA功能的基因操纵的特定手段不足。我们将测试CEA中CEA中的糖皮质激素受体通过控制该部位的皮质激素释放激素（CRH）基因表达来调节对压力的行为和肾上腺反应的假设。我们的具体目的将寻求建立一种新型CEA特异性GR敲除系统，确定HPA轴调节和行为中CEA中GR功能丧失的表型后果，并确定CRH表达的改变是否有助于所得的行为和肾上腺轴通过区域替代CRH的变化。最终，我们的努力旨在进一步了解与精神病有关的神经内分泌电路，并促进针对这些主要健康疾病的新型治疗方法的发展。公共卫生相关性估计有4000万人患有精神疾病，产生了巨大的社会和公共卫生负担。我们计划的研究有关糖皮质激素受体功能在杏仁核中的作用的结果，有望有望对大脑通路进行新的见解，从而调节对压力的反应以及精神疾病的起源和治疗。