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：
8402381
负责人：
Louis J Muglia
金额：
$ 37.26万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8402381
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

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.

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) 发出的信号在正常应激反应和精神疾病中的作用。疾病。 HPA 轴功能障碍（内分泌应激反应）与重度抑郁症、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对压力的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 分泌过多状态下。此外，糖皮质激素在杏仁核中央核 (CeA) 中的作用与介导正反馈回路有关，该回路可增强 HPA 轴的活动、焦虑以及情感显着记忆的获取或表达。这些过程发生的机制仍然知之甚少，部分原因是 CeA 功能的遗传操作手段不够具体。我们将测试以下假设：CeA 中的糖皮质激素受体通过控制该位点的促肾上腺皮质激素释放激素 (CRH) 基因表达来调节行为和肾上腺对压力的反应。我们的具体目标是寻求建立一种新型的 CeA 特异性 GR 敲除系统，确定 CeA 中 GR 功能丧失对 HPA 轴调节和行为的表型后果，并确定 CRH 表达的改变是否有助于由此产生的行为和肾上腺轴通过区域性更换 CRH 进行更改。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，并促进针对这些主要健康疾病的新治疗方法的开发。