AMYGDALA GLUCOCORTICOID RECEPTOR FUNCTION IN STRESS

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）轴和通过糖皮质激素受体（GR）信号传导在正常应激反应和精神疾病中的生物学作用。HPA轴功能障碍，即内分泌应激反应，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应激行为反应的关键前脑结结构，人类抑郁和HPA高分泌状态下会出现杏仁核过度活跃。此外，杏仁核中央核（CeA）的糖皮质激素作用与调节正反馈回路有关，该正反馈回路增强了HPA轴的活动、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不太清楚，部分原因是基因操纵CeA功能的具体方法不充分。我们将测试CeA中的糖皮质激素受体通过控制促肾上腺皮质激素释放激素（CRH）基因表达来调节应激行为和肾上腺反应的假设。我们的具体目标将寻求建立一个新的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通过CRH的区域替代导致行为和肾上腺轴的改变。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治疗方法的发展。据估计，美国有4000万人患有精神疾病，造成了巨大的社会和公共卫生负担。我们计划进行的关于杏仁核中糖皮质激素受体功能作用的研究结果，有望为研究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。

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.