Glucocorticoid Negative Feedback: Intrinsic and Extrinsic Mechanisms

描述（由申请人提供）：不受控制的心理压力和相关的异常皮质醇激素分泌模式是导致我们社会中普遍存在的许多病理生理状况的一个因素，如高血压、动脉粥样硬化、胰岛素抵抗、腹部脂肪堆积、哮喘和免疫改变。在心理压力和一些心理障碍之间有一种特别动态的相互作用，最明显的是抑郁症和创伤后精神障碍（PTSD）。在这两种情况下，都有强有力的证据支持下丘脑-垂体-肾上腺（HPA）轴活动失调，由此导致的皮质醇水平失调可能导致一些正在进行的病理。控制HPA轴活性的最重要因素是糖皮质激素（如皮质醇和皮质酮）提供的负反馈。全面了解糖皮质激素负反馈机制对于确定HPA轴失调及其后果的临床基础至关重要。我们提出的研究将促进我们对糖皮质激素负反馈的分子，细胞和系统水平方面的理解。通过监测应激诱导的基因在系统（垂体、下丘脑和整个大脑）多个水平的表达以及应激诱导的激素分泌，我们可以区分内在（垂体和下丘脑）和外在（整个大脑）糖皮质激素的负反馈行为。我们的初步研究表明，应激诱导的糖皮质激素增加启动了负反馈过程，该过程在时间上可分为三个不同的阶段：快速反馈（< 10分钟），短期反馈（约1小时）和延迟反馈（约3小时）。每个阶段都与不同的应激诱导基因表达模式有关。通过全面研究内在和外在作用点和时间模式的贡献，我们将能够实现以下具体目标：1]确定糖皮质激素的周期性增加对HPA轴对心理应激的功能反应产生内在负反馈的机制；2]表征外源性负反馈对HPA轴对应激的功能反应的影响；3]表征应激诱导的糖皮质激素增加对急性心理应激下HPA轴的即时和后续反应的影响。

DESCRIPTION (provided by applicant): Uncontrolled psychological stress and associated abnormal cortisol hormone secretion patterns are a contributing factor to a number of pathophysiological conditions prevalent in our society, such as hypertension, atherosclerosis, insulin resistance, abdominal fat accumulation, asthma and altered immunity. There is an especially dynamic interplay between psychological stress and some psychological disorders, most notably depression and post traumatic disorder (PTSD). In both cases there is strong supporting evidence for dysregulation of Hypothalamic-Pituitary-Adrenal (HPA) axis activity, and the resulting dysregulated cortisol levels may contribute to some of the ongoing pathology. The most important factor controlling HPA axis activity is the negative feedback provided by glucocorticoids (e.g. cortisol and corticosterone). A comprehensive understanding of glucocorticoid negative feedback mechanisms is essential to determining the clinical basis of HPA axis dysregulation and its ramifications. We propose studies that will advance our understanding of the molecular, cellular and systems level aspects of glucocorticoid negative feedback. By monitoring stress-induced gene expression at multiple levels of the system (pituitary, hypothalamus and throughout brain) in parallel with stress-induced hormone secretion we can distinguish between the intrinsic (pituitary and hypothalamus) and extrinsic (throughout brain) glucocorticoid negative feedback actions. Our preliminary studies suggest that a stress-induced increase in glucocorticoids initiates negative feedback processes that temporally can be divided into three distinct phases: fast feedback (< 10 min), short-term feedback (about 1 hr) and delayed feedback (about 3 hr). Each phase is associated with different stress-induced gene expression patterns. By comprehensively examining the contribution of intrinsic and extrinsic sites of action and temporal patterns we will be able to accomplish the following Specific Aims: 1] Determine mechanisms by which phasic increases in glucocorticoids produce intrinsic negative feedback on the HPA axis functional response to psychological stress, 2] Characterize the extrinsic negative feedback influence on the HPA axis functional response to stress, 3] Characterize the impact of stress-induced increases of glucocorticoids on immediate and subsequent HPA axis responses to acute psychological stress.