CORTICOSTEROID RECEPTORS AND HPA AXIS ADAPTATION

本提案的长期目标是确定 神经激素机制，有助于能力的 下丘脑-垂体-肾上腺（HPA）轴适应反复的压力。 拟议研究的目标是描述 在习惯化过程中皮质类固醇反馈抑制。整体 这些研究假设皮质类固醇反馈抑制 有助于HPA轴适应重复的 应力这些研究可能与理解一些 神经病理学基础的精神疾病，如临床 萧条例如，抑郁症被认为是一种压力- 相关障碍。许多抑郁症患者的HPA轴是 过度活跃，以及许多与之相关的身体和行为症状 抑郁症患者与急性应激状态下的患者相似。因此，在本发明中， 抑郁症可能是一种适应日常生活的能力 压力是受损的。了解导致HPA的机制 轴应力习惯化可能指向抑郁个体的因素 已经被改变，从而阻止了充分的压力适应。的 提出了以下5个具体目标： 具体目标1。为了进一步描述习惯化的程度， HPA轴对重复约束应力的应力响应取决于 皮质酮 具体目标2。为了确定HPA轴的灵敏度是否增强， 皮质类固醇反馈抑制有助于习惯化。 具体目标3。为了确定是否延迟皮质类固醇反馈抑制 有助于习惯化。 具体目标4。以确定是否有皮质类固醇增加 受体水平作为暴露于反复约束压力的结果。 具体目标5.以确定是否有皮质类固醇增加 皮质酮的受体激活作为暴露于 反复束缚应激 提出了一系列研究，这些研究将使用大鼠作为体内 HPA轴习惯化研究系统。这些研究将利用 反复的束缚应激方案，可靠地产生习惯性的 HPA轴应激反应。内源性的作用的特点 将在研究中确定皮质类固醇在习惯化过程中的作用 其中通过肾上腺切除术系统地操作皮质类固醇 和用选择性皮质类固醇受体激动剂治疗， 拮抗剂研究还将探讨一种分子 导致HPA轴应激习惯化的机制是应激诱导的 皮质类固醇受体水平的变化。总的来说，这些研究将 提供了有关适应性的机制的重要信息， HPA轴对重复应力的响应。

The long-term objectives of this proposal are to determine the neurohormonal mechanisms that contribute to the ability of the hypothalamic-pituitary-adrenal (HPA) axis to habituate to repeated stress. The goal of the proposed studies is to characterize the role of corticosteroid feedback inhibition in the habituation process. The overall hypothesis of these studies is that corticosteroid feedback inhibition contributes to the ability of the HPA axis to habituate to repeated stress. These studies may have relevance to understanding some of the neuropathology underlying psychiatric disorders, such as clinical depression. For example, depression has been characterized as a stress- related disorder. The HPA axis of many depressed individuals is hyperactive, and many of the physical and behavioral symptoms associated with depression resemble those present during an acute stress state. Thus, depression may be a condition in which the ability to habituate to daily stress is impaired. An understanding of the mechanisms that lead to HPA axis stress habituation may point to factors in the depressed individual that have been altered, thereby preventing adequate stress adaptation. The following 5 specific aims are proposed: Specific Aim 1. To further characterize the extent to which habituation of the HPA axis stress response to repeated restraint stress is dependent on corticosterone. Specific Aim 2. To determine if an enhanced sensitivity of the HPA axis to corticosteroid feedback inhibition contributes to habituation. Specific Aim 3. To determine if delayed corticosteroid feedback inhibition contributes to habituation. Specific Aim 4. To determine if there is an increase in corticosteroid receptor level as a consequence of exposure to repeated restraint stress. Specific Aim 5. To determine if there is an increase in corticosteroid receptor activation by corticosterone as a consequence of exposure to repeated restraint stress. A series of studies are proposed which will use the rat as an in vivo system for studying HPA axis habituation. These studies will utilize a repeated restraint stress regimen that reliably produces habituation of the HPA axis stress response. Characterization of the role of endogenous corticosteroids in the habituation process will be determined in studies in which corticosteroids are systematically manipulated by adrenalectomy and treatment with selective corticosteroid receptor agonists and antagonists Studies will also explore the possibility that a molecular mechanism leading to HPA axis stress habituation is a stress-induced change at the corticosteroid receptor level. Overall, these studies will provide important information about the mechanisms underlying an adaptive response of the HPA axis to repeated stress.