CORTICOSTEROID RECEPTORS AND HPA AXIS ADAPTATION

这项建议的长期目标是确定 神经荷尔蒙机制，有助于 下丘脑-垂体-肾上腺(HPA)轴，以适应重复的压力。 拟议研究的目标是确定 习惯化过程中的皮质类固醇反馈抑制。整体而言 这些研究的假设是皮质类固醇反馈抑制 有助于HPA轴习惯于重复 压力。这些研究可能对理解一些 精神障碍的神经病理学基础，如临床 抑郁症。例如，抑郁症被描述为一种压力- 相关障碍。许多抑郁症患者的HPA轴是 多动症，以及与之相关的许多身体和行为症状 患有抑郁症的人与处于急性应激状态的人相似。因此， 抑郁症可能是一种习惯于日常生活的能力 压力是受损的。对导致HPA的机制的理解 轴心应激习惯可能指向抑郁个体的因素 被改变的基因，从而阻止了对压力的充分适应。这个 提出了以下5个具体目标： 具体目标1.进一步描述习惯化的程度 Hpa轴对重复约束应力的反应依赖于 皮质酮。 具体目标2.确定HPA轴对 皮质类固醇反馈抑制有助于习惯化。 具体目标3.确定延迟性皮质类固醇反馈抑制 有助于习惯化。 具体目标4.确定是否存在皮质类固醇的增加 受体水平是暴露在反复束缚应激下的结果。 具体目标5.确定皮质类固醇激素是否增加 暴露于空气中皮质酮对受体的激活 反复的束缚压力。 建议进行一系列研究，将大鼠作为活体动物 用于研究HPA轴习服的系统。这些研究将利用 反复束缚应激疗法，可靠地产生习惯化 HPA轴的应激反应。内源性基因的作用特征 习服过程中的皮质类固醇将在研究中确定。 通过肾上腺切除系统地控制皮质类固醇 并使用选择性皮质类固醇受体激动剂和 拮抗剂研究还将探索一种分子 导致HPA轴应激习服的机制是应激诱导的 皮质类固醇受体水平的变化。总体而言，这些研究将 提供有关自适应的基础机制的重要信息 HPA轴对重复应激的反应。

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.