Corticosteroid Dependent Mechanisms of Stress Adaptation

压力不仅触发了专门的压力反应系统的即时反应，而且还触发了适应性过程，这种过程表现为随后压力反应的变化幅度。因此，暴露在反复的压力下往往会导致压力反应的习惯化或敏化。尽管在理解应激的直接生理反应以及反复应激的一些生理后果方面取得了实质性进展，但在理解导致应激反应习惯化或敏化的适应性过程方面却进展甚微。然而，这些适应过程可能在决定压力的长期生理和心理后果方面至关重要。一些心理障碍可能与敏化应激反应的发展（如创伤后应激障碍）或应激反应适应的受损发展（如抑郁症）直接相关。以往的研究发现，大鼠下丘脑-垂体-肾上腺（HPA）轴应激反应习惯化的表达依赖于脑内由矿化皮质激素受体（MR）介导的皮质类固醇激素活性。拟议的项目将进一步研究皮质酮调节压力适应的机制。具体目标是：(1)确定MR拮抗剂调节HPA轴应激适应的解剖部位；(2)确定MR拮抗剂治疗HPA轴应激适应的表达及其阻断是否与下丘脑室旁核促肾上腺皮质激素释放激素（CRH）和精氨酸抗利尿素（AVP）基因表达的变化有关；(3)确定HPA轴应激习惯化是否与HPA轴对MR介质皮质类固醇负反馈依赖的普遍转变有关；(4)确定HPA轴应激习惯化是否与大鼠脑MR或糖皮质激素受体（GR）表达的变化有关。

Stress triggers not only an immediate response from specialized stress response systems, but triggers adaptive processes that are manifest by an altered magnitude of subsequent stress responses. Thus, exposure to repeated stress often leads to either habituation or sensitization of stress responses. Although substantial progress has been made in understanding the immediate physiological response to stress, as well as some of the physiological consequences of repeated stress, very little progress has been made in understanding the adaptive processes that contribute to stress response habituation or sensitization. These adaptive processes, however, may be crucial in determining the long-term physiological and psychological consequences of stress. Some psychological disorders may be directly, related to the development of sensitized stress responses (e.g. post- traumatic stress disorder) or to the impaired development of stress response habituation (e.g. depression). Previous studies have found in rats that the expression of hypothalamic-pituitary- adrenal (HPA) axis stress-response habituation is dependent on corticosteroid hormone activity in the brain mediated by mineralocorticoid receptors (MR). The proposed project will further study mechanisms by which corticosterone regulates stress habituation. The specific aims are: (1) to determine the anatomical site(s) responsible for MR antagonist modulation of HPA axis stress habituation, (2) to determine whether the expression of HPA axis stress habituation and its blockade by MR antagonist treatment is associated with changes in corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) gene expression in the paraventricular nucleus of the hypothalamus (PVH), (3) to determine whether HPA axis stress habituation is associated with a generalized shift in HPA axis dependence on MR- media corticosteroid negative feedback, and (4) to determine whether HPA axis stress habituation is associated with a change in MR or glucocorticoid receptor (GR) expression in the rat brain.