Corticosteroid Dependent Mechanisms of Stress Adaptation

压力不仅会触发专门的压力反应系统的即时反应，还会触发适应性过程，这一过程表现为随后的压力反应的幅度发生了变化。因此，暴露在反复的应激中往往会导致应激反应的习惯性或敏感化。尽管在理解对应激的即时生理反应以及重复应激的一些生理后果方面取得了实质性进展，但在理解有助于应激反应习惯化或敏化的适应过程方面进展甚微。然而，这些适应过程可能对决定压力的长期生理和心理后果至关重要。有些心理障碍可能与敏感化应激反应的发展(例如创伤后应激障碍)或与应激反应习惯化的损害发展(例如抑郁症)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由盐皮质激素受体(MR)介导的脑内皮质类固醇激素活性。拟议中的项目将进一步研究皮质酮调节压力习服的机制。其具体目的是：(1)确定MR拮抗剂调节HPA轴应激习服的解剖部位(S)；(2)确定HPA轴应激习服的表达及其被MR拮抗剂阻断是否与下丘脑室旁核促肾上腺皮质激素释放激素(CRH)和精氨酸加压素(AVP)基因表达的变化有关；(3)确定HPA轴应激习服是否与依赖MR介质皮质类固醇负反馈的HPA轴普遍移位有关。以及(4)确定HPA轴应激习服是否与大鼠脑内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.