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，而且触发了适应性过程，这些适应性过程通过随后压力反应的改变程度来表现。 因此，暴露于反复的压力往往会导致习惯化或敏感化的压力反应。虽然在理解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感化的适应过程方面取得的进展很少。然而，这些适应过程可能是决定压力的长期生理和心理后果的关键。 一些心理障碍可能与敏感应激反应的发展（例如创伤后应激障碍）或应激反应习惯化的受损发展（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盐皮质激素受体（MR）介导的脑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习惯的机制。 具体目标是：（1）确定负责HPA轴应激习惯化的MR拮抗剂调节的解剖学部位，（2）确定HPA轴应激习惯化的表达和MR拮抗剂治疗对其的阻断是否与下丘脑室旁核（PVH）中促肾上腺皮质激素释放激素（CRH）和精氨酸加压素（AVP）基因表达的变化相关，（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的依赖性的一般化转变相关，和（4）确定HPA轴应激习惯化是否与大鼠脑中MR或糖皮质激素受体（GR）表达的变化相关。

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.