CRH RECEPTORS AND AVP IN ACUTE AND CHRONIC STRESS

下丘脑-垂体-肾上腺(HPA)轴是应激系统的重要组成部分，使人类和其他生物能够对感知到的环境威胁做出反应。该系统最重要的调节因子是促肾上腺皮质激素释放激素(CRH)和加压素(AVP)。HPA轴的失调与几种慢性疾病有关，如抑郁症、神经性厌食症、肥胖、酒精中毒、纤维肌痛和慢性焦虑状态。针对CRH受体的治疗这些疾病的药物的开发正在进行中，尽管慢性阻断CRH受体的效果和代偿机制的发展尚不清楚。该项目的总体目标是利用CRH缺陷的小鼠模型，帮助描绘CRH和AVP在调节应激反应中各自的作用。第一个特定目标将检验这样一个假设，即应激引起的CRH释放下调了自身的反应，上调了下丘脑神经元中AVP的反应。CRH缺陷小鼠和正常小鼠在急性和慢性应激模式下，下丘脑CRH、AVP和CRH受体表达的变化将被检测。第二个具体目标涉及检测c-fos的表达，它被用作大脑中与应激相关区域的神经元激活的标志。通过研究CRH缺陷小鼠和正常小鼠c-fos表达的差异，探讨CRH在慢性应激适应中的可能作用。

The hypothalamic-pituitary-adrenal HPA) axis is an important component of the stress system, which enables humans and other organisms to respond to perceived environmental threats. The most important regulators of this system are corticotropin-releasing hormone (CRH) and vasopressin (AVP). Dysregulation of the HPA axis is implicated in several chronic diseases such as depression, anorexia nervosa, obesity, alcoholism, fibromyalgia, and chronic anxiety states. The development of drugs for these disorders targeting CRH receptors is underway, though the effects of chronically blocking CRH receptors and of the development of compensatory mechanisms are unknown. The overall goal of the proposed project is to help delineate the respective roles of CRH and AVP in modulating the stress response, using the CRH deficient mouse model. The first specific aim will test the hypothesis that CRH release, brought on by stress, down-regulates its own response and upregulates the response of AVP in hypothalamic neurons. Changes in CRH, AVP, and CRH receptor expression in the hypothalamus will be examined in CRH-deficient and normal mice subjected to acute and chronic stress paradigms. The second specific aim involves the detection of c-fos expression, which has been used as a marker for neuronal activation of stress-related areas of the brain. By studying differences in c-fos expression in CRH-deficient and normal mice, the possible role of CRH in adaptation to chronic stress will be explored.