Melanocortin system stress and HPA axis

描述(由申请人提供)：压力反应对生存很重要。然而，长期暴露在压力源下会产生有害的影响，增加焦虑症、抑郁症、饮食失调和肥胖的易感性。这些疾病的一个共同特征是下丘脑-垂体-肾上腺(HPA)轴的紊乱。促肾上腺皮质激素释放激素(CRH)在应激反应，特别是HPA激活中起着关键作用。最近，解剖学和功能研究表明，中枢黑素皮质素系统作为能量平衡的重要调节因子，与应激系统相互作用，并通过CRH调节HPA活性。该系统由两个相对的信号成分组成，内源性激动剂α-MSH和内源性拮抗剂AgRP。这个项目的目标是研究黑素皮质素系统在应激反应中的作用，重点是HPA的激活。首先，我们计划通过原位杂交、受体放射自显影和放射免疫分析来检测应激回路中两个关键结构(下丘脑室旁核和杏仁核)的转录和翻译反应，以确定急慢性应激对α-MSH、AgRP及其共同受体MC4R的调节作用；其次，我们将利用药理学和分子手段改变MC4R的激活状态或表达水平，以确定黑素皮质素系统对HPA对急慢性应激反应的影响。鉴于近年来对该系统的研究主要集中在摄食和体重的调节上，本项目中拟议的研究不仅将阐明黑素皮质素信号在应激中的生物学功能，而且将为应激与饮食失调/肥胖之间的接口提供新的见解。

DESCRIPTION (provided by applicant): Stress response is important for survival. However, prolonged exposure to stressors produces detrimental effects, increasing the susceptibility for anxiety disorders, depression, eating disorders and obesity. A common feature of these illnesses is the perturbation of the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) plays a pivotal role in the mediation of stress responses, particularly HPA activation. Recently, anatomical and functional evidence indicates that the central melanocortin system, a critical regulator of energy balance, interacts with the stress system and modulates HPA activity through CRH. This system consists of two opposite signaling components, the endogenous agonist alpha-MSH and the endogenous antagonist AgRP. The goal of this project is to study the role of the melanocortin system in stress responsiveness, focusing on HPA activation. First, we plan to identify the regulatory effects of acute and chronic stress on alpha-MSH, AgRP and their common receptor MC4R by measuring their transcriptional and translational responses in two key structures within stress circuits (the paraventricular nucleus of the hypothalamus and amygdala) using in situ hybridization, receptor autoradiography and radioimmunoassay; Second, we will determine the impact of the melanocortin system on the HPA response to acute and chronic stress using pharmacologic and molecular means to alter activation status or the expression level of MC4R. Given that studies on this system have been primarily focused on the regulation of feeding and body weight in recent years, the proposed studies in this project will not only shed light on biological functions of melanocortin signaling in stress, but also provide new insights into the interface between stress and eating disorders/obesity.