Melanocortin system stress and HPA axis

描述（由申请人提供）：应激反应对生存很重要。然而，长时间暴露于压力源会产生有害影响，增加焦虑症、抑郁症、饮食失调和肥胖症的易感性。这些疾病的一个共同特征是下丘脑-垂体-肾上腺（HPA）轴的扰动。促肾上腺皮质激素释放激素（CRH）在介导应激反应，特别是HPA激活中起着关键作用。最近，解剖学和功能证据表明，中央黑皮质素系统，能量平衡的关键调节器，与应激系统相互作用，并通过CRH调节HPA活性。该系统由两种相反的信号传导组分组成，内源性激动剂α-MSH和内源性拮抗剂AgRP。本项目的目标是研究黑皮质素系统在应激反应中的作用，重点是HPA激活。首先，我们计划通过测量应激回路中两个关键结构的转录和翻译反应来确定急性和慢性应激对α-MSH、AgRP及其共同受体MC 4 R的调节作用（下丘脑室旁核和杏仁核）的原位杂交、受体放射自显影和放射免疫分析;其次，我们将确定黑皮质素系统对HPA对急性和慢性应激的反应的影响，使用药理学和分子手段来改变MC 4 R的激活状态或表达水平。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，本项目的拟议研究不仅将揭示应激中黑皮质素信号传导的生物学功能，而且还将为应激与进食障碍/肥胖之间的界面提供新的见解。

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.