应激假说是抑郁症发病的主要学说之一，认为皮质醇通过其受体介导的对下丘脑-垂体-肾上腺（HPA轴）的“远程负反馈”调节具有重要的生理学意义。在本研究中，申请人提出了促肾上腺皮质激素（ACTH）通过其脑内受体介导了另外一条HPA轴的“短程负反馈”。申请人拟采用微透析及免疫电镜的方法观察下丘脑内源性ACTH在应激情况下的释放，并通过活体钙成像技术和光遗传学技术研究内源性ACTH释放对应激反应的调节作用。ACTH在中枢神经的功能很可能是黑皮质激素受体3或4（MC3R或MC4R）介导的，为了证实这一假说，申请人将通过基因工程技术来选择性敲除下丘脑MC3R或MC4R的表达来研究是否影响ACTH对HPA轴的调节功能，最后，申请人将通过合作研究的方式研究ACTH在抑郁症患者下丘脑中的表达。申请人的研究将为潜在的针对ACTH信号通路的新型药物作用靶点提供理论依据，有望填补我们国家在抗抑郁症药物领域的空白。

In the modern western society, depression is the most frequently diagnosed mental disorder, which cause a poor quality of life and have negative socioeconomic consequence for individuals, families, and society. In the present proposal, we hypothesized that ACTH mediates a short-term negative feedback for HPA axis activity in addition to the classic long-term feedback during stress response. In order to test our hypothesis, we aim to answer the following questions: 1) Whether acute stress triggers the hypothalamic ACTH release? 2) Whether the hypothalamic ACTH regulates HPA axis activity during stress response? 3) Which receptors mediate ACTH effect on HPA axis and how the activation of receptors regulate CRH neuronal activity? 4)Whether the hypothalamic expression of ACTH changed in depression patients? The proposed study will provide a new insight to develop a novel treatment for depression in targeting ACTH signal within hypothalamus.