下丘脑室旁核（PVN）促肾上腺皮质激素释放激素（CRH）神经元过度激活引起的下丘脑-垂体-肾上腺（HPA）轴功能异常在应激和抑郁症中扮演重要角色。一氧化氮（NO）对HPA轴活性具有调控作用。CAPON是神经系统NO合酶（nNOS）的接头蛋白，能够负性调控其活性，我们发现抑郁症患者前额叶皮层（PFC）中CAPON表达增加而nNOS表达下调，慢性应激（CUS）大鼠PVN中nNOS表达明显降低，但CAPON介导的nNOS活性调控参与应激抑郁的具体机制并不清楚。本项目拟研究CAPON和nNOS在抑郁症患者和CUS大鼠PFC、PVN中的表达变化以及二者之间的关联，观察靶向下调CUS大鼠PVN中CAPON的表达对nNOS-NO系统、HPA轴活性和抑郁焦虑行为的影响，阐明CAPON介导的下丘脑nNOS-NO系统活性下调促进抑郁应激的分子机制，旨在为以nNOS接头蛋白作为靶点的抗抑郁药物研发提供科学依据。

The dysfunction of hypothalamo–pituitary–adrenal (HPA) axis that initiated by the hyperactivity of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) plays an important role in the pathogenesis of stress and depression. Nitric oxide (NO) is crucial for the regulation of HPA axis activity. CAPON is an adapter protein for neuronal NO synthase (nNOS) and exerts negative regulation on the nNOS activity. We found an up-regulation of CAPON and a down-regulation of nNOS in the prefrontal cortex (PFC) of depressed patients and a significant reduction of nNOS in the hypothalamic PVN of Chronic Unpredicted Stress (CUS) rats. However, it is largely unknown about the exact mechanism that CAPON-mediated nNOS activity regulation participates in stress and depression. This project plan to study the changes of CAPON and nNOS as well as the association between them in the PFC and the hypothalamic PVN of both depressed patients and CUS rats; to observe the effects of specially down-regulating CAPON expression on the nNOS-NO system, HPA axis activity and anxiety/depression behaviors in CUS rats; to elucidated the molecular mechanism by which the CAPON-medicated hypothalamic nNOS-NO system down-regulation promotes stress and depression. We expect to provide scientific evidence for the research and application of those antidepressants targeting nNOS adapter proteins.