焦虑是多种重大精神疾病的主要临床表型，其神经环路机制迄今未明。我们先前的工作表明，海马nNOS与其转接蛋白PSD95或CAPON相互作用在情感行为调控中有重要作用。本项目将通过临床及动物实验，阐明焦虑行为调控的海马神经环路，同时采用遗传学、药理学、生物化学等特异手段，研究nNOS与其转接蛋白相互作用是否通过影响海马神经细胞新生和突触结构重塑，更新和整合海马神经环路，从而调控应激诱导的恐惧记忆和焦虑行为，并深入探讨其分子信号通路。鉴于现有抗焦虑药要么副作用严重，要么起效极度缓慢，本项目还针对nNOS-PSD95和/或nNOS-CAPON耦联靶点，研究能够避免现有抗焦虑药缺陷的新机制药物。本项目研究结果将从新的角度深入理解以焦虑为主要临床表型的重大精神疾病的病理机制，并发现抗焦虑的新治疗靶点，获得全新机制的候选抗焦虑药物。

Anxiety behaviors are predominant clinical expression of life-threatening and highly prevalent psychiatric disorders. However, the neural circuit underlying anxiety-related behaviors is poorly understood. Our previous findings indicated that the interaction of nNOS in the hippocampus with its adaptor proteins, including PSD95 and CAPON, plays an important role in modulating emotional behaviors. In this project, we will take insight into the hippocmapal neural circuit of anxiety-related behaviors in animal models and clinical patients. At the same time, by selectively disrupting nNOS-PSD95 and or nNOS-CAPON coupling using genetic, pharmacological and biochemical methods, we will investigate whether the interaction of nNOS with its adaptor proteins remodels hippocmapal neural circuit by changing neurogenesis and synapses structure, thereby modifying stree-related fear memory and anxiety-related behaviors. If so, we will explore its signaling pathway. In view of that unfavorable side effects and extremely hysteretic anxiolytic effects render current antianxiety agents use problematic, we will research novel anxiolytic angents targeting nNOS/PSD95 or nNOS/CAPON coupling and avoiding the problems of current anxiolytic. This project will reveal the hippocampal neural circuit underlying the pathogenesis of psychiatric disorders which are clinically expressed as anxiety behaviors, ascertain a novel target for treating anxiety and obtain potential anxiolytic agents with novel mechanism.