nNOS与其转接蛋白相互作用调控焦虑行为的海马神经环路机制

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.

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。

焦虑症是严重影响生命与健康的情感障碍性疾病，需深入研究控制焦虑情绪的机制以发现新的治疗靶标，研发新的抗焦虑剂。本项目研究发现nNOS-CAPON耦联是通过Dexras1-ERK信号通路调控焦虑行为，可作为研发抗焦虑药的新靶点。基于CAPON的羧基端肽与nNOS的PDZ结构域结合的化学机制，我们设计并合成了系列化合物，获得选择性阻断nNOS-CAPON耦联的非肽类小分子化合物，该药物能快速产生抗焦虑作用。创伤后应激障碍和其他焦虑症均源于恐惧记忆调控失常。临床上通过暴露治疗，即反复将患者暴露于诱发恐惧的刺激，以熄灭习得的恐惧记忆，在动物实验成为恐惧消退。恐惧记忆的消退依赖于NMDA受体激活。因激活NMDA受体常导致异常情绪行为，直接靶向NMDA受体是不可取的。本项目研究发现，NMDA受体激活及其介导的nNOS-PSD-95耦联反向调控恐惧记忆消退，加之阻断nNOS-PSD-95有抗抑郁和抗焦虑作用，因此其可以作为恐惧记忆消退的靶标。更为有趣的是，我们发现阻断mPFC的下边缘叶皮层（IL）的nNOS-CAPON可以阻止恐惧记忆的自发恢复。此外，我们还研究了广泛焦虑患者的海马神经环路机制和可能的分子调控机制。本项目研究成果在Nature Med、J Neurosci、Sci Rep 等刊物发表标注本项目基金号论文12篇，另有2篇论文在准备中，申请发明专利9项，授权7项，获教育部自然科学奖二等奖1项。