杏仁核脑区EphrinB2/EphB2信号通路异常介导的负性情绪增强在抑郁症中的作用

临床资料表明，抑郁症患者负性情绪与杏仁核脑区活动增强密切相关，该脑区NMDA受体膜表达亦明显增加。受体酪氨酸激酶EphB2受体及配体EphrinB2是介导NMDA受体膜定位的重要分子。预实验发现，抑郁敏感鼠杏仁核区EphB2蛋白水平较对照组和抵抗组明显增加，其他脑区无明显变化。因此本课题提出，抑郁症可能存在杏仁核区EphrinB2/EphB2信号通路增强，增加NMDA受体的膜簇集和定位，使NMDA受体功能上调，从而促进杏仁核脑区活动，形成持续的负性情绪，介导抑郁症发生发展。本课题拟通过建立应激的体外模型及动物模型，调控EphrinB2/EphB2信号通路不同节点，观察NMDA受体表达、分布及功能改变，探讨杏仁核脑区EphrinB2/EphB2信号通路异常在抑郁症中的作用，为抑郁症防治提供新靶点和新策略，为阐明"厌恶通路"在抑郁症中的意义及机制提供实验依据，为其他情感障碍性疾病防治提供新思路

Numerous clinical studies demonstrate that negative emotions in depressive patients are closely related to the hyperactivity of amygdala mediated by the increase in the surface expression of NMDA receptor. Previous studies show that EphrinB2/EphB2, one of the member of receptor tyrosine kinase family are key regulators of synaptic localization of NMDA receptors. Our preliminary experiments found that the level of EphB2 protein in amygdala was significantly increased in the depression-susceptible mice, but not in other brain areas. Therefore, we hypothesized that the overexpression of EphrinB2/EphB2 signaling pathway in amygdala of depressive patient promoted the synaptic locolization and function of NMDA receptors to increase the amygdala response to negative emotions, resulted in depressive behavior. In this study, the in vitro and in vivo chronic stress models will be employed. The effects of regulation of EphrinB2/EphB2-mediated signaling pathway on the expression, distribution and function of NMDA receptors will be investigated. It is helpful to understand the role and underlying mechanism of the abnormalities of aversive signaling pathway in major depressive disorders. Our study will provide new target and strategy for the treatment of major depressive disorders and other affective disorders.