杏仁核中间神经元集合体的NRG1-ErbB4信号通路对恐惧情感加工的调控作用及其机制研究

Fear emotional deficit is one of the most common negative symptoms of schizophrenia and seriously affect the patients’ rehabilitation and quality of life. So far, there is no effective treatment for fear emotional deficit of schizophrenia. It has been suggested that the pathogenesis of fear emotional deficit is associated with the functional disorder of interneuronal synaptic transmission in the amygdala. But the specific molecular signaling pathways and neural circuits are still not fully elucidated. Our preliminary study showed that Neureglin-1(NRG1, susceptibility gene for schizophrenia) and its ErbB4 receptors in the intercalated cell mass(ITC) of the amygdala are the essential signaling pathway for fear emotion processing. Based on our previous work, the proposed study will use genetically modified mice to perform activity-dependent in-vivo cell labeling, neuronal retrograde/anterograde tracing, electrophysiological recording, optogenetic experiment, fear conditioning test and so on.The present project will further identify the role of ITC NRG1-ErbB4 in regulating the acquisition，expression and extinction of fear memory, and the neuronal circuit and synaptic plasticity mechanisms. This project will shed new light on the pathogenic mechanisms of the aberrant NRG1-ErbB4 signaling, help further understand the pathological mechanisms of the emotional deficit in schizophrenia and suggest potential therapeutic targets for them.

恐惧情感加工障碍是精神分裂症最常见的阴性症状之一，缺乏有效治疗，严重影响患者的康复和生活质量。恐惧情感加工障碍的发生与杏仁核中间神经元突触环路功能异常有关，但具体分子机制不明。神经调节素-1（NRG1）及其受体ErbB4均是精神分裂症易感基因，我们前期研究发现杏仁核中间神经元集合体（ITC）的NRG1-ErbB4通路对恐惧情感加工具有调控作用。本项目拟运用基因敲除或过表达小鼠，结合在体活细胞标记、神经逆行/顺行示踪、电生理、光遗传学以及恐惧条件反射等实验手段，进一步确定ITC的NRG1-ErbB4通路在恐惧记忆的获取、表达和消退三个不同环节的调控作用，及其神经环路和突触可塑性机制。本项目将揭示NRG1--ErbB4通路异常新的致病机理，为精神分裂症恐惧情感加工障碍提供分子基础，且可能为其治疗提供新靶点。

恐惧情感加工障碍是精神分裂症最常见的阴性症状之一，缺乏有效治疗，严重影响患者的康复和生活质量。恐惧情感加工障碍的发生与杏仁核中间神经元突触环路功能异常有关，但具体分子机制不明。我们运用基因敲除或过表达小鼠，结合在体活细胞标记、神经元逆行/顺行示踪、电生理、光遗传学以及恐惧条件反射等实验展开研究，并发现神经调节素-1（NRG1，精神分裂症易感基因）的受体ErbB4在杏仁核中间神经元集合体（ITC）中有大量表达。ITC来源的NRG1及其受体ErbB4对恐惧记忆的消退有调控作用。NRG1-ErbB4信号通路对于调节BLA对CeM的突触前抑制和恐惧记忆消退具有重要作用。抑制NRG1不会增加BLA神经元向ITC神经元的兴奋性输入，但会导致CeM神经元的抑制作用减少和恐惧记忆消退障碍。我们还发现，ITC中的NRG1-ErbB4信号通路可能通过P / Q型Ca2 +通道（VACC），而不是通过L型或N型VACC来调节GABA能突触传递和恐惧记忆消退。本项目将为NRG1--ErbB4通路异常的致病机理供新的分子机制，揭示精神分裂症恐惧情感加工障碍的新机制，且可能为其治疗提供新靶点。