负面情绪记忆遗忘机制的神经环路研究

The onset of depression and post-traumatic stress disorder (PTSD) will have some symptoms such as fear, anxiety and loss of appetite and other negative emotions. How to forget negative emotional memory is the key point for the treatment of these two kinds of diseases. Previous studies have found that the interneurons in BLA (Basolateral amygdala) region play key roles in fear extinction. However, mechanism of fear extinction has not involved in regulating animal behavior level, and there is no more direct evidence showing the role of interneurons. It is known that PBN (Parabrachial nucleus) and BLA are important in regulating the acquisition of the conditions of taste aversion (CTA), but still lack of detailed CTA extinction neural circuit mechanism. Our team successfully construct ArcCreERT2, c - FosCreERT2 CaMKIICreERT2, GAD67CreERT2 transgenic mice, which can be crossbreed with R26RSTOP-floxed-tdTomato mice to mark various types of neural circuits stimulated by negative emotions extinction such as fear and disgust memory. And we have established stable fear extinction and CTA extinction models. So we plan to use these transgenic mice and with the help of optogenetic, GCaMP imaging, in vivo neural electrophysiology, fluorescence micro-optical section tomography and some AAV virus to study (1) the exact role of specific types of interneurons in fear extinction and (2) the function of BLA - PBN neural circuit in CTA extinction and to illustrate whether interneurons play an important role in the mechanism.

抑郁症和创伤后应激障碍的发病过程中均出现恐惧、焦虑及食欲不振等负面情绪。如何遗忘负面情绪记忆是治疗这两类疾病的关键。研究发现杏仁核BLA脑区中间神经元在恐惧记忆的消退中起关键作用，到目前为止恐惧的遗忘机制研究还没有做到在动物行为水平的调控，没有直接证据表明中间神经元的调节作用。在条件味觉厌恶记忆获取研究中，PBN及BLA脑区有重要的调控作用，但其遗忘机制尚无详细研究。本课题组成功构建不同启动子CreERT2转基因小鼠，通过与工具鼠进行交配成功标记恐惧及厌恶等负面情绪记忆及遗忘过程所激活的神经环路，建立出稳定的负面情绪消退模型。因此本课题计划利用上述转基因小鼠，并借助光遗传、钙流监测、在体神经电生理、荧光显微断层切片成像技术及光遗传病毒（1）探究中间神经元在恐惧记忆消退调控机制中的作用，（2）研究BLA-PBN环路在CTA extinction中的调控作用并阐释中间神经元是否发挥重要作用。

抑郁症和创伤后应激障碍的发病过程中均出现恐惧、焦虑及食欲不振等负面情绪。如何遗忘负面情绪记忆是治疗这两类疾病的关键。研究发现基底外侧杏仁核BLA脑区中间神经元在恐惧记忆的消退中起关键作用，到目前为止恐惧的遗忘机制研究还没有做到在动物行为水平的调控，没有直接证据表明中间神经元的调节作用。在条件味觉厌恶记忆CTA的研究中，臂旁核PBN及BLA脑区有重要的调控作用，但其遗忘机制尚无详细研究。本课题组成功构建不同启动子ERT2CreERT2转基因小鼠，通过与工具鼠进行交配成功标记恐惧及厌恶等负面情绪记忆及遗忘过程所激活的神经环路，建立出稳定的负面情绪消退模型。本课题利用上述转基因小鼠，并借助化学遗传学、光遗传学、电生理等技术发现（1）Arc-ERT2CreERT2 x Ai9小鼠恐惧记忆消退阶段在BLA脑区有更多的GABA能神经元激活；（2）化学遗传学抑制恐惧记忆消退阶段参与的神经元能够阻碍恐惧记忆的消退；（3）特异抑制恐惧记忆消退阶段参与的中间神经元也能够阻碍恐惧记忆的消退；（4）光遗传学激活PBN到BLA的投射抑制了CTA记忆的消退。我们的研究结果揭示了（1）中间神经元在恐惧记忆消退调控机制中的重要作用，（2）BLA-PBN环路在味觉厌恶记忆消退中的调控作用。本课题的研究将会为治疗相关疾病和服务人类精神健康提供新的方向。