dPAG谷氨酸能神经元功能环路在恐惧相关防御行为中的调控机制

Great attention is paid to mental disorder such as panic and anxiety disorders. The dPAG stimulation could induce fear-associated defensive behaviors, which was considered as good models of anxiety disorder and panic disorder. Although upstream neural circuits of dPAG were reported, the regulations of dPAG neuron subtypes and subgroups are still vague. It is a key question how does a subtype neuron work and regulate the fear-associated defensive behaviors. In this study, we first aim to find out the relationship between dPAG glutamatergic neurons activity and the fear-associated defensive behavior by applying optogenetic strategy. And then combine the reversed genetics, we take a further step to illustrate the “up-stream/down-stream neuron networks” of the single subtype--glutamatergic neurons of dPAG. Moreover, the subtype of up-stream neurons will be identified, the subgroups of dPAG glutamatergic neurons will be found. After all, the function and mechanism of a certain subtype of such up-stream neurons will be investigate to show how the dPAG glutamatergic neuron related neural circuit regulates fear-associated defensive behaviors. Our work will provide a more detailed description of the mechanism of fear by a restricted vision on subtype-specific neurons. As a result, it is foreseen that our work may provide expanded theoretical basis for clinical treatment of fear- or anxiety-associated mental diseases. Moreover, new targets for medical manipulation might be discovered.

社会竞争和突发状况造成恐惧焦虑相关的精神疾病日益高发。研究表明，刺激动物dPAG可诱发恐惧相关防御行为，是良好的模拟人类广泛性焦虑和恐慌发作的动物模型。与此相关的dPAG神经环路虽已有研究，但dPAG内部单一亚型及神经亚群的作用并不明确。我们拟首先通过光遗传技术特异性调节dPAG中谷氨酸能神经元的活性，结合动物行为学和在体电生理技术，探讨该亚型神经元活性与恐惧相关防御行为之间的联系。而后标记dPAG中谷氨酸能神经元的直接上下游，进行神经亚型确认及光遗传操控，阐述不同上下游对应的dPAG谷氨酸能神经元的亚群，细致描述各亚群调控的功能性神经通路，深入探讨它们在恐惧相关防御行为神经环路中的作用。通过本项目的研究，将阐明dPAG中谷氨酸能神经元在恐惧相关防御性行为中的作用机制，同时有望以特定类型神经元的调节作用为突破口，为人类恐惧、焦虑相关精神疾病的临床治疗提供新的基础理论依据和药物靶点。

社会竞争和突发状况造成恐惧焦虑相关的精神疾病日益高发。研究表明，刺激动物dPAG可诱发恐惧相关防御行为，是良好的模拟人类广泛性焦虑和恐慌发作的动物模型。与此相关的dPAG神经环路虽已有研究，但dPAG内部单一亚型/亚群的作用并不明确。我们应用光遗传技术，对dPAG中单一亚型的谷氨酸能神经元进行激活，观察到了恐惧相关防御行为，不同刺激参数可以诱发不同程度的行为响应。Plexon在体电生理记录结果显示，不同程度的防御行为是神经元时域与频域活动的共同结果。应用RV逆行示踪技术，我们追踪了直接支配dPAG中谷氨酸能神经元的多个上游核团，通过脑片免疫荧光来尝试判定部分上游投射神经元的亚型。利用逆行的AAVretro及顺行的AAV1标定了dPAG谷氨酸能神经元所支配的下游核团。进而使用光遗传学对单一下游投射通路激活，拟考察其在恐惧相关防御性为中的作用。本项目研究阐述了dPAG中谷氨酸能神经元活动在恐惧相关防御性行为中的作用机制，描绘了其所在的三级环路，寄希望以特定类型神经元或其支配的下游核团活性调节为突破口，为人类恐惧、焦虑相关精神疾病的临床治疗提供新的基础理论依据和潜在的药物靶点。