中央杏仁核GABA神经元调控异氟醚麻醉-觉醒的神经环路机制

全麻药物引起意识消失与恢复的神经网络基础尚未阐明，研究显示全麻药物可以影响脑内应激响应核团，但应激网络如何参与麻醉效应仍未可知。研究发现，脑内应激响应核团中脑腹侧被盖区（VTA）多巴胺（DA）神经元激活促进麻醉觉醒，并发现VTA区DA神经元受到该区GABA神经元的前馈抑制调节。已知VTA区GABA神经元是中央杏仁核（CeA）区GABA神经元的重要投射下游。申请者预实验发现兴奋CeA区GABA神经元及其VTA区投射终末，均能使麻醉深度变浅，提示CeA-VTA通路参与麻醉效应。据此提出假说：CeA区GABA神经元对VTA区GABA神经元产生抑制，从而减弱其对VTA区DA神经元的前馈抑制，介导全麻觉醒。本项目拟利用特异性神经元调控结合环路研究手段，通过麻醉行为与EEG特征分析，阐明CeA区GABA神经元通过作用于VTA区调控麻醉意识状态的机制，为明确应激相关神经环路的全麻觉醒调控作用提供依据。

How general anesthetics induce a series of systematic effects including unconsciousness, analgesia, immobility, and amnesia remains elusive. A recent study suggested that, as an external stimulus, anesthetics could activate brain circuits involved in regulation of stress or emotion to exert their clinical effects. The central amygdala (CeA) and ventral tegmental area (VTA) have been verified to be the core brain areas regarding stress, sleep-wakefulness or other behaviors. Moreover, GABAergic neurons in the VTA are one of the most important projection targets of GABAergic neurons in the CeA. Preliminary experiments of this project found that activation of both GABAergic neurons in the CeA and their projection terminals in the VTA could significantly reduce the burst suppression ratios of the cortical electroencephalograms during anesthesia in mice, indicating a decreased depth of general anesthesia. In summary, we proposed the hypothesis that CeA GABAergic neurons could exert a disinhibitory effect on the wake-promoting VTA dopaminergic neurons to facilitate emergence from general anesthesia, through direct inhibition on their downstream VTA GABAergic neurons. Combining electrophysiology, behavioral tests, genetically defined neuronal manipulations, and in vivo microscopic imaging techniques, we plan to explore the regulatory role of CeA GABAergic neurons in the hypnotic effects of general anesthetics, and further reveal the underlying mechanism regarding neural circuits, especially the circuits from CeA GABAergic neurons to VTA GABAergic neurons and then to VTA dopaminergic neurons. This project would not only lay the foundation for the role of stress or emotion-related nuclei and circuits in the regulation of general anesthesia, but also provide a new prespective for comprehensively elucidating the mechanism of general anesthesia.