eCB介导的DSI效应在麻醉-觉醒调节中的作用及机制

全球每年近2亿人需要接受麻醉，而全麻机制研究已被Science杂志列为全球125个未解科学谜团之一。申请者及国外研究证实网络调控是全麻机制的核心，并且orexin及GABA等神经递质调控麻醉-觉醒，然而其通过何种调控途径实现相互抑制或激动，从而实现麻醉-觉醒这一转换过程尚缺乏线索。新近发现去极化诱导的去抑制（DSI）在不同种类的神经突触调控中发挥重要作用，且orexin可通过内源性大麻素2-AG及其受体产生DSI效应，减少GABA的释放。我们的假说是，麻醉觉醒过程中orexin含量急剧增高，激活突触后orexin受体，通过DSI逆行性抑制突触前膜GABA信号，从而产生麻醉向觉醒转换的主动调节过程。本研究拟构建神经元特异性基因敲除小鼠，利用free-moving动物模型结合微注射、在体微透析及电生理技术，阐明DSI突触信号在全麻觉醒主动调节中的作用机制，为揭示麻醉-觉醒神经网络调控奠定基础。

Although 200 million patients are undergone anesthesia procedures each year in the world, the mechanism of general anesthetics is still a fundamental question puzzling the neuroscience world. It has been listed as one of the 125 leading unsolved science questions by Science in 2005. Up to date, it is well accepted that neural signals network may be attributed to the mechanism of general anesthesia.Accumulated evidences from our and other groups support that orexinergic and GABAergic neural pathways are crucial for regulating anesthesia-arousal cycle.However,how do the neural pathways regulate each other is unclear. A novel retrograde synaptic signals regulation, which called DSI (depolarization induced suppression of inhibitory), has been found recently. Orexinergic signal can induce DSI effect on GABAergic neural through endocannabinoids system. The aim of current project is to explore the role of DSI in regulative effect of orexin to GABA neuronal pathway in the transformation from anesthesia to wakefulness. This hypothesis will be tested through in vivo and in vitro studies by the neuropharmacological and electrophysological techniques as well as the transgenic animal models. The findings of current research project will facilitate the understanding of proactive role of orexin in awakening, and to lay the foundation for exploring the regulation of neuronal network among various neuronal pathways in anesthesia-arousal transformation.