Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical College, Zunyi 563000, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
Cell Rep. 2018 Sep 18;24(12):3146-3155.e3. doi: 10.1016/j.celrep.2018.08.046.
How general anesthesia causes loss of consciousness has been a mystery for decades. It is generally thought that arousal-related brain nuclei, including the locus coeruleus (LC), are involved. Here, by monitoring locomotion behaviors and neural activities, we developed a larval zebrafish model for studying general anesthesia induced by propofol and etomidate, two commonly used intravenous anesthetics. Local lesion of LC neurons via two-photon laser-based ablation or genetic depletion of norepinephrine (NE; a neuromodulator released by LC neurons) via CRISPR/Cas9-based mutation of dopamine-β-hydroxylase (dbh) accelerates induction into and retards emergence from general anesthesia. Mechanistically, in vivo whole-cell recording revealed that both anesthetics suppress LC neurons' activity through a cooperative mechanism, inhibiting presynaptic excitatory inputs and inducing GABA receptor-mediated hyperpolarization of these neurons. Thus, our study indicates that the LC-NE system plays a modulatory role in both induction of and emergence from intravenous general anesthesia.
全身麻醉如何导致意识丧失几十年来一直是个谜。人们普遍认为，与觉醒相关的脑核，包括蓝斑（LC），参与其中。在这里，我们通过监测运动行为和神经活动，建立了一个幼鱼斑马鱼模型，用于研究异丙酚和依托咪酯诱导的全身麻醉，异丙酚和依托咪酯是两种常用的静脉麻醉剂。通过双光子激光消融局部损伤 LC 神经元或通过 CRISPR/Cas9 基于突变多巴胺-β-羟化酶（dbh）的基因耗竭去甲肾上腺素（LC 神经元释放的神经调质）加速全身麻醉的诱导和苏醒。从机制上讲，体内全细胞膜片钳记录显示，两种麻醉剂都通过协同机制抑制 LC 神经元的活性，抑制突触前兴奋性输入，并诱导这些神经元的 GABA 受体介导的超极化。因此，我们的研究表明，LC-NE 系统在静脉全身麻醉的诱导和苏醒中发挥调节作用。
