Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia
Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia
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DOI：
10.1073/pnas.1614340113
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发表时间：
2016-11-08
影响因子：
11.1
通讯作者：
Solt, Ken
中科院分区：
文献类型：
--
作者：
Taylor, Norman E.;Van Dort, Christa J.;Solt, Ken
多巴胺（DA）促进觉醒，DA转运蛋白抑制剂如苯丙胺和哌醋甲酯可有效增加唤醒和诱导苏醒，或从全身麻醉中主动苏醒。腹侧被盖区（VTA）中的DA神经元参与奖赏加工、动机、情感、强化和认知，但它们在调节觉醒中的作用尚不清楚。进行本研究以检验以下假设：腹侧被盖区DA神经元的选择性光遗传学激活足以诱导从无意识的麻醉状态唤醒。在DA转运蛋白（DAT）-cre小鼠（ChR 2+组; n = 6）中，将氟代反（FLEX）-视紫红质2（ChR 2）表达靶向VTA DA神经元。在使用异氟烷的连续稳态全身麻醉（CSSGA）期间，ChR 2+小鼠的光学VTA刺激产生了唤醒的行为和EEG证据，并恢复了6/6只小鼠的翻正反射。在光学VTA刺激前用D1受体拮抗剂SCH-23390预处理可抑制6/6 ChR 2+小鼠的觉醒反应和翻正恢复。在对照DAT-cre小鼠中，用缺乏ChR 2基因的病毒载体靶向VTA（ChR 2组; n = 5）。ChR 2-小鼠中的VTA光学刺激在5/5只小鼠的异氟烷CSSGA期间没有恢复翻正或产生EEG变化。这些结果提供了令人信服的证据表明，选择性刺激腹侧被盖区DA神经元足以诱导从麻醉，无意识状态到清醒状态的过渡，这表明在行为唤醒的关键参与。
Dopamine (DA) promotes wakefulness, and DA transporter inhibitors such as dextroamphetamine and methylphenidate are effective for increasing arousal and inducing reanimation, or active emergence from general anesthesia. DA neurons in the ventral tegmental area (VTA) are involved in reward processing, motivation, emotion, reinforcement, and cognition, but their role in regulating wakefulness is less clear. The current study was performed to test the hypothesis that selective optogenetic activation of VTA DA neurons is sufficient to induce arousal from an unconscious, anesthetized state. Floxed-inverse (FLEX)-Channelrhodopsin2 (ChR2) expression was targeted to VTA DA neurons in DA transporter (DAT)-cre mice (ChR2+ group; n = 6). Optical VTA stimulation in ChR2+ mice during continuous, steady-state general anesthesia (CSSGA) with isoflurane produced behavioral and EEG evidence of arousal and restored the righting reflex in 6/6 mice. Pretreatment with the D1 receptor antagonist SCH-23390 before optical VTA stimulation inhibited the arousal responses and restoration of righting in 6/6 ChR2+ mice. In control DAT-cre mice, the VTA was targeted with a viral vector lacking the ChR2 gene (ChR2-group; n = 5). VTA optical stimulation in ChR2-mice did not restore righting or produce EEG changes during isoflurane CSSGA in 5/5 mice. These results provide compelling evidence that selective stimulation of VTA DA neurons is sufficient to induce the transition from an anesthetized, unconscious state to an awake state, suggesting critical involvement in behavioral arousal.