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Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):12826-12831. doi: 10.1073/pnas.1614340113. Epub 2016 Oct 24.

Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia.

Taylor NE1,2,3, Van Dort CJ1,2,3, Kenny JD1,3, Pei J1,3, Guidera JA1,3, Vlasov KY1,3, Lee JT1,3, Boyden ES3,4,5,6, Brown EN7,2,3,8,9, Solt K1,2,3.

Author information

1
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114.
2
Department of Anaesthesia, Harvard Medical School, Boston, MA 02114.
3
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
4
Media Lab, Massachusetts Institute of Technology, Cambridge, MA 02139.
5
McGovern Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.
6
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
7
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114; enb@neurostat.mit.edu.
8
The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139.
9
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.

Abstract

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.

KEYWORDS:

anesthesia; arousal; dopamine; optogenetics; ventral tegmental area

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