Journal
CELL REPORTS
Volume 24, Issue 12, Pages 3146-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.08.046
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Funding
- Shanghai Science and Technology Committee [18JC1410100]
- Key Research Program of Frontier Sciences [QYZDY-SSW-SMC028]
- Strategic Priority Research Program of the Chinese Academy of Science [XDBS01000000]
- Natural Science Foundation of China [31325011, 81571026]
- China Wan-Ren Program
- Shanghai Leading Scientist Program
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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-beta-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(A) 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.
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