The Locus Coeruleus Modulates Intravenous General Anesthesia of Zebrafish via a Cooperative Mechanism

• Published in: Cell reports (Cambridge) Vol. 24; no. 12; pp. 3146 - 3155.e3
• Main Authors: Du, Wen-jie, Zhang, Rong-wei, Li, Jia, Zhang, Bai-bing, Peng, Xiao-lan, Cao, Song, Yuan, Jie, Yuan, Cheng-dong, Yu, Tian, Du, Jiu-lin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.09.2018; Elsevier
• Subjects: Anesthetics, Intravenous - pharmacology; Animals; Dopamine beta-Hydroxylase - genetics; etomidate; Etomidate - pharmacology; GABAergic Neurons - drug effects; GABAergic Neurons - metabolism; GABAergic Neurons - physiology; intravenous general anesthesia; Locomotion; locus coeruleus; Locus Coeruleus - drug effects; Locus Coeruleus - metabolism; Locus Coeruleus - physiology; norepinephrine; Norepinephrine - metabolism; propofol; Propofol - pharmacology; Synaptic Potentials; Zebrafish; Zebrafish Proteins - genetics; norepinephrine; etomidate; zebrafish; propofol; intravenous general anesthesia; locus coeruleus
• ISSN: 2211-1247; 2211-1247
• 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 GABAA 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. [Display omitted] •Intravenous anesthetics induce general anesthesia in larval zebrafish•Impairment of the locus coeruleus (LC)-norepinephrine system affects anesthesia•Anesthetics suppress LC neuronal activities via pre- and postsynaptic mechanisms•Larval zebrafish is an ideal model for investigation of general anesthesia The locus coeruleus (LC)-norepinephrine (NE) system is involved in general anesthesia. Here, Du et al. show that the LC-NE system plays a modulatory role in the induction and emergence of intravenous general anesthesia induced by propofol and etomidate, both of which suppress LC neuronal activities through a cooperative mechanism.