A direct central amygdala-ventral tegmental area GABAergic circuit modulates anaesthesia through dopaminergic disinhibition in mice.

Abstract

The central nucleus of the amygdala (CeA) is a multifunctional structure involved in the regulation of fear, pain, and feeding behaviours, and also plays a key role in modulating consciousness. CeA GABAergic neurones, activated by general anaesthetics, mediate analgesic effects that appear to be independent of sedation. However, the extent to which a circuit-based CeA GABAergic framework contributes to anaesthesia-arousal regulation remains unclear. In vivo electrophysiology and fibre photometry were used to monitor CeA^Vgat neuronal activity during anaesthesia. Optogenetic and chemogenetic manipulations, combined with EEG and behavioural assessments, were used to test neurocircuit modulation of the transition between anaesthesia-arousal states. In vitro patch-clamp electrophysiology was used to explore the underlying mechanism of the CeA^Vgat-ventral tegmental area (VTA) circuitry under isoflurane anaesthesia. CeA^Vgat neuronal activity was associated with isoflurane anaesthesia: 63.3% of CeA^Vgat neurones exhibited reduced firing during anaesthetic induction, with a gradual recovery observed during emergence. Chemogenetic activation of CeA^Vgat neurones delayed anaesthetic induction and accelerated emergence. Optogenetic activation of CeA^Vgat neurones and their terminals in the VTA reduced EEG burst suppression and altered spectral power during maintenance. Patch-clamp recordings demonstrated mutual disinhibition via inhibitory CeA^Vgat projections to VTA dopaminergic neurones. These findings highlight a critical role for CeA^Vgat neurones in modulating wakefulness. Disinhibitory projections from CeA to VTA promote behavioural and cortical emergence from isoflurane anaesthesia, identifying a novel neural circuit underlying consciousness regulation.