Orexin signalling in the nucleus accumbens promotes arousal from isoflurane anaesthesia and restores communication between the nucleus accumbens and frontal cortex

Abstract

Background: Orexin can induce arousal from general anaesthesia; however, the underlying mechanisms are not fully understood. Nucleus accumbens (NAc), a downstream target of orexinergic neurones, plays a role in regulating consciousness. We aimed to clarify whether and how the NAc mediates the arousal effects of orexin.

Methods: Fibre photometry was used to track changes of orexinergic afferent activity during isoflurane anaesthesia and arousal from anaesthesia. Optogenetics was used to study the effects of orexinergic afferents to the NAc. Neuropharmacology approaches were used to assess receptor mechanisms. Optogenetics and in vivo electrophysiology were used to assess the influence of orexin on NAc neuronal firing and communication between the NAc and the frontal cortex.

Results: Orexinergic afferents in the NAc were wake-active during isoflurane anaesthesia and the arousal process. Optogenetic activation of orexinergic terminals in the NAc prolonged the time to induction, shortened time to emergence, and reduced the burst suppression ratio (from 67.4% [2.5%] to 14.5% [1.0%]; n=6, P<0.001) during 1.4 vol% isoflurane anaesthesia. Microinjection of orexin-A into the NAc promoted arousal from isoflurane anaesthesia. Orexin-1 receptors were primarily expressed in NAc D1 receptor-positive (D1R⁺) neurones. Optogenetic activation of orexinergic terminals increased D1R⁺ neuronal firing (from 0.77 [0.54] spikes s^-1 to 2.53 [0.46] spikes s^-1; n=24, P=0.0194) and restored NAc-to-frontal cortex coherence during isoflurane anaesthesia.

Conclusions: Orexin restores communication between the NAc and frontal cortex by upregulating the activity of D1R⁺ neurones, thereby promoting arousal from isoflurane anaesthesia.

Keywords: D1 receptor; arousal; coherence; general anaesthesia; isoflurane; nucleus accumbens; orexin.