Orexinergic innervations at GABAergic neurons of the lateral habenula mediates the anesthetic potency of sevoflurane

AimsThe circuitry mechanism associated with anesthesia-induced unconsciousness is still largely unknown. It has been reported that orexinergic neurons of the lateral hypothalamus (LHA) facilitate the emergence from anesthesia through their neuronal projections to the arousal-promoting brain areas. However, the lateral habenula (LHb), as one of the orexin downstream targets, is known for its anesthesia-promoting effect. Therefore, the current study aimed to explore whether and how the orexinergic projections from the LHA to the LHb have a regulatory effect on unconsciousness induced by general anesthesia. MethodsWe applied optogenetic, chemogenetic, or pharmacological approaches to regulate the orexinergic(LHA-LHb) pathway. Fiber photometry was used to assess neuronal activity. Loss or recovery of the righting reflex was used to evaluate the induction or emergence time of general anesthesia. The burst-suppression ratio and electroencephalography spectra were used to measure the anesthetic depth. ResultsWe found that activation of the orexinergic(LHA-LHb) pathway promoted emergence and reduced anesthetic depth during sevoflurane anesthesia. Surprisingly, the arousal-promoting effect of the orexinergic(LHA-LHb) pathway was mediated by excitation of glutamate decarboxylase (GAD2)-expressing neurons, but not glutamatergic neurons in the LHb. ConclusionThe orexinergic(LHA-LHb) pathway facilitates emergence from sevoflurane anesthesia, and this effect was mediated by OxR2 in GAD2-expressing GABA neurons.