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

Abstract Aims The 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. Methods We 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. Results We 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. Conclusion The orexinergic LHA–LHb pathway facilitates emergence from sevoflurane anesthesia, and this effect was mediated by OxR2 in GAD2‐expressing GABA neurons.