Activation of Glutamatergic Neurons in the Supramammillary Nucleus Promotes the Recovery of Consciousness under Sevoflurane Anesthesia

Abstract Volatile anesthetics have been widely applied during surgery, but the potential mechanisms by which they influence loss of consciousness (LOC), anesthesia maintenance, and recovery of consciousness (ROC) from anesthesia remain largely unknown. Recent studies have suggested that anesthesia‐induced unconsciousness may be due to specific interactions between neural circuits that regulate sleep and wakefulness. Supramammillary (SuM) glutamatergic neurons are essential for sleep‐wakefulness regulation. However, whether SuM glutamatergic neurons are involved in the modulation of consciousness under sevoflurane anesthesia is unclear. Here, it is shown that the activity of SuM glutamatergic neurons decreased prior to sevoflurane‐induced LOC and gradually increased following ROC. Selective lesioning of SuM glutamatergic neurons promoted the induction of and delayed emergence from sevoflurane anesthesia and increased sevoflurane sensitivity. In addition, optogenetic stimulation of SuM glutamatergic neurons or the SuM‐MS projection promoted behavioral arousal and cortical activation under steady‐state sevoflurane anesthesia (SSSA) and reduced the depth of anesthesia and caused cortical arousal under sevoflurane‐induced burst‐suppression conditions. Collectively, these results provide compelling evidence that SuM glutamatergic neurons contribute to regulating states of consciousness under sevoflurane anesthesia.