Dorsal raphe serotonergic neurons facilitate arousal from sevoflurane anesthesia by heterogeneously modulating neuronal activity in the basolateral amygdala

Background: Although the dorsal raphe nucleus (DRN) serotonergic neurons-which play a key role in consciousness-send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying their role in general anesthesia regulation remain elusive.

Methods: Fiber photometry was used to monitor DRN serotonergic activity changes in the BLA during sevoflurane anesthesia and arousal process. Optogenetics and neuropharmacology were taken advantage to study the effects and receptor mechanisms. Additionally, in vivo electrophysiology was applied to elucidate the neurophysiological mechanisms underlying DRN serotonergic modulating BLA during sevoflurane anesthesia and arousal process.

Results: DRN serotonergic afferents in the BLA exhibited decreased activity during sevoflurane anesthesia compared to wakefulness. Optogenetic activation of DRN serotonergic terminals in BLA accelerated arousal from sevoflurane anesthesia, as evidenced by electroencephalographic (EEG) signatures and behavioral recovery. Microinjection of 5-hydroxytryptamine (5-HT)1A receptors agonist (but not 5-HT2A or 5-HT2C agonists) into the BLA similarly promoted anesthetic emergence. Mechanistically, DRN serotonergic input inhibited GABAergic neurons while exciting glutamatergic neurons in the BLA, with these effects persisting across both wakefulness and anesthetic states.

Conclusions: Our findings establish a functional role for the DRN serotonergic-BLA neural pathway in promoting arousal from sevoflurane general anesthesia. These results provide novel mechanistic insights into the neural circuitry underlying consciousness recovery.

Arousal; Basolateral amygdala; Dorsal raphe nucleus; General anesthesia; Serotonin.