Dopaminergic Projections From The Ventral Tegmental Area To The Nucleus Accumbens Mediate Sevoflurane Anesthesia

Objective:Studies have demonstrated that sleep-wake pathways in the brain is implicated in the underlying mechanism of general anesthesia,of which dopaminergic pathway play a vital role in modulation of sleep-wake.The projection from ventral tegmental area（VTA）to the nucleus accumbens（NAc）is an essential dopaminergic pathway and participates in reward,addiction,and sleep-wake.However,the role of the dopaminergic pathway in general anesthesia and its potential mechanisms are still unknown.Methods:1.We used c-Fos staining combined with calcium fiber photometry recording to explore the activity of VTA dopaminergic neurons during sevoflurane anesthesia.To observe the alteration in anesthesia-related behavior and electroencephalogram（EEG）,optogenetics were used to active the VTA dopaminergic neurons of mice under sevoflurane anesthesia.2.We using chemogenetics and optogenetics to activate or inhibit the VTA^DA-NAc pathways,observed the change in behavior and EEG during sevoflurane anesthesia.The VTA dopaminergic neurons in sevoflurane anesthesia.EEG spectra and behavioral were recorded as assessment indicators.3.We used c-Fos staining combined with calcium fiber photometry recording to explore the activity of NAc neurons during sevoflurane anesthesia.Then a genetically encoded dopamine sensor was used to investigate the chang of the extracellular dopamine transmitters in NAc during sevoflurane anesthesia.Results:1.The results showed that the VTA dopaminergic neurons were inhibited during the induction period and were activated during the recovery period of sevoflurane anesthesia.Activation of VTA dopaminergic neurons delayed the induction and facilitated the emergence,decreased theδband,which accompanies the gamma band,in EEG.2.Activation of VTA^DA-NAc pathway by chemogenetics prolonged the LORR time of sevoflurane anesthesia,and decreased theδband and increased theγband in EEG.Meanwhile,shortened the RORR time,decreased theδband and increased theγband.Inhibition the VTA^DA-NAc pathway by chemogenetics decreased the LORR time,increased theδband,decrease theθandγband.With the increase of RORR time,increasedδband and decreasedα,θandγband.In addition,photoactivation or photoinhibition of the VTA^DA-NAc pathway produced similar to those of chemical genetic in behavioral and EEG.3.The NAc neurons were inhibited during the induction period and were activated during the recovery period of sevoflurane anesthesia.The amount of extracellular dopamine decreased in the induction of and increased in the emergence from sevoflurane anesthesia.Conclusion:1.VTA^DA neurons were involved in sevoflurane anesthesia;2.Dopamine pathway projecting from VTA to NAc is involved in the regulation of induction and emergence of sevoflurane anesthesia;3.NAc involved in sevoflurane anesthesia by neurons expressing dopamine receptor.