Ventral Tegmental Area Glutamatergic Neurons Facilitated Emergence From Isoflurane Anesthesia Involves Excitation of Lateral Septum GABA-ergic Neurons in Mice

BACKGROUND:Ventral tegmental area (VTA) glutamatergic neurons promote wakefulness in the sleep-wake cycle; however, their roles and neural circuit mechanisms during isoflurane (ISO) anesthesia remain unclear. METHODS:Fiber photometry and in vivo electrophysiology were used to observe the changes in neuronal or terminal activity during ISO anesthesia and arousal processes. Optogenetic and anesthesia behaviors were used to investigate the effects of VTA glutamatergic neurons and their projections to the lateral septum (LS) during ISO anesthesia and arousal. Anterograde and retrograde tracings were performed to identify the connections between VTA glutamatergic neurons and the LS. RESULTS:Population activity and firing rates of VTA glutamatergic neurons decreased during ISO anesthesia (ISO: 95% confidence interval [CI], 0.83-2.06 Spikes.s(-1) vs wake: 95% CI, 3.53-7.83 Spikes.s(-1); P =.0001; n = 34 from 4 mice). Optogenetic activation of VTA glutamatergic neurons reduced the burst-suppression ratio in electroencephalography (laser: 95% CI, 13.09%-28.76% vs pre: 95% CI, 52.85%-71.59%; P =.0009; n = 6) and facilitated emergence (ChR2: 95% CI, 343.3-388.0 seconds vs mCherry: 95% CI, 447.6-509.8 seconds; P < .0001; n = 11/12) from ISO anesthesia. VTA glutamatergic neurons monosynaptically innervated LS gamma-aminobutyric acid (GABA)-ergic neurons. The activity of VTA glutamatergic terminals in the LS decreased during ISO anesthesia, and optogenetic activation of the VTA glutamatergic terminals in the LS facilitated emergence from ISO anesthesia. Furthermore, optogenetic activation of VTA glutamatergic terminals increased the firing rates of LS gamma-aminobutyric acid-ergic (GABAergic) neurons (laser: 95% CI, 0.85-4.03 Spikes.s-1 vs pre: 95% CI, 0.24-0.78 Spikes.s-1; P =.008; n = 23 from 4 mice) during ISO anesthesia. CONCLUSIONS:VTA glutamatergic neurons facilitated emergence from ISO anesthesia involving excitation of LS GABAergic neurons.