Basal Forebrain to Ventral Tegmental Area Glutamatergic Pathway Promotes Emergence from Isoflurane Anesthesia in Mice

Recent evidence highlights the importance of glutamatergic neurons in the basal forebrain (BF) in promoting cortical activity; however, whether BF glutamatergic neurons are involved in regulating general anesthesia and the underlying neural circuits remains unclear. Here, we showed that the activity of BF glutamatergic neurons decreased during the induction of isoflurane anesthesia and restored during the emergence in mice. Optogenetic activation of these neurons significantly enhanced cortical activation, accelerated behavioral emergence, and improved physiological indicators in both male and female mice under isoflurane anesthesia. Specifically, activation of BF glutamatergic neurons shortened emergence time from isoflurane anesthesia, decreased isoflurane sensitivity, and increased arousal scores of mice. Moreover, optogenetic activation of BF glutamatergic neurons decreased EEG delta power and burst suppression ratio, while increasing pupil size and respiration rate in mice during isoflurane anesthesia. Similar results were observed during the optogenetic activation of BF glutamatergic terminals in the ventral tegmental area (VTA). Additionally, we found that the activity of BF glutamatergic neurons and VTA glutamatergic neurons synchronously fluctuated during isoflurane anesthesia, and optogenetic activation of BF glutamatergic terminals in the VTA potently increased the calcium signals in VTA glutamatergic neurons during isoflurane anesthesia. Collectively, these findings demonstrate that BF glutamatergic neurons promote emergence from isoflurane anesthesia by activating VTA glutamatergic neurons.