Basal forebrain-ventral tegmental area glutamatergic pathway promotes emergence from isoflurane anesthesia in mice

Abstract

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, the authors show that the activity of BF glutamatergic neurons decreased during the induction of isoflurane anesthesia and restored during the emergence in mice. Optogenetic activation of BF glutamatergic neurons accelerated the emergence from isoflurane anesthesia, decreased isoflurane sensitivity, and increased arousal score of mice. Moreover, optogenetic activation of BF glutamatergic neurons decreased EEG delta power and burst-suppression ratio, while increased pupil size and respiration rate of mice during isoflurane anesthesia. Similar results were observed during the optogenetic activation of BF glutamatergic terminals in the ventral tegmental area (VTA). Additionally, the authors found that the activity of BF glutamatergic neurons and VTA glutamatergic neurons synchronously fluctuate during isoflurane anesthesia, and optogenetic activation of BF glutamatergic terminals in the VTA potently increased the calcium signals of VTA glutamatergic neurons during isoflurane anesthesia. Collectively, their study illustrated that BF glutamatergic neurons promote isoflurane anesthesia emergence via activating VTA glutamatergic neurons. Both male and female mice were used in this study.Statement of Significance General anesthesia is widely used in modern medicine; however, its specific neural mechanisms remain poorly understood. The basal forebrain (BF) is a critical component of the ascending arousal system, and its glutamatergic neurons were implicated in sleep-wake behavior and cortical activity. Here, we report that optogenetic activation of BF glutamatergic neurons significantly promoted cortical activation, behavioral emergence and physiological indicators in mice under isoflurane anesthesia. Photostimulation of BF glutamatergic terminals in the ventral tegmental area (VTA) produced similar effects, and significantly increased the activity of VTA glutamatergic neurons. Our findings illustrated that BF glutamatergic neurons promote emergence from isoflurane anesthesia via VTA glutamatergic neurons, highlighting a potential target for attenuating anesthesia depth and accelerating anesthesia emergence in clinical anesthesia.