A glutamatergic projection from the central medial thalamic nucleus to the red nucleus regulates states of consciousness during sevoflurane anesthesia in mice

General anesthetics like sevoflurane are clinically essential, yet the neural circuits governing their induction of unconsciousness and recovery remain incompletely defined. Here, we show the potential involvement of the vesicular glutamate transporter 2 (Vglut2)-expressing glutamatergic neurons in the central medial thalamus (CMT Vglut2 neurons) in modulation states of consciousness under sevoflurane anesthesia. Results show that CMT Vglut2 neuron activity revealed a reduction during the loss of consciousness and a subsequent elevation upon recovery of consciousness under sevoflurane anesthesia. Chemogenetic activation of CMT Vglut2 neurons delays induction and hastened recovery from sevoflurane anesthesia. Moreover, during sustained sevoflurane anesthesia at steady state, optogenetic activation of CMT Vglut2 neurons facilitates cortical activation and behavioral recovery. During burst suppression under sevoflurane, this stimulation elicits cortical arousal and declines the burst-suppression ratio. Conversely, inhibiting CMT Vglut2 neurons via chemogenetic or optogenetic methods produces greater sensitivity to sevoflurane anesthesia and deepens cortical suppression, respectively. Monosynaptic connections from CMT Vglut2 neurons to red nucleus glutamatergic neurons (RN Vglut2 neurons) are identified using combined retrograde and anterograde tracing. During sevoflurane anesthesia, optogenetic activation of CMT Vglut2 -RN terminals triggers cortical activation. Overall, these findings identify the CMT Vglut2 -RN pathway as a neural circuit regulating cortical activation and behavioral arousal under various stages of sevoflurane-induced anesthesia.