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 (CMTVglut2 neurons) in modulation states of consciousness under sevoflurane anesthesia. Results show that CMTVglut2 neuron activity revealed a reduction during the loss of consciousness and a subsequent elevation upon recovery of consciousness under sevoflurane anesthesia.

Chemogenetic activation of CMTVglut2 neurons delays induction and hastened recovery from sevoflurane anesthesia. Moreover, during sustained sevoflurane anesthesia at steady state, optogenetic activation of CMTVglut2 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 CMTVglut2 neurons via chemogenetic or optogenetic methods produces greater sensitivity to sevoflurane anesthesia and deepens cortical suppression, respectively. Monosynaptic connections from CMTVglut2 neurons to red nucleus glutamatergic neurons (RNVglut2 neurons) are identified using combined retrograde and anterograde tracing. During sevoflurane anesthesia, optogenetic activation of CMTVglut2-RN terminals triggers cortical activation.

Overall, these findings identify the CMTVglut2-RN pathway as a neural circuit regulating cortical activation and behavioral arousal under various stages of sevoflurane-induced anesthesia. We are grateful to the Medical Subcenter of the HUST Analytical & Testing Center for their assistance with data acquisition (VS120). This study was supported by the National Natural Science Foundation of China (82471289, 82271291, and 82071556 to W.M.) and the Fundamental Research Funds for the Central Universities (YCJJ20242420 to X.-Y.D.).

These authors contributed equally: Xin-Yi Dai, Jia-Yi Wu. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Xin-Yi Dai, Lin Liu, Wen-lu Song, Hong Wu, Shao-Jie Gao, Long-Qing Zhang, Dai-Qiang Liu, Ya-Qun Zhou & Wei Mei Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China Department of Pain, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, P.R. China Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China Shi-Ling Chen, Ping Zhang & Zhou-Ping Tang Correspondence to Wei Mei or Zhou-Ping Tang.

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