Role of Supramammillary Nucleus Glutamatergic Neurons in Modulating Consciousness Transitions during Propofol Anesthesia in Mice

Background: Glutamatergic neurons in the supramammillary nucleus (SuM) have previously been shown to be pivotal parts of the wakefulness–sleep regulation system. However, whether they play a role in propofol-mediated modulation of consciousness remains unclear. This study hypothesized that glutamatergic neurons in the SuM contribute to the regulation of altered states of consciousness under propofol anesthesia in mice. Methods: The effects of propofol anesthesia on neuronal activity were measured by calcium fiber photometry recording. Lesions and chemogenetic activation were used to investigate the role of glutamatergic neurons in the SuM in anesthesia induction, emergence, and sensitivity to propofol. Optogenetic methods were used to further explore the effects of SuM glutamatergic neurons or the projections from the SuM to the medial septum (MS) on cortical activity and behavioral changes during the maintenance of propofol anesthesia. Results: Activities of glutamatergic neurons in the SuM decreased before propofol-induced loss of consciousness and rapidly increased at the onset of consciousness recovery. Chemogenetic ablation of glutamatergic neurons in the SuM reduced the induction time (monomeric Cherry [mCherry] vs. Caspase 3; mean ± SD, 150.1 ± 25.3 s vs. 97.3 ± 22.2 s; P < 0.001; n = 12) and prolonged the recovery time (1,536.0 ± 422.8 s vs. 2,672.0 ± 1,048.0 s; P < 0.001; n = 12) under propofol anesthesia. Chemogenetic activation of glutamatergic neurons in the SuM had opposite effects. Optogenetic stimulation of glutamatergic neurons in the SuM or the neuronal projections from the SuM to the MS induced behavioral arousal and cortical activation during the maintenance of propofol anesthesia. Conclusions: Glutamatergic neurons in the SuM and their projections to the MS contribute to the regulation of altered states of consciousness under propofol anesthesia in mice.