The role of the dorsomedial periaqueductal gray glutamatergic neurons in promoting arousal under multiple general anesthetics in mice.

Summary

In mice, dmPAG glutamatergic neurons are suppressed during anesthesia and active during wakefulness across volatile and intravenous agents. Optogenetic or chemogenetic activation delays induction, accelerates emergence, and reduces burst-suppression during anesthesia, while inhibition strengthens anesthetic effects. These neurons likely form a shared neural substrate governing loss and recovery of consciousness under general anesthesia.

Key Findings

• dmPAG glutamatergic neuronal activity is suppressed during anesthesia and elevated during wakefulness across sevoflurane, propofol, ketamine, and dexmedetomidine.
• Optogenetic activation prolongs induction (218.8±50.83 s vs 372.5±40.18 s; P<0.001) and shortens emergence (230.8±40.44 s vs 135±19.82 s; P<0.001) under sevoflurane.
• EEG shows wake-like changes with markedly reduced burst-suppression ratio during maintained anesthesia upon dmPAG activation (50.08±8.21% vs 2.15±3.38%; P<0.001).
• Chemogenetic activation mimics, while chemogenetic inhibition potentiates anesthetic effects for all tested agents.

Clinical Implications

Although preclinical, identifying dmPAG glutamatergic neurons as a common arousal node suggests neuromodulatory strategies to hasten emergence, reduce burst-suppression, or counter delayed awakening. It also informs EEG interpretation under anesthesia.

Limitations

• Mouse model limits direct translatability to humans.
• Potential off-target effects and network-level compensations were not fully dissected.

Future Directions

Define upstream/downstream circuits of dmPAG neurons, test targeted neuromodulation for accelerating emergence, and validate translatability with human neuroimaging and intraoperative EEG paradigms.