Role of the Supramammillary Nucleus-Medial Septum Glutamatergic Pathway in Mediating the Effects of Isoflurane Anesthesia.

Summary

In mice, SuM glutamatergic neuron activity is suppressed by isoflurane and rebounds upon emergence. Optogenetic/chemogenetic activation of SuM→medial septum projections reduced EEG delta and burst suppression, increased arousal-related physiology, and markedly shortened emergence time. This identifies a discrete arousal circuit that can bidirectionally modulate anesthetic depth and emergence.

Key Findings

• SuM glutamatergic activity decreased during isoflurane anesthesia and recovered with emergence.
• Optogenetic activation reduced EEG delta power (≈51% to ≈32%, n=8, P=0.002) and burst suppression ratio (≈82% to ≈45%, n=8, P=0.002).
• Activation enlarged pupil diameter, increased respiratory rate and blood pressure, and accelerated emergence (≈171 s to ≈60 s, n=8, P=0.007).
• Chemogenetic activation mirrored, and inhibition opposed, these effects.
• Stimulating SuM terminals in the medial septum replicated cortical/physiologic effects and increased medial septum glutamatergic neuron activity.

Clinical Implications

While preclinical, the SuM→medial septum pathway could be a target to speed emergence, reduce burst suppression, or stabilize respiration under anesthesia. It may inform development of pro-emergence adjuncts or closed-loop depth-of-anesthesia algorithms.

Limitations

• Preclinical mouse model; translational validity to humans remains to be established
• Focused on isoflurane; generalizability to other anesthetics is uncertain

Future Directions

Test whether pharmacologic or neuromodulatory manipulation of SuM or medial septum can safely hasten emergence in larger animals/humans and integrate circuit biomarkers into closed-loop anesthesia systems.