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

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Abstract
Background: Glutamatergic neurons in the supramammillary nucleus (SuM) have been recently identified as a key node in arousal system, yet their role in regulating general anesthesia remains unclear. The aim of the current study is to examine the role of the glutamatergic supramammillary neurons and their projections to the medial septum in mediating the effects of isoflurane anesthesia. Methods: Fiber photometry recording was used to determine the changes in calcium signals of glutamatergic neurons in the SuM during isoflurane anesthesia. Optogenetic and chemogenetic approaches were employed to manipulate SuM glutamatergic neuron activity, and the effects on cortical activity, behavioral responses, and physiologic parameters—including pupil diameter, respiratory rate, and blood pressure—were examined in anesthetized mice. Both male and female mice were used in this study. Results: The activities of SuM glutamatergic neurons decreased during isoflurane anesthesia and recovered after the emergence. Optogenetic activation of these neurons enhanced cortical activity, decreasing electroencephalogram delta power (mean ± SD, prestimulation vs. stimulation: 51.35 ± 7.26% vs. 32.08 ± 10.48%, n = 8, P = 0.002) and burst suppression ratio (81.82 ± 7.83% vs. 44.53 ± 28.62%, n = 8, P = 0.002). Furthermore, optogenetic activation altered physiologic parameters including enlarged pupil diameter (prestimulation vs. stimulation: 1.05 ± 0.08% vs. 1.95 ± 0.46%, n = 8, P < 0.001), increased respiratory rate (0.98 ± 0.08% vs. 1.57 ± 0.39%, n = 10, P < 0.001) and elevated blood pressure and induced behavioral responses including increased arousal scores and accelerated emergence (light off vs. light on, 171.40 ± 56.39 s to 59.88 ± 27.18 s, n = 8, P = 0.007). Moreover, chemogenetic activation produced similar effects, whereas inhibition led to opposite effects. Finally, optogenetically activating SuM glutamatergic terminals projecting to the medial septum mimicked the effects of activating SuM glutamatergic soma and increased the activity of medial septum glutamatergic neurons. Conclusions: This study identifies glutamatergic neurons of the SuM as key neural substrates regulating isoflurane anesthesia and facilitating emergence through their projections to the medial septum.

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