45: Activation of Glutamatergic MS-LH Circuit Promotes Emergence from Sevoflurane Anesthesia in Mice

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Electrophysiology, Neurocircuit modulation (could include opto, DREADDs), Neuroanatomical circuit analysis

Background and Aims: General anesthesia (GA) induces reversible unconsciousness for surgery, yet mechanisms underlying changes of consciousness during GA remain largely unknown (1). Glutamatergic neurons in the medial septum (MS, a midline structure located in the basal forebrain) are identified to promote emergence from sevoflurane general anesthesia (GA), with the potential downstream neural circuit remaining to be explored (2). Glutamatergic MS neurons have been identified to promote wakefulness through glutamatergic neurons in the lateral hypothalamus (LH) (3). Here, we aimed to investigate the role of the glutamatergic MS-LH circuit in regulating states of consciousness during sevoflurane GA.

Methods: Rabies virus (RV)-mediated monosynaptic retrograde tracing and anterograde tracing were firstly used to identify the anatomical connectivity between glutamatergic MS neurons to glutamatergic LH neurons. We then conducted in vivo fiber photometry to investigate functional dynamics of this circuit during sevoflurane GA. Finally, optogenetic bidirectional manipulations, anesthesia behavioral tests, and electroencephalogram/electromyogram (EEG/EMG) recordings were used to causally examine the role of this circuit under two different states of sevoflurane GA: continuous, steady-state general anesthesia (CSSGA) and burst-suppression (BS) oscillations.

Results: The retrogradely labeled upstream neurons of glutamatergic LH neurons were extensively detected in the MS and co-labeled by Vesicular glutamate transporter 2 (Vglut2). Glutamatergic MS neurons project to three arousal-promoting LH neuronal populations (glutamatergic, GABAergic, and orexinergic), with glutamatergic LH neurons representing the predominant target. The calcium activity of this circuit was inhibited concurrently as the process of loss of consciousness during 2.4% sevoflurane induction. Optogenetic activation of this circuit promoted behavioral arousal and cortical activation during CSSGA and BS. In contrast, optogenetic inhibition of this circuit deepened cortical inhibition during CSSGA and BS.

Conclusions: Our results verified that activation of the glutamatergic MS-LH circuit promotes behavioral arousal and cortical activation during sevoflurane GA. These findings consummate the emergence-promoting neural circuits of sevoflurane GA.

References: 1. Mashour GA. Anesthesia and the neurobiology of consciousness. Neuron. May 15 2024;112(10):1553-1567.
2. Xia JM, Fan BQ, Yi XW, et al. Medial Septal Glutamatergic Neurons Modulate States of Consciousness during Sevoflurane Anesthesia in Mice. Anesthesiology. Jan 1 2024;140(1):102-115.
3. An S, Sun H, Wu M, et al. Medial septum glutamatergic neurons control wakefulness through a septo-hypothalamic circuit. Curr Biol. Apr 12 2021;31(7):1379-1392 e4.

Presenting Author: Jia-Yi Wu
Submitting Author: Jia-Yi Wu

Senior Author: Wei Mei

IASP 2026 Global Year theme of Neuropathic Pain: No

• Zheng Gan: MD, PhD - Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
• Wei Mei: MD, PhD - Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology