Anesthetic State-Dependent Bidirectional Control of States of Consciousness via Heterogeneous Medial Septum to Ventral Tegmental Area Circuits under Sevoflurane in Mice

General anesthesia (GA) induces reversible unconsciousness for surgery, yet mechanisms underlying bidirectional transitions of states of consciousness during GA remain largely unknown. Here, we focused on states of consciousness, rather than contents of consciousness, which reflects the capacity for responsiveness to stimuli. Electroencephalography/electromyography was applied in both male and female mice to investigate states of consciousness during sevoflurane GA. We identified the population activity of glutamatergic neurons in the medial septum (MS) to change synchronously with altered states of consciousness during sevoflurane GA. Activation of glutamatergic MS neurons (MSVglut2) or their projections in the ventral tegmental area (VTA) facilitated behavioral emergence and cortical activation during sevoflurane GA, while their inhibition deepened cortical inhibition. Nevertheless, we further identified anesthetic state-dependent dual control of states of consciousness by monosynaptic innervations from MSVglut2 neurons to heterogeneous downstream VTA neurons. Specifically, optogenetic activation of MS-innervated glutamatergic VTA neurons promoted cortical activation during both continuous steady-state GA (CSSGA) and burst-suppression (BS). With current stimulation protocol, optogenetic activation of MS-innervated dopaminergic VTA neurons promoted cortical activation mainly under CSSGA. Optogenetic activation of MS-innervated GABAergic VTA neurons enhanced cortical inhibition mainly under BS. Our findings reveal an anesthetic state-dependent mechanism where MSVglut2 neurons bidirectionally regulate states of consciousness through heterogeneous VTA neurons, providing insights to the complexity in the regulation of states of consciousness under GA.Significance Statement While neuronal circuits modulating general anesthesia (GA) are increasingly mapped, bidirectional control of states of consciousness by the same neuronal ensemble and its anesthetic state-dependence remain overlooked. We reveal heterogeneous MS (medial septum)-VTA (ventral tegmental area) circuits where glutamatergic MS neurons recruit distinct VTA subpopulations to bidirectionally regulate states of consciousness: downstream glutamatergic neurons promote cortical activation during both light and deep GA, downstream dopaminergic neurons promote cortical activation mainly during light GA, while downstream GABAergic populations enhance cortical inhibition during deep GA. Our findings demonstrate subcortical complexity in the regulation of states of consciousness, offering novel targets for precise anesthetic control.