Gabaergic Neurons In The Dorsal-Intermediate Lateral Septum Regulate Sleep-Wakefulness And Anesthesia In Mice

Background: The.-aminobutyric acid-mediated (GABAergic) inhibitory system in the brain is critical for regulation of sleep-wake and general anesthesia. The lateral septum contains mainly GABAergic neurons, being cytoar-chitectonically divided into the dorsal, intermediate, and ventral parts. This study hypothesized that GABAergic neurons of the lateral septum participate in the control of wakefulness and promote recovery from anesthesia.Methods: By employing fiber photometry, chemogenetic and optogenetic neuronal manipulations, anterograde tracing, in vivo electrophysiology, and electroencephalogram/electromyography recordings in adult male mice, the authors measured the role of lateral septum GABAergic neurons to the control of sleep-wake transition and anesthesia emergence and the corresponding neuron circuits in arousal and emergence control.Results: The GABAergic neurons of the lateral septum exhibited high activities during the awake state by in vivo fiber photometry recordings (awake vs. non-rapid eye movement sleep: 3.3 +/- 1.4% vs. -1.3 +/- 1.2%, P < 0.001, n = 7 mice/group; awake vs. anesthesia: 2.6 +/- 1.2% vs. -1.3 +/- 0.8%, P < 0.001, n = 7 mice/group). Using chemogenetic stimulation of lateral septum GABAergic neurons resulted in a 100.5% increase in wakefulness and a 51.2% reduction in non- rapid eye movement sleep. Optogenetic activation of these GABAergic neurons promoted wakefulness from sleep (median [25th, 75th percentiles]: 153.0 [115.9, 179.7] s to 4.0 [3.4, 4.6] s, P = 0.009, n = 5 mice/group) and accelerated emergence from isoflurane anesthesia (514.4 +/- 122.2 s vs. 226.5 +/- 53.3 s, P < 0.001, n = 8 mice/group). Furthermore, the authors demonstrated that the lateral septum GABAergic neurons send 70.7% (228 of 323 cells) of monosynaptic projections to the ventral tegmental area GABAergic neurons, preferentially inhibiting their activities and thus regulating wakefulness and isoflurane anesthesia depth.Conclusions: The results uncover a fundamental role of the lateral septum GABAergic neurons and their circuit in maintaining awake state and promoting general anesthesia emergence time.