Background

The γ-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 cytoarchitectonically 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.

Editor’s Perspective
What We Already Know about This Topic
  • The lateral septum of the brain is known to play a key role in emotional processes and stress responses

  • Inhibitory γ-aminobutyric acid–mediated neurons of the lateral septum send synaptic connections to multiple brain regions involved in the regulation of sleep/wakefulness

  • The role of the lateral septum in the regulation of sleep/wakefulness is incompletely understood

What This Article Tells Us That Is New
  • A combination of genetic and electrophysiologic techniques in male mice revealed that γ-aminobutyric acid–mediated neurons of the lateral septum are highly active during the awake state

  • Genetic activation of γ-aminobutyric acid–mediated neurons in the lateral septum promotes recovery from isoflurane anesthesia through the projection of these cells to the ventral tegmental area

  • These observations suggest a role for γ-aminobutyric acid–mediated neurons in the lateral septum to maintain wakefulness and to promote recovery from isoflurane anesthesia

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