γ-Aminobutyric Acid-mediated Parafacial Zone: Integrating Consciousness and Respiratory Control in Sevoflurane Anesthesia.

Abstract

General anesthesia induces both unconsciousness and respiratory depression, but whether these effects share a common neural substrate remains unclear. The parafacial zone, a γ-aminobutyric acid-mediated (GABAergic) sleep-promoting region, has been proposed to modulate respiration. This study investigates whether parafacial zone GABAergic neurons function as a common neural node coordinating anesthetic-induced unconsciousness and respiratory suppression. A total of 95 male mice (10 to 12 weeks old) were used. Chemogenetic and optogenetic methods targeted parafacial zone GABAergic neurons to assess anesthetic efficacy and respiratory changes. Immunostaining evaluated neuronal activation, and awake-state stimulation tested for anesthesia-like effects. Chemogenetic activation of parafacial zone GABAergic neurons enhanced anesthetic sensitivity, shifting the sevoflurane dose-response curve leftward (50% effective dose, 0.662%; 95% confidence interval, 0.624 to 0.699% vs . 1.569%; 95% confidence interval, 1.502 to 1.637%) and lowering the concentration required for loss of righting reflex (0.735 ± 0.027% vs . 1.601 ± 0.048%; P < 0.0001; n = 10). Induction was faster (48 ± 4 s vs . 112 ± 3 s; P < 0.0001; n = 8), and emergence was delayed (435 ± 12 s vs . 89 ± 12 s; P < 0.0001; n = 8). Electroencephalogram showed increased delta and decreased theta power. Respiratory rate declined significantly (183 ± 24 breaths/min vs . 471 ± 3 breaths/min; P < 0.0001; n = 8). During anesthesia, brief optogenetic activation of parafacial zone GABAergic neurons immediately elevated the burst suppression ratio (69.5 ± 5.1% vs . 32.5 ± 7.7%; P < 0.0001; n = 9) and reduced the respiratory rate (38 ± 13 breaths/min vs . 120 ± 21 breaths/min; P = 0.0016; n = 7), indicating concurrent modulation of cortical and respiratory function. Chemogenetic inhibition weakened anesthetic potency. Increased c-Fos expression in parafacial zone GABAergic neurons during sevoflurane anesthesia confirmed their recruitment. In awake mice, optogenetic activation alone induced a low-arousal state with several features of anesthesia, including hypoactivity, analgesia, respiratory depression, and cortical suppression without abolishing righting reflex. The GABAergic parafacial zone is a shared critical node regulating both respiration and consciousness during sevoflurane anesthesia. Its activation suppresses both, helping explain anesthesia-related respiratory depression.