The GABAergic Parafacial Zone: Integrating Consciousness and Respiratory Control in Sevoflurane Anesthesia

Background: General anesthesia induces both unconsciousness and respiratory depression, but whether these effects share a common neural substrate remains unclear. The parafacial zone (PZ), a GABAergic sleep-promoting region, has been proposed to modulate respiration. This study investigates whether PZ GABAergic neurons function as a common neural node coordinating anesthetic-induced unconsciousness and respiratory suppression. Methods: A total of 95 male mice (10-12 weeks) were used. Chemogenetic and optogenetic methods targeted PZ GABAergic neurons to assess anesthetic efficacy and respiratory changes. Immunostaining evaluated neuronal activation, and awake-state stimulation tested for anesthesia-like effects. Results: Chemogenetic activation of PZ GABAergic neurons enhanced anesthetic sensitivity, shifting the sevoflurane dose-response curve leftward (ED 50 : 0.662%, 95% CI: 0.624–0.699% vs. 1.569%, 95% CI: 1.502–1.637%) 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 delayed (435 ± 12 s vs. 89 ± 12 s, P < 0.0001, n = 8). EEG showed increased delta and decreased theta power. Respiratory rate declined significantly (183 ± 24 bpm vs. 471 ± 3 bpm, P < 0.0001, n = 8). During anesthesia, brief optogenetic activation of PZ GABAergic neurons immediately elevated burst suppression ratio (69.5 ± 5.1% vs. 32.5 ± 7.7%, P < 0.0001, n = 9) and reduced respiratory rate (38 ± 13 bpm vs. 120 ± 21 bpm, P = 0.0016, n = 7), indicating concurrent modulation of cortical and respiratory function. Chemogenetic inhibition weakened anesthetic potency. Increased c-Fos expression in PZ 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. Conclusions: The GABAergic PZ is a shared critical node regulating both respiration and consciousness during sevoflurane anesthesia; its activation suppresses both, helping explain anesthesia-related respiratory depression.