Laparotomy and burst suppression-inducing sevoflurane induce subtle long-term changes in anxiety and social behavior in late postnatal mice

Background: Despite strong preclinical evidence, clinical studies have reported minimal effects of early anesthesia on neurodevelopment. This discrepancy may be due to limitations of preclinical studies, including the absence of clear criteria for appropriate anesthetic depth, lack of physiological monitoring, and absence of a surgical insult. Therefore, we aimed to evaluate the effects of sevoflurane in a more clinically relevant setting by addressing these known limitations. Methods: After confirming robust burst suppression (BS) at 2.5% sevoflurane, postnatal day 17 (PND17) mice were assigned to three groups: a Control group, no intervention; BS (-) group, surgery with 1.4% sevoflurane; and a BS (+) group, surgery with 1.4%–2.5% sevoflurane. Total duration of anesthesia was 2 h, and blood pressure was non-invasively measured in a subset of mice. Long-term behavioral changes were evaluated from PND56 to PND62 at a two-day interval. Results: We found subtle but significant changes in anxiety and sociability only in BS (+) group mice. Change in anxiety level was observed in the light/dark box test, with the number of transitions between chambers significantly lower in the BS (+) group (P = 0.025). Reduced sociability was observed in the three-chamber test, as mice in the BS (+) group did not significantly prefer the chamber containing a stranger mouse (P = 0.065). Conclusions: Both surgery and excessive anesthesia depth are necessary to induce subtle yet long-term behavioral changes in young mice. Future preclinical studies should reconsider sevoflurane concentration and account for surgical trauma as a significant factor when investigating anesthesia-induced neurotoxicity.