Neonatal Sevoflurane Exposure Induces Mice Impulsive Behavioral Deficit Via Activating The Medial Prefrontal Cortex Neurons

Clinical evidence-based medicine data indicates that multiple exposure to anesthesia in early childhood is closely related to the development of attention deficit/hyperactivity disorder(ADHD).Sevoflurane is the most widely used volatile anesthetic in clinical pediatric anesthesia.Many studies have shown that exposure to sevoflurane can cause neurotoxicity and cognitive dysfunction in the developing brain,but whether it participates in the development of ADHD and the specific neural mechanism involved are still unclear.In this study,we found that when neonatal mice were repeatedly exposed to sevoflurane at the critical neurodevelopment period(postnatal day 6,7 and 8),they showed ADHD-like impulsive behavior in the adulthood.After c-Fos immunohistochemical staining and quantitative analysis of the results,neurons in the medial prefrontal cortex(m PFC)of the sevoflurane-exposure group were highly activated compared with the control group,thus indicating that the ADHD-like impulsive behavior caused by sevoflurane exposure was closely related to the m PFC.The immunostaining of c-Fos and the excitatory neuron marker in the m PFC revealed significant colocalization.To further identify the role of the m PFC excitatory neurons in the ADHD-like impulsive behavioral disorder,we manipulated the m PFC excitatory neurons via viral tools of chemogenetics.The results suggested that the activation of the m PFC excitatory neurons remarkbly increased the impulsive level of the control group.Whereas specifically inhibition of the corresponding neurons in thesevoflurane-exposure group effectively reversed the high level of impulsivity.In summary,our study showed that multiple exposure to sevoflurane in childhood could activate the m PFC excitatory neurons and thus induced the ADHD-like impulsive behavior.Notably,this finding elucidated a neural mechanism of the ADHD-like impulsive behavior and provided a novel theoretical basis for the prevention and treatment of neurotoxicity caused by neonatal multiple sevoflurane exposure.