Linkage between early-life exposure to anesthesia and subsequent learning disabilities is of great concern to children and their families. Here we show that early-life exposure to midazolam (MDZ), a widely used drug in pediatric anesthesia, persistently alters chromatin accessibility and the expression of quiescence-associated genes in neural stem cells (NSCs) in the mouse hippocampus. The alterations led to a sustained restriction of NSC proliferation toward adulthood, resulting in a reduction of neurogenesis that was associated with the impairment of hippocampal-dependent memory functions. Moreover, we found that voluntary exercise restored hippocampal neurogenesis, normalized the MDZ-perturbed transcriptome, and ameliorated cognitive ability in MDZ-exposed mice. Our findings thus explain how pediatric anesthesia provokes long-term adverse effects on brain function and provide a possible therapeutic strategy for countering them.

早年接触麻醉与随后的学习障碍之间的联系是儿童及其家人非常关注的问题。在这里，我们表明，早期接触咪达唑仑 (MDZ)，一种广泛用于儿科麻醉的药物，持续改变染色质可及性和小鼠海马神经干细胞 (NSC) 中静止相关基因的表达。这些改变导致 NSC 向成年期的增殖持续受到限制，导致与海马依赖性记忆功能受损相关的神经发生减少。此外，我们发现自愿运动恢复了海马神经发生，使 MDZ 扰动的转录组正常化，并改善了 MDZ 暴露小鼠的认知能力。