Epigenetic and transcriptomic profiling of neural stem cells after midazolam exposure

Here we show that early-life exposure to midazolam (MDZ), a widely used drug in pediatric anesthesia, persistently alters chromatin accessibility and expression of quiescence-associated genes in neural stem cells (NSCs) in mouse hippocampus. The alterations led to a continuous restriction of NSC proliferation toward adulthood, resulting in reduction of neurogenesis associated with the impairment of hippocampal-dependent memory functions. Moreover, we found that voluntary exercise restored hippocampal neurogenesis accompanied by the normalization of MDZ-perturbed transcriptome and ameliorated declined cognitive ability in MDZ-exposed mice. Overall design: Nestin-EGFP mice were injected with 10mg/kg of MDZ or dH2O. RNA-seq and ATAC-seq was performed using EGFP-positive NSCs and their progenies isolated from Nestin-EGFP mice at 10-day-old (P10) and 8-week-old (8W) mice with or without voluntary exercise (RUN). For ChIP-seq analysis, Egr1 was transduced in cultured NSC and collected samples were then subjected to ChIP assay using anti-FLAG antibody..