Journal Article

Early-life midazolam exposure persistently changes chromatin accessibility to impair adult hippocampal neurogenesis and cognition

Doi, Hiroyoshi, Yamaura, Ken, Nakashima, Kinichi, Sakai, Atsuhiko, Matsuda, Taito, Matsubara, Shuzo, Hoka, Sumio

2021

Overview

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-termadverse effects on brain function and provide a possible therapeutic strategy for countering them.

• Publisher: National Academy of Sciences
• Subject: Accessibility / Anesthesia / Animals / Biological Sciences / Cell Differentiation - drug effects / Cell Proliferation - drug effects / Cells, Cultured / Chromatin / Chromatin - drug effects / Chromatin - metabolism / Cognition / Cognition - drug effects / Cognition - physiology / Cognitive ability / Disabilities / Exposure / Female / Gene expression / Hippocampus / Hippocampus - drug effects / Hippocampus - metabolism / Male / Memory / Mice / Mice, Inbred C57BL / Midazolam / Midazolam - adverse effects / Midazolam - pharmacology / Models, Animal / Neural stem cells / Neural Stem Cells - metabolism / Neurogenesis / Neurogenesis - drug effects / Neurogenesis - physiology / Neuroscience / Pediatrics / Stem cell transplantation / Stem cells / Transcriptomes