Early-life midazolam exposure persistently changes chromatin accessibility to impair adult hippocampal neurogenesis and cognition.
Hiroyoshi DoiTaito MatsudaAtsuhiko SakaiShuzo MatsubaraSumio HokaKen YamauraKinichi NakashimaPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- early life
- cerebral ischemia
- neural stem cells
- genome wide
- subarachnoid hemorrhage
- blood brain barrier
- brain injury
- gene expression
- dna methylation
- dna damage
- poor prognosis
- transcription factor
- young adults
- childhood cancer
- white matter
- signaling pathway
- physical activity
- high intensity
- single cell
- temporal lobe epilepsy
- adverse drug
- multiple sclerosis
- metabolic syndrome
- mild cognitive impairment
- long non coding rna
- emergency department
- human immunodeficiency virus
- resistance training
- hepatitis c virus
- electronic health record
- body composition
- prefrontal cortex
- skeletal muscle
- antiretroviral therapy
- genome wide analysis