Abstract
MicroRNAs (miRNAs), when subjected to environmental stimuli, can exhibit differential expression. As critical regulators of gene expression, differential miRNA expression has been implicated in numerous disorders of the nervous system. In this study, we focused on the effect of a general anesthetic, as an environmental stimulus, on miRNA expression of the developing brain. General anesthetics have potential long-lasting neurotoxic effects on the developing brain, resulting in behavioral changes in adulthood. We first carried out an unbiased profiling approach to examine the effect of single-episode neonatal general anesthetic, sevoflurance (sevo), exposure on miRNA expression of the brain. Neonatal sevo has a significant effect on the expression of specific miRNAs of the whole brain and the hippocampus that is both immediate – directly after neonatal treatment, as well as long-lasting - during adulthood. Functionally, neonatal sevo-associated miRNA gene-targets share potential neurodevelopmental pathways related to axon guidance, DNA transcription, protein phosphorylation and nervous system development. Our understanding on the role of miRNAs provides a putative epigenetic/molecular bridge that links neonatal general anesthetic’s effect with its associated functional change.
Highlights
In the brain, regulation of gene expression is orchestrated in a spatiotemporal manner to ensure proper development and function of neurons. microRNAs have been recognized to fulfill this regulatory role by fine-tuning gene expression in the intricate network of neurons. miRNAs are endogenously expressed, ~21 bp small noncoding RNAs and have been found in plants and all animals[1,2]
In order to understand neonatal sevo’s immediate impact on miRNA expression, brain tissue was harvested directly after treatment and miRNA expression profiling was performed for this postnatal day 7 (P7)-P7 group (Fig. 1A)
Data show that P7 sevo treatment did not influence miRNA expression as a group and the difference in the expression of miRNAs is not related to the effect of the treatment
Summary
Regulation of gene expression is orchestrated in a spatiotemporal manner to ensure proper development and function of neurons. microRNAs (miRNAs) have been recognized to fulfill this regulatory role by fine-tuning gene expression in the intricate network of neurons. miRNAs are endogenously expressed, ~21 bp small noncoding RNAs and have been found in plants and all animals[1,2]. Numerous studies have shown long-lasting cellular and behavioral changes as a result of neonatal anesthetic exposure, the underlying epigenetic/molecular mechanism, the role of miRNAs is unknown. We conducted an unbiased investigation on the role of brain miRNAs as a result of neonatal sevoflurane (sevo) exposure, one of the most commonly used volatile anesthetics for pediatric patients[10]. Expression of miRNA is critical for the survival of differentiating, and mature neurons. In addition to the overview on the expression pattern of brain miRNAs, we learned that neonatal sevo has immediate and long-lasting effects on the expression of specific miRNAs. Bioinformatics analysis provides insightful understanding of the functional relevance of these miRNAs on the neurodevelopmental process and gene expression regulation. Our data provides a putative epigenetic/molecular bridge that links neonatal sevo’s effect with the observed functional outcome at the behavioral level
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