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Hippocampal transcriptome analysis following environmental enrichment in a mouse model of fetal alcohol spectrum disorder

ABSTRACT: Maternal alcohol consumption during pregnancy results in a spectrum of lifelong behavioral and cognitive deficits collectively known as Fetal Alcohol Spectrum Disorders (FASD). FASD is a major health burden in most societies, there is no cure, and the molecular mechanism involved in its development is poorly understood. Human neurodevelopment is a continuum that extends over two decades after birth, with the potential to influence outcomes both prenatally and postnatally. Here, we experimentally investigate if positive postnatal environment enrichment ameliorates behavioral deficits caused by ethanol exposure. Furthermore, we assessed if this modulation is associated with alterations in hippocampal gene expression. To accomplish this, we used a binge model of ethanol exposure followed by environmental enrichment in C57BL/6 mice to generate four groups of animals: (1) control mice raised in standard conditions, (2) mice raised in enriched environments, (3) ethanol-exposed mice raised in standard conditions, and (4) ethanol-exposed mice raised in enriched environments. The environmental enrichment includes larger home cages with more individuals for social interaction, regular exposure to novel items, and access to running wheels. Ethanol exposure results in anxiety-like behavior (light-dark box) as well as learning and memory deficits (Barnes maze) that are at least partially ameliorated by enrichment. Environmental enrichment also improves performance for individuals not exposed to ethanol. Ethanol exposure induces changes in adult hippocampal gene expression (RNA-Seq). Some of the changes in adult hippocampal gene expression following ethanol exposure are reversed by environmental enrichment. The results offer a potential mechanism of behavioral deficits caused by ethanol exposure, including the potential for amelioration after an FASD diagnosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE184615 | GEO | 2021/09/24

REPOSITORIES: GEO

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Project description:Fetal alcohol spectrum disorder (FASD) is a common developmental behavioral disorder caused by maternal drinking during pregnancy. Children born with FASD often face additional stress, particularly maternal separation that adds yet additional deficits. The mechanism associated with this phenomenon is not known. Using a mouse model, prenatal ethanol exposure and maternal separation stress have resulted in behavioral deficits and the combination of treatments results in more than additive effects. In addition, behavioral alterations are associated with changes in hippocampal gene expression that persist into adulthood. What initiates and maintains these changes remains to be established and forms the focus of this research. Specifically, MeDIP-Seq was used to assess how changes in promoter DNA methylation are affected by the combination of prenatal ethanol exposure and maternal separation stress with the potential to affect gene expression. The novel results show different sets of genes implicated by promoter DNA methylation affected by both treatments independently, and a relatively unique set of genes affected by the combination of treatments. Prenatal ethanol exposure leads to altered promoter DNA methylation at genes important for brain function and transcriptional regulation. Maternal separation stress leads to changes at genes important for histone methylation and immune response, and the combination of two treatments results in DNA methylation changes at genes important for neuronal migration and immune response. Our dual results on gene expression and DNA methylation from the same samples have allowed comparison of the two observations. There is minimal reciprocal overlap between changes in promoter DNA methylation and gene expression, although overlapping genes tend to be critical for brain development and function. These results suggest that epigenetic mechanisms beyond promoter DNA methylation must be involved in lasting gene expression alterations leading to behavioral deficits implicated in FASD.

Project description:Purpose: Fetal alcohol spectrum disorders (FASD) result from ethanol exposure to the developing fetus. FASD occur in up to 1-5% of live births in the United States and there currently is no cure. Ethanol exposure to the developing central nervous system (CNS) has profound effects on learning and memory, impulse control, and motor function, resulting from neuropathology. The purpose of the current study was to perform transcriptome analysis to evaluate the effects of early postnatal ethanol exposure in the hippocampus and cerebellum. Methods: Postnatal C57BL/6 mice were treated with 4g/kg of ethanol from P4-P9, brains were harvested 24h after the final treatment at P10, hippocampi and cerebella were microdissected, RNA was isolated, and RNASeq analysis was performed. We compared differences in gene expression, sex-dependent expression, and global biological pathways associated with disruptions in hippocampal and cerebellar genes between the ethanol and vehicle treated neonates. Results: Ethanol caused both an up and down regulation of genes associated with the hippocampus and cerebellum, which may result in the disruption of normal circuitry and maturation and growth in these brain regions. Ethanol increased the expression of genes associated with the S phase of the cell cycle in both the hippocampus and cerebellum. In the cerebellum, ethanol increased effector gene expression, and in the hippocampus, genes associated with different interneuron lineages were altered. Postnatal ethanol exposure also resulted in altered expression of genes associated with oligodendrocyte lineages and myelination, along with alterations in microglia associated genes. Conclusion: Collectively, these data indicate that ethanol has profound effects on the hippocampus and cerebellum, resulting in alterations of gene expression and biological pathways regulating neurodevelopment. These studies may have important implications concerning alcohol-induced neuropathology and the neurological effects seen across the life span in FASD.

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Hippocampal transcriptome analysis following environmental enrichment in a mouse model of fetal alcohol spectrum disorder

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