Date of Award

Summer 2020

Document Type

Open Access Dissertation

Department

Psychology

First Advisor

Sandra J. Kelly

Abstract

Fetal Alcohol Spectrum Disorders (FASD) refers to the effects of alcohol exposure during development on individuals. Some of the most frequent deficits seen in children with FASD and in animal models of FASD are spatial memory impairments and impaired executive functioning, which are likely related to alcohol-induced alterations of the hippocampus and medial prefrontal cortex (mPFC), respectively. Choline, a nutrient supplement, has been shown in a rat model to ameliorate some of alcohol‟s teratogenic effects and this effect may be mediated through choline‟ effects on DNA methylation. This study used a rat model of FASD to investigate the underlying mechanisms of alcohol-induced deficits and the impact of choline on these deficits by examining changes in DNA methylation in the PFC and hippocampal areas. Alcohol was given by intragastric intubation to rat pups during the neonatal period (postnatal days 2-10) (ET group), which is equivalent to the third trimester in humans and a period of heightened vulnerability of the brain to alcohol exposure. Control groups included an intubated control group given the intubation procedure without alcohol (IC) and a non-treated control group (NC). Choline or saline was administered subcutaneously to each subject from postnatal day 2 to 20. On postnatal day 21, the brains of the subjects were removed and processed for relative optical density (ROD) of immunohistochemical staining for neuronal-specific enolase (NSE) and global DNA methylation as measured by chemiluminescence using the cpGlobal assay. In the mPFC, choline supplementation led to significant increases in ROD of staining for NSE, regardless of treatment or sex. No differences in NSE staining were found in the CA1 region of the hippocampus. Alcohol exposure caused hypermethylation in the hippocampus and mPFC, which was significantly reduced after choline supplementation. In contrast, control animals showed increases in DNA methylation in both regions after choline supplementation, suggesting that choline supplementation has different effects depending upon the initial state of the brain. This study is the first to show in a rat model of FASD changes in global DNA methylation of the hippocampus CA1 region and mPFC after neonatal alcohol exposure with and without choline supplementation. Molecular mechanisms of alcohol‟s teratogenesis leading to a state of hypermethylation are proposed based on alcohol‟s and choline‟s effects in the folate/choline path to DNA methylation.

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