Gene expression, regulation, and implication in the rat models of opioid use disorder

Abstract

Substance use disorders (SUDs), including opioid use disorder (OUD), remain a major global health problem with substantial individual differences in vulnerability. Given the chronic nature of SUDs and the long-term impact of early-life experiences (e.g., childhood trauma) on addiction vulnerability in adulthood, changes in SUD vulnerability likely involve long-term epigenetic dysregulation. However, molecular mechanisms in the brain underlying individual differences in SUD vulnerability remain unclear. The goal of this dissertation was to evaluate how early-life experiences affect epigenetic regulation into adulthood using a prenatal-neonatal iron deficiency and choline supplementation rat model, and to characterize transcriptional and epigenetic signatures associated with morphine exposure and individual differences in OUD vulnerability in rat models capturing 3 distinct stages of human OUD. Study 1 showed that early-life ID and choline supplementation interacted to epigenetically regulate the expression of genes encoding JmjC-ARID domain-containing protein 1B and brain-derived neurotrophic factor, a potential biomarker for heroin use, in the rat hippocampus into adulthood. Study 2 showed that repeated exposure to the opioid morphine activated synaptogenesis and other neuroplasticity-related gene networks in the dorsomedial prefrontal cortex of rats. Study 3 showed that differential gene expression and chromatin accessibility in the medial prefrontal cortex were associated with individual differences in rat behavioral models of OUD. Overall, these studies emphasized the significant long-term effects of environmentally induced epigenetic dysregulation and extended the understanding of brain molecular mechanisms underlying individual differences in OUD vulnerability in rat models.