Abstract
BACKGROUND: Studies in humans and animal models have documented relationships between initial sensitivity to alcohol and alcohol drinking behavior.Prior expression profiling studies of C57BL/6J and DBA/2J mice and rhesus macaques within the prefrontal cortex (PFC) have shown variation in myelin gene expression may be linked with alcohol sensitivity and consumption. METHODS: Combining gene expression studies from human and mouse PFC, we identified a cross-species gene network enriched for myelin-associated genes. Since myelin expression is correlated to alcohol sensitivity and alcohol drinking behavior, we hypothesized basal levels of PFC myelin gene expression may be a genomic determinant for these behavioral responses. Using an animal model of CNS demyelination, and localized knock down of N-myc downstream regulated gene 1 (Ndrg1), we measured effects of cortical myelin reduction on initial alcohol sensitivity and drinking behavior. RESULTS: Reducing myelin-related gene expression significantly altered sensitivity to alcohol and decreased alcohol consumption. Mouse genetic-based studies identified Ndrg1 as a putative quantitative trait gene for sedative-hypnotic responses to alcohol. Site-specific injections of shNdrg1 lentivirus into PFC led to a significant decrease in NDRG1 expression, causing increased alcohol behavioral sensitivity and reduced preference for high concentrations of alcohol. CONCLUSION: Myelin is an important biological component underlying CNS disorders. Our studies demonstrate the role of a novel candidate gene (Ndrg1), and myelin-associated gene expression, as an important factor modulating initial sensitivity to alcohol and alcohol consumption. Differences in the expression of myelin-related genes, including Ndrg1, may serve as future therapeutic targets for the treatment of alcohol use disorders.