Choline ameliorates adult learning deficits and reverses epigenetic modification of chromatin remodeling factors related to adolescent nicotine exposure

Earlier initiation of smoking correlates with higher risk of nicotine dependence, mental health problems, and cognitive impairments. Additionally, exposure to nicotine and/or tobacco smoke during critical developmental periods is associated with lasting epigenetic modifications and altered gene expression. This study examined whether adolescent nicotine exposure alters adult hippocampus-dependent learning, involving persistent changes in hippocampal DNA methylation and if choline, a dietary methyl donor, would reverse and mitigate these alterations. Mice were chronically treated with nicotine (12.6 mg/kg/day) starting at post-natal day 23 (pre-adolescent), p38 (late adolescent), or p54 (adult) for 12 days followed by a 30-day period during which they consumed either standard chow or chow supplemented with choline (9 g/kg). Mice then were tested for fear-conditioning and dorsal hippocampi were dissected for whole genome methylation and selected gene expression analyses. Nicotine exposure starting at p21 or p38, but not p54, disrupted adult hippocampus-dependent fear conditioning. Choline supplementation ameliorated these deficits. 462 genes in adult dorsal hippocampus from mice exposed to nicotine as adolescents showed altered promoter methylation that was reversed by choline supplementation. Gene network analysis revealed that chromatin remodeling genes were the most enriched category whose methylation was altered by nicotine and reversed by choline dietary supplementation. Two key chromatin remodeling genes, Smarca2 and Bahcc1, exhibited inversely correlated changes in methylation and expression due to nicotine exposure; this was reversed by choline. Our findings support a role for epigenetic modification of hippocampal chromatin remodeling genes in long-term learning deficits induced by adolescent nicotine and their amelioration by dietary choline supplementation.