Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice

Abstract

Continued vulnerability to relapse during abstinence is characteristic of cocaine addiction and suggests that drug-induced neuroadaptations persist during abstinence. However, the precise cellular and molecular attributes of these adaptations remain equivocal. One possibility is that cocaine self-administration leads to enduring changes in DNA methylation. To address this possibility, we isolated neurons from medial prefrontal cortex and performed high throughput DNA sequencing to examine changes in DNA methylation following cocaine self-administration. Twenty-nine genomic regions became persistently differentially methylated during cocaine self-administration, and an additional 28 regions became selectively differentially methylated during abstinence. Altered DNA methylation was associated with isoform-specific changes in the expression of co-localizing genes. These results provide the first neuron-specific, genome-wide profile of changes in DNA methylation induced by cocaine self-administration and protracted abstinence. Moreover, our findings suggest that altered DNA methylation facilitates long-term behavioral adaptation in a manner that extends beyond the perpetuation of altered transcriptional states.

DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment

“…Furthermore, it is likely that gene expression depends on a dynamic interaction of epigenetic regulation with transcriptional signals such as neural activity leading to activation of transcription factors. Finally, while we provide a 2 weeks delay between behavioral testing and examination of DNA methylation, it is possible that experience produces long-lasting changes in DNA methylation ( Miller et al, 2010 ; Provencal et al, 2012 ; Mychasiuk et al, 2013 ; Anier et al, 2014 ; Baker-Andresen et al, 2015 ; Barbier et al, 2015 ). Despite these possible confounds, we found that hypermethylation during aging or in cognitively impaired animals was correlated with decreased expression of genes linked to synaptic function.…”

How the epigenome integrates information and reshapes the synapse

“…DNA methylation regulates memory processes, including consolidation, extinction 103,143,144 and reconsolidation 61 , as well as synaptic processes such as synaptic scaling (BOX 3), and could be targeted to enhance memory formation. For example, in mice, overexpression of DNMT3A2 before training, similar to HDAC inhibition, resulted in the long-term memory of normally subthreshold training.…”

Increased 5‐hydroxymethylation levels in the hippocampus of rat extinguished from cocaine self‐administration

“…Our previous study demonstrated prolonged cocaine‐induced changes in RE1 Silencing Transcription Factor (REST) and miRNA expression in the rat striatum that may contribute to epigenetic regulation (Sadakierska‐Chudy et al ). Several studies demonstrated the effects of cocaine on DNA methylation (a relatively stable epigenetic mark) in brain regions including the nucleus accumbens (NAc), the striatum, and the prefrontal cortex (Baker‐Andresen et al, ; Fragou et al, ). In addition, study by Barros et al () has revealed that methylation of TACR3 promoter region decreased after cocaine‐induced place preference in marmoset monkeys.…”