Dataset Information

DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

ABSTRACT: Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism.

SUBMITTER: Barbier E

PROVIDER: S-EPMC4397609 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

Barbier Estelle E Tapocik Jenica D JD Juergens Nathan N Pitcairn Caleb C Borich Abbey A Schank Jesse R JR Sun Hui H Schuebel Kornel K Zhou Zhifeng Z Yuan Qiaoping Q Vendruscolo Leandro F LF Goldman David D Heilig Markus M

The Journal of neuroscience : the official journal of the Society for Neuroscience 20150401 15

Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expres ...[more]

PMID: 25878287

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Project description:Previous neuroimaging studies have suggested that the experience of flow aligns with a relative increase in activation of the dorsal raphe nucleus (DRN), and relative activation decreases of the medial prefrontal cortex (MPFC) and of the amygdala (AMY). In the present study, Dynamic Causal Modeling (DCM) was used to explore effective connectivity between those brain regions. To test our hypothesis that the DRN causally down-regulates activity of the MPFC and/or of the AMY, 23 healthy male students solved mental arithmetic tasks of varying difficulty during functional magnetic resonance imaging. A "flow" condition, with task demands automatically balanced with participants' skill level, was compared with conditions of "boredom" and "overload". DCM models were constructed modeling full reciprocal endogenous connections between the DRN, the MPFC, the AMY, and the calcarine. The calcarine was included to allow sensory input to enter the system. Experimental conditions were modeled as exerting modulatory effects on various possible connections between the DRN, the MPFC, and the AMY, but not on self-inhibitory connections, yielding a total of 64 alternative DCM models. Model space was partitioned into eight families based on commonalities in the arrangement of the modulatory effects. Random effects Bayesian Model Selection (BMS) was applied to identify a possible winning family (and model). Although BMS revealed a clear winning family, an outstanding winning model could not be identified. Therefore, Bayesian Model Averaging was performed over models within the winning family to obtain representative DCM parameters for subsequent analyses to test our hypothesis. In line with our expectations, Bayesian averaged parameters revealed stronger down-regulatory influence of the DRN on the MPFC when participants experienced flow relative to control conditions. In addition, these condition-dependent modulatory effects significantly predicted participants' experienced degree of flow. The AMY was down-regulated irrespective of condition. The present results suggest a causal role for the DRN in modulating the MPFC, contributing to the experience of flow.

Dataset Information

DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

Publications

DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

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