The Role of DNA Methylation in Addiction and Depression

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2010-11-02

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LaPlant, Quincey Charles

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Abstract

Despite abundant expression of DNA methyltransferases (Dnmt’s) in brain, the regulation and behavioral role of DNA methylation remain poorlyunderstood. I found that Dnmt3a expression is persistently regulated in nucleus accumbens (NAc),a key brain reward region, by chronic cocaine or chronic social defeat stress. Moreover, NAc specific manipulations that block DNA methylation potentiate cocaine reward and exert antidepressant-like effects, whereas NAc specific Dnmt3a overexpression attenuates cocaine reward and is pro-depressant. On a cellular level, I discovered that chronic cocaine selectively increases thin dendritic spines on NAc neurons and that DNA methylation is both necessary and sufficient to mediate these effects. I then used complementary genome wide techniques aimed at identifying cocaine-induced DNA methylation at gene targets. Transcriptional profiling experiments in which I virally overexpressed Dnmt3a or pharmacologically blocked DNA methylation identified an important role of DNA methylation in regulating the mRNA expression of a number of immediate early genes—several of which are known to regulate dendritic spine morphology. Taken together, these data establish the importance of Dnmt3a in the NAc in regulating molecular, cellular, and behavioral plasticity to emotional stimuli.

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