Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice.
Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice.
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DOI：
10.1016/j.nepig.2015.10.001
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Bredy T
中科院分区：
文献类型：
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作者：
Baker-Andresen D;Zhao Q;Li X;Jupp B;Chesworth R;Lawrence AJ;Bredy T
持续的脆弱性，复吸在禁欲是可卡因成瘾的特点，并表明药物诱导的神经适应持续禁欲期间。然而，这些适应的精确细胞和分子属性仍然是模棱两可的。一种可能性是可卡因自我给药导致DNA甲基化的持久变化。为了解决这种可能性，我们从内侧前额叶皮层分离神经元，并进行高通量DNA测序，以检查可卡因自我给药后DNA甲基化的变化。29个基因组区域在可卡因自我给药期间持续差异甲基化，另外28个区域在戒断期间选择性差异甲基化。改变的DNA甲基化与共定位基因表达的同种型特异性变化相关。这些结果提供了第一个神经元特异性的，全基因组的可卡因自我管理和长期禁欲诱导的DNA甲基化的变化。此外，我们的研究结果表明，改变DNA甲基化促进长期的行为适应的方式，超出了改变转录状态的永久化。
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.