Epigenetic Regulation of Cocaine-Induced Neuroadaptations

药物成瘾是一种慢性复发性疾病，其中与药物相关的协会（例如，离散的药物线索， 毒品消费的地点和毒品用具）能够发挥巨大的控制作用 在停止吸毒很久之后，滥用药物的一个显著特点是， 持续的，持久的功能和结构的变化，在大脑的奖励电路，如核 快来最近的发现表明，表观遗传修饰，如胞嘧啶的甲基化， DNA中的核苷酸，是长期突触可塑性，学习和长期甚至 跨代行为改变此外，新的发现表明，滥用药物，如可卡因， 诱导神经核的表观遗传变化，这些变化控制可卡因相关的 神经适应然而，很少有人知道可卡因如何改变DNA甲基化 以及这种修饰是否有助于可卡因诱导的神经元和 行为可塑性这项提案将研究DNA甲基化的变化（以及最近的 发现大脑富集的中间修饰，DNA羟甲基化）是由可卡因诱导的 经验，以及这些变化是否与可卡因相关的行为有意义。变化 DNA甲基化和羟甲基化将使用各种尖端技术进行研究， 包括甲基化DNA免疫沉淀、DNA的直接亚硫酸氢盐测序和全基因组测序。 世代排序更多的研究将首次检查这些变化是否发生在 单个细胞群的细胞核。这些分析不仅能让我们确定 可卡因的经验与核内DNA甲基化的变化有关，但也会 揭示这些变化影响了哪些基因和哪些神经元亚型。此外，DNA的能力 甲基化改变在功能上调节可卡因诱导的行为可塑性， 阻断或过度表达可卡因暴露过程中关键的DNA甲基化和去甲基化机制。 这些结果将为可卡因相关神经适应的表观遗传控制提供突破性的见解 并增强我们对调节动机行为的分子途径的理解。

Drug addiction is a chronic, relapsing disorder in which drug-related associations (e.g., discrete drug cues, locations in which drugs were consumed, and drug paraphernalia) are capable of exerting tremendous control over behavior long after drug taking has ceased. A hallmark feature of drugs of abuse is that they result in persistent, long-lasting functional and structural alterations in brain reward circuits such as the nucleus accumbens. Recent discoveries have revealed that epigenetic modifications, such as methylation of cytosine nucleotides in DNA, are key regulators of long-term synaptic plasticity, learning, and long-term or even transgenerational behavioral change. Moreover, novel findings indicate that drugs of abuse such as cocaine induce epigenetic changes in the nucleus accumbens, and that these changes control cocaine-related neuroadaptations. However, very little is known about how experience with cocaine alters DNA methylation within the nucleus accumbens, and whether this modification subserves cocaine-induced neuronal and behavioral plasticity. This proposal will examine whether changes in DNA methylation (and a recently discovered brain-enriched intermediate modification, DNA hydroxymethylation) are induced by cocaine experience, and whether these changes are meaningfully related to cocaine-related behaviors. Changes in DNA methylation and hydroxymethylation will be investigated using a variety of cutting-edge techniques, including methylated DNA immunoprecipitation, direct bisulfite sequencing of DNA, and whole-genome next generation sequencing. Additional studies will examine for the first time whether these changes occur within individual cell populations in the nucleus accumbens. These assays will allow us to determine not only whether cocaine experience is associated with changes in DNA methylation in the nucleus accumbens, but will also reveal which genes and which neuronal subtypes such changes are affecting. Furthermore, the ability of DNA methylation changes to functionally modulate cocaine-induced behavioral plasticity will be examined by blocking or overexpressing critical DNA methylation and demethylation machinery during cocaine exposure. The results will provide groundbreaking insight into the epigenetic control of cocaine-related neuroadaptations and enhance our understanding of the molecular pathways that regulate motivated behavior.