Role of DNA Methylation in Cocaine Addiction

DNA甲基化在可卡因成瘾中的作用 摘要 药物成瘾是一种慢性、复发性大脑疾病，其特征是强迫性寻求和使用药物。 尽管有有害的后果。它是一个紧迫的社会和健康问题，导致9万多人死亡 在美国每年造成超过7000亿美元的成本(见NIDA网站)。人们相信，从长远来看 中脑边缘多巴胺奖赏系统的不适应变化在脑性痴呆的发生发展中起核心作用。 令人上瘾的障碍。然而，其潜在的分子机制在很大程度上仍不清楚。 药物对动物行为的长期影响和人类吸毒者复发的风险表明 滥用药物引起的大脑奖励系统的一些稳定变化调节了这些长期行为 改编。因此，越来越多的证据表明，药物引起的表观遗传学变化，特别是 DNA甲基化和组蛋白修饰的改变，在药物成瘾中起着重要作用。然而，由于 处理哺乳动物大脑细胞异质性的技术困难，大多数分子 到目前为止进行的研究使用的是混合细胞群体，这使得对现有数据的解释变得困难。 因此，在了解药物成瘾的分子基础方面取得的进展有限。 克服细胞异质性的问题，促进我们对表观遗传学的理解 机制，我们建议全面分析DNA甲基化在药物成瘾中的作用。 使用临床相关静脉注射的神经元亚型和投射特异性方式的药物成瘾 可卡因自我给药(IVSA)模型。具体地说，我们试图阐明腹侧的DNA甲基化是如何 被盖区(VTA)多巴胺能神经元调节可卡因的增强。为了实现这一目标，我们有 确立了以下具体目标： 1)用小鼠可卡因IVSA模型对VTA多巴胺(DA)能神经元的转录组和甲基组进行了分析； 2)VTA DA神经元DNA甲基化调控关键基因的功能分析； 3)了解DNA甲基化在VTA DA投射神经元可卡因强化中的作用。 拟议研究的完成不仅将促进我们对DNA甲基化如何 有助于药物成瘾，但也揭示了治疗这种疾病的新的治疗靶点。重要的是，我们的 这项研究为理解神经元亚型的表观遗传调控提供了一种新的、广泛适用的策略。 和投影特定的方式。

Role of DNA methylation in cocaine addiction Abstract Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug seeking and use despite harmful consequences. It is an urgent social and health problem contributing to more than 90,000 deaths and incurs a yearly cost of over $700 billion in the United States (see NIDA website). It is believed that long-term maladaptive changes in the mesolimbic dopamine reward system play a central role in the development of addictive disorders. However, the underlying molecular mechanism remains largely unknown. The long-lasting effect of drugs on animal behavior and the risk of relapse in human addicts indicate that some stable changes in the brain reward system induced by drugs of abuse mediate these long-term behavioral adaptions. Accordingly, accumulating evidence suggests that drug-induced epigenetic changes, particularly DNA methylation and histone modifications changes, play important roles in drug addiction. However, due to technical difficulties in dealing with the cellular heterogeneity of the mammalian brain, most of the molecular studies performed so far used mixed cell populations, making interpretation of the available data difficult. Consequently, limited progress has been made in understanding the molecular basis of drug addiction. To overcome the issue of cell heterogeneity and to advance our understanding of the epigenetic mechanisms underlying drug addiction, we propose to comprehensively analyze the role of DNA methylation in drug addiction in a neuron subtype- and projection-specific manner using a clinically relevant intravenous cocaine self-administration (IVSA) model. Specifically, we seek to elucidate how DNA methylation in ventral tegmental area (VTA) dopaminergic neurons regulates cocaine reinforcement. To achieve this goal, we have established the following specific aims: 1) Profile transcriptome and methylome of VTA dopaminergic (DA) neurons using a mouse cocaine IVSA model; 2) Functional analysis of key genes regulating DNA methylation in VTA DA neurons; 3) Understand the role of DNA methylation in cocaine reinforcement in projection-specific VTA DA neurons. Completion of the proposed study will not only advance our understanding of how DNA methylation contributes to drug addiction, but also reveal novel therapeutic targets for treating this disorder. Importantly, our study provides a novel, broadly applicable strategy for understanding epigenetic regulation in a neuron subtype- and projection-specific manner.