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Role of DNA Methylation in Cocaine Addiction

DNA 甲基化在可卡因成瘾中的作用

基本信息

批准号：
10113569
负责人：
Yi Zhang
金额：
$ 56.64万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113569
关键词：
Address Animal Behavior Behavioral Brain Brain Diseases CRISPR/Cas technology Cell Nucleus Cells Cessation of life Chronic Cocaine Cocaine Dependence Coupled DNA Methylation DNA Modification Methylases Data Data Set Dependovirus Development Disease Dopamine Dose Drug Addiction Electrophysiology (science)Epigenetic Process Extinction (Psychology)Fluorescence Gene Expression Genes Goals Health Herpesvirus 1 Heterogeneity Human Intravenous Knock-out Label Maintenance Mediating Methyl-CpG-Binding Protein 2 Modeling Molecular Mus National Institute of Drug Abuse Neurons Pharmaceutical Preparations Phase Play Population Process Psychological reinforcement RNA analysis Relapse Rewards Role Self Administration Sorting - Cell Movement System Techniques Transcriptional Regulation United States Ventral Tegmental Area Viral addiction base bisulfite sequencing clinically relevant cocaine self-administration comparative cost dopaminergic neuron drug of abuse epigenetic regulation genetic approach genetic manipulation histone modification methylome new therapeutic target novel relapse risk response social transcriptome transcriptome sequencing web site whole genome

项目摘要

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.

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的、复发性的脑部疾病，其特征是强迫性的药物寻求和使用尽管会有有害的后果。这是一个紧迫的社会和健康问题，导致9万多人死亡在美国，每年的成本超过7000亿美元（见NIDA网站）。据信，长期中脑边缘多巴胺奖励系统的适应不良变化在脑缺血的发展中起着核心作用。成瘾性障碍然而，其潜在的分子机制在很大程度上仍然未知。药物对动物行为的长期影响和人类成瘾者复发的风险表明，滥用药物引起的大脑奖赏系统的一些稳定变化介导了这些长期行为，适应。因此，越来越多的证据表明，药物引起的表观遗传变化， DNA甲基化和组蛋白修饰改变在药物成瘾中起重要作用。但由于在处理哺乳动物大脑细胞异质性的技术困难，大多数分子迄今为止进行的研究使用的是混合细胞群，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。为了克服细胞异质性的问题，并促进我们对表观遗传的理解，药物成瘾的潜在机制，我们建议全面分析DNA甲基化在药物成瘾中的作用。使用临床相关的静脉注射，以神经元亚型和投射特异性方式研究药物成瘾可卡因自我给药（IVSA）模型。具体地说，我们试图阐明腹侧海马中的DNA甲基化是如何发生的。被盖区（VTA）多巴胺能神经元调节可卡因强化。为了实现这一目标，我们确定了以下具体目标： 1)利用小鼠可卡因IVSA模型分析腹侧被盖区多巴胺能神经元的转录组和甲基化组 2)腹侧被盖区DA能神经元DNA甲基化调控关键基因的功能分析 3)了解DNA甲基化在投射特异性腹侧被盖区DA神经元中可卡因强化中的作用。这项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- 具体的项目方式。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spatial transcriptomics reveals the distinct organization of mouse prefrontal cortex and neuronal subtypes regulating chronic pain.

DOI：
10.1038/s41593-023-01455-9
发表时间：
2023-11
期刊：
NATURE NEUROSCIENCE
影响因子：
25
作者：
Bhattacherjee, Aritra;Zhang, Chao;Watson, Brianna R.;Djekidel, Mohamed Nadhir;Moffitt, Jeffrey R.;Zhang, Yi
通讯作者：
Zhang, Yi

Accurate inference of genome-wide spatial expression with iSpatial.

DOI：
10.1126/sciadv.abq0990
发表时间：
2022-08-26
期刊：
Science advances
影响因子：
13.6
作者：
通讯作者：

In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function.

体内核捕获和分子分析将 Gmeb1 确定为多巴胺神经元功能必需的转录调节因子。

DOI：
10.1038/s41467-019-10267-0
发表时间：
2019
期刊：
Nature communications
影响因子：
16.6
作者：
Tuesta,LuisM;Djekidel,MohamedN;Chen,Renchao;Lu,Falong;Wang,Wengang;Sabatini,BernardoL;Zhang,Yi
通讯作者：
Zhang,Yi

Single-Cell RNA-Seq Reveals Hypothalamic Cell Diversity.

单细胞RNA-Seq揭示了下丘脑细胞的多样性。

DOI：
10.1016/j.celrep.2017.03.004
发表时间：
2017-03-28
期刊：
Cell reports
影响因子：
8.8
作者：
Chen R;Wu X;Jiang L;Zhang Y
通讯作者：
Zhang Y

Decoding molecular and cellular heterogeneity of mouse nucleus accumbens.

DOI：
10.1038/s41593-021-00938-x
发表时间：
2021-12
期刊：
Nature neuroscience
影响因子：
25
作者：
Chen R;Blosser TR;Djekidel MN;Hao J;Bhattacherjee A;Chen W;Tuesta LM;Zhuang X;Zhang Y
通讯作者：
Zhang Y