Understanding neuronal subtype-specific function of NAc in cocaine addiction

了解 NAc 在可卡因成瘾中的神经元亚型特异性功能

• 批准号: 10569638
• 负责人: Yi Zhang
• 金额: $ 72.3万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569638
• 关键词: Abstinence; Animal Behavior; Behavioral; Brain; Brain Diseases; Brain region; Cell Nucleus; Cells; Cessation of life; Chronic; Cocaine; Cocaine Dependence; Coupled; Data; Development; Disease; Dissociation; Drug Addiction; Enzymes; Epigenetic Process; Gene Expression Profile; Gene Expression Profiling; Genetic; Genetic Transcription; Goals; Health; Heterogeneity; Human; Intravenous; Label; Mediating; Mental disorders; Modeling; Molecular; Motivation; Mus; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Persons; Pharmaceutical Preparations; Phase; Play; Process; Psychological reinforcement; Regulation; Relapse; Rewards; Role; Saline; Self Administration; System; Therapeutic Intervention; Tissue-Specific Gene Expression; United States; Viral; addiction; cell type; clinically relevant; cocaine self-administration; cost; drug of abuse; epigenetic profiling; experimental study; genetic approach; knock-down; mouse model; neural circuit; neuronal circuitry; new therapeutic target; overexpression; relapse risk; single-cell RNA sequencing; social; targeted treatment; transcriptome; transcriptomic profiling; web site

Understanding neuronal subtype-specific function of NAc 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 brain reward system play a central role in the development of addictive disorders. However, the underlying 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. Accumulating evidence suggests that drug-induced molecular, cellular and circuitry changes, especially those in the nucleus accumbens (NAc), play important roles in drug addiction. However, due to the cellular heterogeneity of the mammalian brain, the cell type-specific mechanism of addition is unknown. To overcome the cell heterogeneity issue and to advance our understanding of the cell subtype- specific mechanisms of drug addiction, we propose to identify the neuronal subtypes in NAc involved in addiction by comprehensively analyzing the transcriptional profiles of this brain region in a neuron subtype-specific manner, using a clinically relevant intravenous cocaine self-administration (IVSA) mouse model. Furthermore, cell type-specific profiling/manipulation approaches will be used to understand the function and mechanism of specific neuron subtypes during addictive process. To achieve this goal, we have the following specific aims: 1) Profile cell type-specific transcriptome of different neuron subtypes of NAc using a mouse model of cocaine IVSA; 2) The function and circuitry mechanisms of Tac2+ D1 MSN subtype in cocaine addiction; 3) Understand the epigenetic mechanism of the neuron subtype-specific functions in cocaine addiction. Completion of the proposed study will not only advance our understanding on how different NAc neuron subtypes contribute to drug addiction, but also reveal novel therapeutic targets for treating this disorder.

了解NAc在可卡因成瘾中的神经元亚型特异性功能 摘要 药物成瘾是一种慢性的、复发性的大脑疾病，其特征是强迫性药物寻求 尽管有有害的后果。这是一个紧迫的社会和健康问题， 超过90，000人死亡，在美国每年造成超过7000亿美元的损失（见NIDA网站）。 据信，大脑奖励系统的长期适应不良变化在大脑发育中起着核心作用。 成瘾性疾病的发展。然而，其基本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励系统的一些稳定变化介导了这些变化。 长期的行为适应。越来越多的证据表明，药物诱导的分子，细胞 神经回路的改变，尤其是丘脑核（NAc）的改变，在药物治疗中起着重要作用。 成瘾然而，由于哺乳动物脑的细胞异质性，细胞类型特异性 添加的机制是未知的。 为了克服细胞异质性的问题，并促进我们对细胞亚型的理解- 药物成瘾的具体机制，我们建议确定参与NAc的神经元亚型 通过全面分析神经元中这一大脑区域的转录谱， 亚型特异性方式，使用临床相关的静脉内可卡因自我给药（IVSA） 小鼠模型此外，细胞类型特异性分析/操作方法将用于 了解特定神经元亚型在成瘾过程中的功能和机制。到 为达致这个目标，我们有以下的具体目标： 1)使用小鼠模型分析NAc不同神经元亚型的细胞类型特异性转录组 可卡因IVSA; 2)Tac 2 + D1 MSN亚型在可卡因成瘾中的功能及通路机制 3)了解可卡因中神经元亚型特异性功能的表观遗传机制 成瘾 完成拟议的研究不仅会加深我们对不同NAc的理解， 神经元亚型有助于药物成瘾，但也揭示了治疗这种疾病的新的治疗靶点。 disorder.