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: 10115270
• 负责人: Yi Zhang
• 金额: $ 76.94万
• 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/10115270
• 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; Drug Addiction; Enzymes; Epigenetic Process; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Goals; Health; Heterogeneity; Human; Intravenous; Label; Mediating; Mental disorders; Modeling; Molecular; Motivation; Mus; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; 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; base; brain cell; 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; 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.

了解可卡因成瘾中NAC的神经元亚型特异性功能 抽象的 吸毒成瘾是一种慢性复发的脑部疾病，其特征是寻求强迫性药物 并使用有害后果。这是一个紧迫的社会和健康问题，促成更多 在美国，超过90,000人死亡，每年造成7000亿美元的费用超过7000亿美元（请参阅NIDA网站）。 人们认为，大脑奖励系统的长期适应不良变化在 成瘾性疾病的发展。但是，基本机制在很大程度上仍然未知。 药物对动物行为的持久影响和人类瘾君子复发的风险 表明滥用药物引起的大脑奖励系统的某些稳定变化使这些 长期行为适应。积累的证据表明，药物诱导的分子，细胞 电路变化，尤其是伏隔核（NAC）中的电路变化，在药物中起重要作用 瘾。但是，由于哺乳动物大脑的细胞异质性，细胞类型特异性 添加机制尚不清楚。 要克服细胞异质性问题，并促进我们对细胞亚型的理解 药物成瘾的特定机制，我们建议识别涉及的NAC中的神经元亚型 通过全面分析神经元中该大脑区域的转录特征来成瘾 使用临床相关的可卡因自我管理（IVSA），亚型特异性方式 鼠标模型。此外，将使用特定细胞类型的分析/操纵方法 了解成瘾过程中特定神经元亚型的功能和机制。到 实现这一目标，我们有以下具体目标： 1）使用鼠标模型 可卡因IVSA； 2）可卡因成瘾中Tac2+ D1 MSN亚型的功能和电路机制； 3）了解可卡因中神经元亚型特异性功能的表观遗传机制 瘾。 拟议研究的完成不仅会促进我们对不同NAC的理解 神经元亚型有助于吸毒，但也揭示了治疗此治疗的新型治疗靶标 紊乱。