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

基本信息

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
项目类别：
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

项目摘要

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抽象的毒瘾是一种慢性、复发性脑部疾病，其特征是强迫性寻求药物并在不顾有害后果的情况下使用。这是一个紧迫的社会和健康问题，导致更多美国每年有超过 90,000 人死亡，造成的损失超过 7000 亿美元（参见 NIDA 网站）。据信，大脑奖赏系统的长期适应不良变化在成瘾性疾病的发展。然而，其根本机制仍然很大程度上未知。药物对动物行为的长期影响和人类成瘾者复吸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的行为适应。越来越多的证据表明药物诱导的分子、细胞和电路的变化，特别是伏隔核（NAc）的变化，在药物中起着重要作用瘾。然而，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。为了克服细胞异质性问题并增进我们对细胞亚型的理解- 为了了解药物成瘾的具体机制，我们建议确定涉及 NAc 的神经元亚型通过全面分析神经元中该大脑区域的转录谱来研究成瘾亚型特异性方式，使用临床相关的静脉注射可卡因自我给药（IVSA）鼠标模型。此外，细胞类型特异性分析/操作方法将用于了解成瘾过程中特定神经元亚型的功能和机制。到为实现这一目标，我们有以下具体目标： 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）Tac2+ D1 MSN亚型在可卡因成瘾中的功能和电路机制； 3）了解可卡因神经元亚型特异性功能的表观遗传机制瘾。完成拟议的研究不仅将加深我们对不同 NAc 如何神经元亚型会导致药物成瘾，但也揭示了治疗这种药物成瘾的新治疗靶点紊乱。