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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