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 摘要 毒瘾是一种慢性、复发性的大脑疾病，其特征是强迫性寻求毒品。 并不顾有害后果使用。这是一个紧迫的社会和健康问题，导致更多 在美国，死亡人数超过90,000人，每年造成的损失超过7,000亿美元(见NIDA网站)。 据认为，大脑奖励系统中长期的适应不良变化在 成瘾障碍的发展。然而，潜在的机制在很大程度上仍不清楚。 药物对动物行为的长期影响和人类吸毒者复发的风险 表明滥用药物引起的大脑奖赏系统的一些稳定的变化调节了这些 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 而电路的变化，特别是伏隔核(NAC)的变化，在药物中起着重要的作用 上瘾。然而，由于哺乳动物大脑的细胞异质性，特定的细胞类型 加成的机理尚不清楚。 为了克服细胞异质性问题，促进我们对细胞亚型的理解-- 关于药物成瘾的具体机制，我们建议确定NAC中涉及的神经元亚型 通过全面分析神经元中这一大脑区域的转录图谱 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) 老鼠模型。此外，还将使用特定细胞类型的分析/操作方法来 了解特定神经元亚型在成瘾过程中的作用和机制。至 实现这一目标，我们有以下具体目标： 1)使用小鼠模型分析不同神经元亚型NAC的细胞类型特异性转录组 可卡因静脉注射； 2)Tac2D1MSN亚型在可卡因成瘾中的作用和电路机制； 3)了解可卡因中神经元亚型特异性功能的表观遗传机制 上瘾。 拟议研究的完成不仅将加深我们对不同的新来港儿童 神经元亚型与药物成瘾有关，但也揭示了治疗药物成瘾的新靶点 无序。

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.