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Ventral pallidum molecular mediators in cocaine addiction

可卡因成瘾中的腹侧苍白球分子介质

基本信息

批准号：
10530659
负责人：
Mary Kay Lobo
金额：
$ 43.43万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530659
关键词：
Actins Behavior Biochemical Chronic Disease Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Abuse Cocaine Dependence Cytoskeleton Data Dendritic Spines Drug Exposure Drug abuse Exposure to Foundations Future G Actin Genetic Genetic Diseases Genetic Induction Genetic Transcription Globus Pallidus Guanosine Triphosphate Phosphohydrolases Habenula Label Lateral Maintenance Mediating Mediator Messenger RNA Molecular Molecular Analysis Mus NR4A1 gene Neurons Nucleus Accumbens Output PLK1 gene Pathway interactions Pharmaceutical Preparations Physiology Process Relapse RiboTag Role Self Administration Synapses Synaptic plasticity Therapeutic Intervention Time Up-Regulation addiction behavioral response brain reward regions cocaine exposure cocaine self-administration conditioned place preference density drug of abuse genetic manipulation knock-down molecular targeted therapies neural circuit overexpression pharmacologic postsynaptic prevent psychostimulant tool transcription factor transcriptome sequencing

项目摘要

Drug abuse is a debilitating chronic disease characterized by compulsive drug seeking and use despite negative personal consequences. Repeated exposure to drugs of abuse is accompanied by persistent alterations in molecular processes. This includes alterations in transcription factors that regulate synaptic and structural plasticity molecules, which underlie the persistent behavioral responses to repeated drug exposure. Psychostimulant induced molecular alterations have been well characterized in critical reward brain regions, such as the nucleus accumbens (NAc). The two NAc medium spiny-projection neuron (MSN) subtypes display classically distinct projection outputs but recent studies demonstrate converging output from these neurons to the ventral pallidum (VP) in the actions of cocaine. Surprisingly, there is no information into psychostimulant induced molecular adaptations in VP, despite it being a main target of both NAc MSN subtypes and its critical role in behavioral responses to drugs of abuse. Our studies will investigate the underlying molecular processes occurring in VP after cocaine self-administration and determine how the two NAc MSN subtypes contribute to cocaine induced molecular alterations in the VP. We will focus on the transcription factor nuclear receptor subfamily 4 group A member 1 (Nr4a1) and the Nr4a1 transcriptional target, polo like kinase 2 (Plk2), which we identified to be upregulated in VP after cocaine self-administration using RNA-seq. Our studies will first identify which VP neuron subtype displays upregulation of these molecules after cocaine-self administration. We will then use genetic tools to overexpress or knockdown Nr4a1 and Plk2 in specific VP neuron subtypes during cocaine self-administration and relapse behavior. We will additionally determine if Nr4a1 transcriptionally regulates Plk2 in VP in these conditions. Next we will explore how VP neuron subtype structural and synaptic plasticity is regulated through Nr4a1 and Plk2. Finally, we will determine if the upstream NAc MSN subtypes can regulate these transcriptional and cellular adaptations in VP during cocaine self-administration. Our studies will for the first time provide information into the molecular adaptations that mediate cellular adaptations in VP neuron subtypes, which ultimately underlies drug self-administration or relapse behavior. Our studies can provide a foundation for molecular analysis in VP in addiction that in the future can be applied to other drugs of abuse. Finally, our studies have the ability to identify molecular targets for therapeutic intervention in addiction.

药物滥用是一种使人衰弱的慢性疾病，其特征是强迫性寻求和使用药物，消极的个人后果。反复接触药物滥用伴随着持续的分子过程的改变。这包括调节突触的转录因子的改变，结构可塑性分子，这是对重复药物暴露的持续行为反应的基础。精神兴奋剂诱导的分子改变已经在关键的奖励脑区域得到了很好的表征，例如，神经核（NAc）。两种NAc中型棘投射神经元（MSN）亚型显示经典的不同投影输出，但最近的研究表明，这些神经元的输出收敛到腹侧苍白球（VP）在可卡因的作用。令人惊讶的是，没有关于精神兴奋剂的信息诱导VP的分子适应，尽管它是NAc MSN亚型的主要靶点，在药物滥用的行为反应中的作用。我们的研究将调查潜在的分子过程发生在可卡因自我管理后VP，并确定如何两个NAc MSN亚型有助于可卡因诱导VP的分子改变。我们将重点介绍转录因子核受体亚家族4 A组成员1（Nr 4a 1）和Nr 4a 1转录靶蛋白波罗样激酶2（Plk 2），我们使用RNA-seq鉴定在可卡因自我施用后VP上调。我们的研究将首先确定该VP神经元亚型在可卡因自身给药后显示这些分子的上调。我们将然后使用遗传工具在特定VP神经元亚型中过表达或敲低Nr 4a 1和Plk 2，可卡因自我管理和复发行为。我们还将确定Nr 4a 1是否转录在这些条件下调节VP中的Plk 2。接下来，我们将探讨VP神经元亚型的结构和突触可塑性通过Nr 4a 1和Plk 2调节。最后，我们将确定上游NAc MSN子类型可以调节这些转录和细胞适应VP可卡因自我管理期间。我们的研究将首次提供信息到介导细胞适应VP的分子适应神经元亚型，这最终是药物自我管理或复发行为的基础。我们的研究可以为VP成瘾的分子分析提供了基础，将来可以应用于其他药物，虐待最后，我们的研究有能力确定成瘾治疗干预的分子靶点。