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：
10306374
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306374
关键词：
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 F-Actin Foundations Future G Actin Genetic Genetic Transcription Globus Pallidus Guanosine Triphosphate Phosphohydrolases Habenula Label Lateral Maintenance Mediating Mediator of activation protein Messenger RNA Molecular Molecular Analysis Mus NR4A1 gene Neurons Nucleus Accumbens Output PLK1 gene Pathway interactions Pharmaceutical Preparations Pharmacology 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 knock-down molecular targeted therapies neural circuit overexpression 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，以强迫性药物寻求和使用为特征负面的个人后果。反复接触滥用药物的药物伴随着持久分子过程的改变。这包括调节突触和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。精神刺激诱导的分子改变已经在临界奖励大脑区域中得到很好的特征，例如伏隔核（NAC）。两个NAC中棘刺神经元（MSN）亚型显示经典不同的投影输出，但最近的研究表明，从这些神经元到可卡因作用中的腹侧颗粒（VP）。令人惊讶的是，没有信息尽管它是NAC MSN亚型及其关键的诱导分子适应，尽管它是NAC MSN亚型的主要靶标在行为对虐待药物的行为反应中的作用。我们的研究将研究潜在的分子过程可卡因自我管理后发生在VP中，并确定两个NAC MSN亚型如何促进可卡因诱导VP中的分子改变。我们将专注于转录因子核受体亚家族4组成员1（NR4A1）和NR4A1转录靶标，Polo类似激酶2（PLK2），我们可卡因自我给药后使用RNA-seq确定在VP中上调。我们的研究将首先确定在可卡因自发给药后，VP神经元亚型显示这些分子的上调。我们将然后在特定VP神经元亚型中使用遗传工具过表达或敲除NR4A1和PLK2 可卡因自我管理和复发行为。我们还将确定NR4A1是否在转录上在这些条件下，调节VP中的PLK2。接下来，我们将探讨VP神经元亚型结构和突触可塑性通过NR4A1和PLK2调节。最后，我们将确定上游NAC MSN子类型是否可以调节可卡因自我管理期间VP中的这些转录和细胞适应。我们的研究将首次将信息提供到介导VP中细胞适应的分子适应中神经元亚型，最终是药物自我给药或复发行为的基础。我们的研究可以在成瘾中为VP中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，我们的研究能够鉴定成瘾中治疗干预的分子靶标。