Ventral pallidum molecular mediators in cocaine addiction

药物滥用是一种使人衰弱的慢性疾病，其特征是强迫寻求和使用药物，尽管 负面的个人后果。反复接触药物的滥用伴随着坚持不懈 分子过程中的变化。这包括调节突触和突触的转录因子的变化 结构可塑性分子，这是对反复药物暴露的持久行为反应的基础。 精神刺激剂诱导的分子变化在关键的奖赏脑区得到了很好的表征， 如伏隔核(NAC)。显示两种NAC中棘突投射神经元(MSN)亚型 经典的截然不同的投影输出，但最近的研究表明，这些神经元的输出会聚到 可卡因作用中的腹侧苍白球(VP)。令人惊讶的是，没有关于精神刺激剂的信息 诱导VP的分子适应，尽管它是NAC MSN亚型和其关键的 在对滥用药物的行为反应中的作用。我们的研究将探讨潜在的分子过程。 在可卡因自我给药后发生在VP中，并确定两种NAC MSN亚型如何参与 可卡因引起VP的分子改变。我们将重点关注转录因子核受体 亚家族4 A组成员1(Nr4a1)和Nr4a1转录靶标Polo like kinase2(PLK2)。 用RNA-seq鉴定可卡因自身给药后VP上调。我们的研究将首先确定 可卡因自身给药后，哪个VP神经元亚型表现出这些分子的上调。我们会 然后使用基因工具在特定的VP神经元亚型中过度表达或敲除Nr4a1和PLK2 可卡因自我给药和复吸行为。我们还将确定Nr4a1在转录水平上是否 在这些情况下调节VP中的PLK2。接下来，我们将探索VP神经元的亚型结构和突触 可塑性通过Nr4a1和PLK2调节。最后，我们将确定上游NAC MSN亚型 在可卡因自身给药期间，可以调节VP中的这些转录和细胞适应。我们的研究 将首次为调节VP细胞适应的分子适应提供信息 神经元亚型，这最终是药物自我给药或复发行为的基础。我们的研究可以 为药物成瘾中VP的分子分析提供了基础，可应用于其他成瘾药物的分析 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。

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.