Determining The Role of HDAC3 Within D1R-MSNs in Cocaine-Associated Behaviors

项目摘要/摘要 众所周知，药物引起调节基因表达的表观遗传机制的改变 有助于发展毒品寻觅行为。例如，急性和慢性暴露于 可卡因增加伏核(NAC)内的组蛋白乙酰化。此外，我们的实验室已经确定 组蛋白乙酰转移酶CBP和组蛋白去乙酰基酶HDAC3是可卡因的关键调节因子。 相关记忆的形成。我们的工作表明，NAC内的HDAC3对可卡因- 诱导组蛋白乙酰化、基因表达和记忆形成的变化。然而，它是未知的 可卡因是否通过诱导细胞类型特异性改变NAC促进药物联想记忆的功能 突触可塑性和基因表达的变化。NAC包含两个主要的细胞亚型，分为两个 基于受体表达的中等刺神经元(MSN)亚群，主要通过 多巴胺D1受体(D1R)或多巴胺D2受体(D2R)的表达。这些不同的细胞亚型 已知可调节对可卡因的不同行为反应，D1R-MSN促进可卡因寻求。 有大量证据表明，接触可卡因会导致体内基因表达的差异 这两种亚型，D1R-MSN中几个HDAC3靶基因表达增加。然而，它 关于这些不同类型的细胞内的HDAC3活动如何受到影响和调节，仍然是一个悬而未决的问题 寻找毒品。这个应用程序中提出的实验将使我能够解决总体假设 可卡因诱导的D1R-MSN内HDAC3活性的破坏促进可卡因相关的获得 行为。

Project Summary/Abstract It is well established that drug-induced alterations to epigenetic mechanisms that regulate gene expression contribute to the development of drug-seeking behaviors. For instance, both acute and chronic exposure to cocaine increases histone acetylation within the nucleus accumbens (NAc). Furthermore, our lab has identified that the histone acetyltransferase CBP and histone deacetylase HDAC3 are critical regulators of cocaine- associated memory formation. Our work demonstrated that HDAC3 within the NAc negatively regulates cocaine- induced changes in histone acetylation, gene expression, and memory formation. However, it is unknown whether cocaine alters the function of the NAc to promote drug-associative memory by inducing cell-type specific changes in synaptic plasticity and gene expression. The NAc contains two major cell subtypes, divided into two subpopulations of medium spiny neurons (MSNs) based on the expression of receptors, primarily through expression of either dopamine D1 receptors (D1R) or dopamine D2 receptors (D2R). These distinct cell subtypes are known to mediate differential behavioral responses to cocaine, with D1R-MSNs promoting cocaine-seeking. There is substantial evidence demonstrating that cocaine exposure induces differential gene expression within these two subtypes, with increased expression of several HDAC3 target genes in D1R-MSNs. However, it remains an open question as to how HDAC3 activity within these distinct cell types is affected by and regulates drug-seeking. The experiments proposed in this application will allow me to address the overall hypothesis that cocaine-induced disruption of HDAC3 activity within D1R-MSNs promotes acquisition of cocaine-associated behaviors.