Psychostimulant-Induced Plasticity of Nucleus Accumbens Interneurons

滥用精神刺激性药物会导致神经奖赏回路功能的持续变化 这是成瘾发展的基础。伏隔核(NAC)在动机中起着重要作用， 奖赏和强化学习，而这个大脑区域是心理刺激剂诱导的细胞的主要部位 导致吸毒成瘾的适应。大量数据表明，基因转录的变化， 通过心理刺激剂对染色质的依赖调节，在推动NAC持续变化中发挥关键作用 功能。尽管过去的许多研究都集中在这些转录和染色质的诱导上 NAC的棘突投射神经元(SPN)中的调节事件，NAC由多种细胞类型组成， NAC的输出受到几类中间神经元活动的强烈调制。我们有 研究表明，沉默这些中间神经元群体之一的功能，表达小白蛋白(PV) NAc GABA能中间神经元群体阻断运动敏化和条件化表达 苯丙胺反复暴露小鼠的位置偏爱(CPP)。纹状体的功能可塑性 PV中间神经元也与可卡因自我管理和习惯学习有关，这表明 这些神经元在许多动机行为背后的电路适应中具有保守的功能。 尽管如此，我们对精神刺激剂调节大脑的分子机制知之甚少。 PV中间神经元的功能可塑性对成瘾样行为的影响。为了识别和识别 将PV神经元间分子可塑性与NAC中的细胞和电路适应联系起来，这是成瘾的基础- 与行为类似，我们必须确定染色质调节和基因转录的细胞类型特定程序和 确定它们的功能后果。在这里，我们将从转录到 行为的分子中介物。我们将使用PV-中间神经元特异性识别和操纵 AMPH在体内的调节基因，并研究融合对NAC-PV中间神经元和 小鼠对Amph诱导的CPP的敏感性。这项提议的目标是检验总体假设。 精神刺激剂对NAC PV中间神经元转录的依赖调节改变了这些神经元的功能 神经元可以减缓成瘾行为的发展。在目标1中，我们将对此进行具体测试 通过确定神经周网络蛋白Brivican作为一种 心理刺激剂调节的PV神经元间突触可塑性和成瘾样行为的调节器。在……里面 目的2我们将使用前沿的表观基因组编辑和染色质分析方法来更广泛地发现 心理刺激剂依赖的转录因子如何在NAC的PV中间神经元中诱导 基因表达的下游程序，以调节PV神经元功能的长期变化。已被占用 总之，这些研究将揭示细胞可塑性机制如何在NAC的PV中间神经元中起作用 开启NAC功能的适应，这是成瘾行为的基础。

Psychostimulant drugs of abuse induce persistent changes in the function of neural reward circuits that underlie the development of addiction. The nucleus accumbens (NAc) plays a significant role in motivation, reward, and reinforcement learning, and this brain region is a major site of the psychostimulant-induced cellular adaptations that lead to drug addiction. Substantial data indicate that changes in gene transcription, mediated by psychostimulant-dependent regulation of chromatin, play a key role in driving persistent changes in NAc function. Though many past studies have focused on the induction of these transcriptional and chromatin regulatory events in spiny projections neurons (SPNs) of the NAc, the NAc is comprised of multiple cell types, and the output of the NAc is powerfully modulated by the activity of several classes of interneurons. We have shown that silencing the function of one of these interneuron populations, the parvalbumin (PV)-expressing population of NAc GABAergic interneurons, blocks the expression of locomotor sensitization and conditioned place preference (CPP) induced by repeated amphetamine exposure in mice. Functional plasticity of striatal PV+ interneurons has also been implicated in both cocaine self-administration and habit learning, suggesting a conserved function for these neurons in the circuit adaptations underlying a number of motivational behaviors. Nonetheless, we know very little about the molecular mechanisms by which psychostimulants modulate the functional plasticity of PV+ interneurons to effect changes in addictive-like behaviors. In order to identify and link PV+ interneuron molecular plasticities to the cellular and circuit adaptations in NAc that underlie addictive- like behaviors, we must identify cell type specific programs of chromatin regulation and gene transcription and determine their functional consequences. Here we will create this roadmap from transcription through molecular mediators to behavior. We will use PV+-interneuron specific identification and manipulations of AMPH-regulated genes in vivo and study convergent effects on the physiology of NAc PV+ interneurons and the sensitivity of mice to AMPH-induced CPP. The goal of this proposal is to test the overarching hypothesis that psychostimulant-dependent regulation of transcription in NAc PV+ interneurons alters the function of these neurons to slow the development of addictive-like behaviors. In Aim 1 we will conduct a specific test of this hypothesis by determining the functional importance of the perineuronal net protein Brevican as a psychostimulant-regulated modulator of PV+ interneuron synaptic plasticity and addictive-like behaviors. In Aim 2 we will use leading edge epigenome-editing and chromatin analysis methods to discover more broadly how psychostimulant-dependent transcription factor induction in PV+ interneurons of the NAc coordinates downstream programs of gene expression to mediate long-lasting changes in PV+ neuron function. Taken together these studies will reveal how cellular plasticity mechanisms act within PV+ interneurons of the NAc to gate the adaptations of NAc function that underlie addictive-like behaviors.