Psychostimulant-Induced Plasticity of Nucleus Accumbens Interneurons

精神兴奋剂诱导的伏核中间神经元的可塑性

• 批准号: 9903277
• 负责人: Anne Elizabeth West
• 金额: $ 38.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903277
• 关键词: Acute; Address; Amphetamines; Amygdaloid structure; Automobile Driving; Behavior; Behavioral; Biological Models; Brain; Brain region; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Cocaine; Complex; Corpus striatum structure; Data; Development; Drug Addiction; Electrophysiology (science); Elements; Enhancers; Epigenetic Process; Event; Experimental Models; Exposure to; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Interneuron function; Interneurons; Investigation; Lead; Learning; Link; Measurement; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Methods; Modeling; Molecular; Molecular Genetics; Motivation; Mus; Neurons; Neurophysiology - biologic function; Nuclear; Nucleus Accumbens; Output; Parvalbumins; Physiological; Physiology; Play; Population; Proteins; Protocols documentation; Psychological reinforcement; Regulation; Rewards; Role; Self Administration; Site; Societies; Stimulus; Synapses; Synaptic plasticity; Testing; Transcriptional Regulation; Transgenic Organisms; addiction; behavioral response; brevican; cell type; combat; conditioned place preference; cost; drug of abuse; epigenome editing; functional plasticity; genetic manipulation; habit learning; in vivo; neural circuit; novel; prevent; programs; psychostimulant; transcription factor

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.

滥用精神兴奋剂药物会引起神经奖赏回路功能的持续变化， 是成瘾的基础丘脑核（NAc）在动机中起着重要作用， 奖励和强化学习，这个大脑区域是精神兴奋剂诱导的细胞的主要部位。 导致吸毒成瘾的适应。大量的数据表明，基因转录的变化，介导 通过染色质的精神兴奋剂依赖性调节，在驱动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， 在NAc的多刺投射神经元（SPN）中的调节事件，NAc由多种细胞类型组成， 并且NAc的输出由几类中间神经元的活动有力地调制。我们有 表明沉默这些中间神经元群体之一的功能，即表达小白蛋白（PV）的 NAc GABA能中间神经元群体，阻断运动敏化和条件反射的表达。 重复苯丙胺暴露诱导的小鼠位置偏爱（CPP）。纹状体的功能可塑性 PV+中间神经元也与可卡因自我给药和习惯学习有关，这表明PV+中间神经元可能是一种神经元。 这些神经元在许多激励行为背后的回路适应中具有保守的功能。 尽管如此，我们对精神兴奋剂调节神经元的分子机制知之甚少。 PV+中间神经元的功能可塑性影响成瘾样行为的变化。以查明和 将PV+中间神经元分子可塑性与NAc中的细胞和电路适应联系起来， 像行为一样，我们必须确定染色质调节和基因转录的细胞类型特异性程序， 确定其功能后果。在这里，我们将创建从转录到 分子介导的行为。我们将使用PV+-中间神经元特异性识别和操纵， AMPH调节的基因在体内，并研究对NAc PV+中间神经元生理学的会聚效应， 小鼠对AMPH诱导的CPP的敏感性。本提案的目的是检验总体假设 在NAc PV+中间神经元中，依赖于精神兴奋剂的转录调节改变了这些神经元的功能。 神经元来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 假设通过确定神经元周围的净蛋白短蛋白作为一个功能的重要性， PV+神经元间突触可塑性和成瘾样行为的精神兴奋剂调节调节剂。在 目标2我们将使用前沿的表观基因组编辑和染色质分析方法， 在PV+ NAc中间神经元中精神兴奋剂依赖性转录因子的诱导如何协调 基因表达的下游程序介导PV+神经元功能的长期变化。采取 这些研究将揭示细胞可塑性机制如何在NAc的PV+中间神经元内发挥作用， 门适应NAc功能的基础成瘾样行为。