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: 10089433
• 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/10089433
• 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; cocaine self-administration; 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.

虐待的心理刺激药物会导致神经奖励电路功能的持续变化 基础成瘾的发展。伏隔核（NAC）在动机中起重要作用， 奖励和增强学习，这个大脑区域是精神刺激诱导的细胞的主要部位 导致吸毒的适应。大量数据表明基因转录的变化，介导 通过染色质的心理刺激依赖性调节，在推动NAC的持续变化方面起着关键作用 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的多刺神经元（SPN）中的调节事件，NAC由多种细胞类型组成， NAC的输出通过几类中间神经元的活性进行了强大的调节。我们有 表明将这些神经元人群之一的函数沉默，即parvalbumin（PV）表达 NAC GABA能中间神经元的种群阻止了运动敏化的表达和条件 小鼠反复暴露于苯丙胺诱导的放置偏好（CPP）。纹状体的功能塑性 PV+中间神经元也与可卡因的自我管理和习惯学习有关，这表明 这些神经元在电路适应中的保守功能是许多动机行为的基础。 尽管如此，我们对精神刺激物调节的分子机制知之甚少 PV+中间神经元的功能可塑性会影响成瘾性行为的变化。为了识别和 将PV+中间神经元的可塑性与NAC中的细胞和电路适应性联系起来 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定程序以及 确定其功能后果。在这里，我们将创建此路线图，从转录到 分子介体行为。我们将使用PV+ - interneuron的特定识别和操纵 体内受调节的基因和研究对NAC PV+中间神经元生理的收敛作用和 小鼠对AMPH诱导的CPP的敏感性。该提议的目的是检验总体假设 NAC PV+中间神经元中转录的精神刺激依赖性调节会改变这些功能 神经元减缓类似上瘾的行为的发展。在AIM 1中，我们将对此进行特定的测试 通过确定周围神经元净蛋白Brevican作为A的功能重要性来假设 PV+中间神经元的突触可塑性和上瘾的行为的精神刺激调节器。在 AIM 2我们将使用前沿表观基因组编辑和染色质分析方法来更广泛地发现 NAC坐标的PV+中间神经元中的精神刺激依赖性转录因子诱导如何 基因表达的下游程序介导PV+神经元功能的长期变化。拍摄 这些研究共同揭示了NAC的PV+中间神经元内的细胞可塑性机制如何作用 门是基于成瘾性行为的NAC功能的适应。