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: 10550188
• 负责人: Anne Elizabeth West
• 金额: $ 38.14万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10550188
• 关键词: Acceleration; Acute; 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; Interneuron function; Interneurons; Investigation; Learning; Link; Measurement; Mediating; Mediator; 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; Repression; 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; stimulant exposure; 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.

滥用精神兴奋药物会引起神经奖励回路功能的持续变化， 是成瘾发展的基础。伏隔核 (NAc) 在动机方面发挥着重要作用， 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。大量数据表明，基因转录的变化，介导 通过精神兴奋剂依赖性染色质调节，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 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， NAc 的输出受到几类中间神经元活动的强烈调节。我们有 研究表明，沉默这些中间神经元群体之一的功能，即表达小清蛋白（PV）的 NAc GABA能中间神经元群，阻断运动敏化和条件反射的表达 小鼠反复接触安非他明诱导的位置偏好（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 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。为了识别和 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，这是成瘾的基础 像行为一样，我们必须识别细胞类型特定的染色质调节和基因转录程序， 确定它们的功能后果。在这里，我们将创建从转录到 行为的分子介质。我们将使用 PV+-中间神经元特异性识别和操作 体内 AMPH 调节基因并研究对 NAc PV+ 中间神经元生理学的聚合效应 小鼠对 AMPH 诱导的 CPP 的敏感性。该提案的目标是检验总体假设 NAc PV+ 中间神经元中精神兴奋剂依赖性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 通过确定神经周围网络蛋白 Brevican 作为 PV+ 中间神经元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来更广泛地发现 精神兴奋剂依赖性转录因子如何在 NAc 坐标的 PV+ 中间神经元中诱导 下游基因表达程序可介导 PV+ 神经元功能的长期变化。采取 这些研究将共同​​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，从而 控制 NAc 功能的适应，这是成瘾行为的基础。

项目成果

Single-nucleus transcriptional profiling of GAD2-positive neurons from mouse lateral habenula reveals distinct expression of neurotransmission- and depression-related genes.

小鼠外侧缰核 GAD2 阳性神经元的单核转录谱揭示了神经传递和抑郁相关基因的独特表达。

• DOI: 10.1101/2023.01.09.523312
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Green,MatthewV;Gallegos,DavidA;Boua,Jane-Valeriane;Bartelt,LukeC;Narayanan,Arthy;West,AnneE
• 通讯作者: West,AnneE