Modulation of the Perineuronal Net Protein Brevican in the Nucleus Accumbens, and its Impact on Addiction-related Behavior

伏核中神经周围网络蛋白 Brevican 的调节及其对成瘾相关行为的影响

• 批准号: 10196957
• 负责人: Mariah F Hazlett
• 金额: $ 3.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196957
• 关键词: Acute; Addictive Behavior; Address; Adult; Affect; Amphetamines; Amygdaloid structure; Area; Behavior; Behavioral; Biological Models; Cell Nucleus; Cells; Cocaine; Complex; Data; Development; Disease; Dose; Drug Addiction; Excitatory Synapse; Experimental Models; Exposure to; Fluorescent in Situ Hybridization; Future; Genetic Transcription; Goals; Hippocampus (Brain); Inhibitory Synapse; Interneuron function; Interneurons; Messenger RNA; Molecular; Molecular Target; Mus; Neurons; Nucleus Accumbens; Parvalbumins; Pharmaceutical Preparations; Phenotype; Play; Protein Isoforms; Proteins; Regulation; Rewards; Role; Self Administration; Societies; Synapses; Synaptic Potentials; Synaptic plasticity; Testing; Time; Virus; addiction; behavior test; brevican; cell type; cocaine self-administration; combat; conditioned place preference; cost; density; drug of abuse; drug reward; druggable target; functional plasticity; in vivo; knock-down; novel; overexpression; prevent; psychostimulant; relating to nervous system; reward circuitry; single molecule

Project Summary Psychostimulant drugs of abuse induce persistent functional changes in the neural reward circuitry that underlie the development of addiction. These regions include the nucleus accumbens (NAc), a key area for drug reward. Growing evidence suggests that altered interneuron function in NAc makes key contributions to the drug-induced circuit adaptations leading to addiction behaviors. We have shown that NAc parvalbumin- expressing (PV+) inhibitory interneurons are required for multiple addiction-related behaviors in mice, including amphetamine (AMPH)-induced locomotor sensitization and conditioned place preference (CPP). Others have shown that cocaine self-administration strengthens excitatory inputs from basolateral amygdala onto NAc PV+ interneurons, and artificially potentiating these synapses accelerates acquisition of cocaine self-administration in naïve mice, suggesting that synaptic plasticity in NAc PV+ interneurons is behaviorally relevant for the development of addiction-like behaviors. However, little is known about the molecular mechanisms by which psychostimulants alter PV+ inhibitory interneuron function, and how this contributes to addictive behaviors. A promising mechanistic target is the perineuronal net protein Brevican (Bcan), which plays a cell-autonomous role in stabilizing excitatory inputs onto PV+ interneurons. The overarching goal of this proposal is to test the hypothesis that repeated psychostimulant exposure modulates PV+ interneuron activity through regulation of Bcan expression. In Aim 1 I will characterize the regulation of Bcan expression in NAc PV+ interneurons over the development of AMPH CPP. In Aim 2 I will test how manipulating Bcan expression affects the synaptic inputs to these neurons. In Aim 3 I will test the effect of manipulating Bcan in NAc PV+ cells on the threshold to develop CPP. These studies will investigate cellular transcriptional and synaptic plasticity mechanisms within PV+ interneurons, and how they affect the expression of addiction-related behaviors.

项目摘要 虐待的心理刺激药物会导致神经奖励电路的持续功能变化 基础成瘾的发展。这些区域包括伏隔核（NAC），这是一个关键区域 毒品奖励。越来越多的证据表明，NAC中的中间神经元功能改变了关键贡献 药物诱导的电路适应导致成瘾行为。我们已经表明NAC白蛋白 - 在包括 苯丙胺（AMPH）诱导的运动敏感性和条件位置偏好（CPP）。其他人有 表明可卡因的自我给药强度从基础杏仁核到NAC PV+兴奋性输入 中间神经元和人为潜在的这些突触加速可卡因自我管理 在幼稚的小鼠中，表明NAC PV+中间神经元中的合成可塑性在行为上与 发展类似成瘾的行为。但是，关于分子机制知之甚少 精神刺激因素会改变PV+抑制性中间神经元的功能，以及这如何促进添加剂行为。一个 有前途的机械靶标的是会周围净蛋白BREVICAN（BCAN），该蛋白具有细胞自主的作用 在将兴奋性输入稳定到PV+中间神经元上的作用。该提案的总体目标是测试 重复的心理刺激暴露的假设通过调节调节PV+中间神经元活动 bcan表达。在AIM 1中，我将表征NAC PV+中间神经元中BCAN表达的调节 AMPH CPP的发展。在AIM 2中，我将测试操纵BCAN表达如何影响突触 这些神经元的输入。在AIM 3中，我将测试在NAC PV+细胞中操纵BCAN对阈值的效果 开发CPP。这些研究将研究细胞转录和突触可塑性机制 在PV+中间神经元中，以及它们如何影响与成瘾相关行为的表达。