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: 10432046
• 负责人: Mariah F Hazlett
• 金额: $ 2.34万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432046
• 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; stimulant exposure

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 滥用精神兴奋剂药物会诱导神经奖赏回路的持续功能变化， 是成瘾的基础这些区域包括神经核（NAc），这是一个关键区域， 毒品奖励越来越多的证据表明，NAc中中间神经元功能的改变对NAc的形成起着关键作用。 药物诱导的回路适应性导致成瘾行为。我们已经证明，NAc小清蛋白- 表达（PV+）抑制性中间神经元是小鼠多种成瘾相关行为所必需的，包括 苯丙胺（AMPH）诱导的运动敏化和条件性位置偏爱（CPP）。其他人已经 表明可卡因自我给药加强了从基底外侧杏仁核到NAc PV+的兴奋性输入 人工增强这些突触加速可卡因自我给药的获得 在幼稚小鼠中，表明NAc PV+中间神经元的突触可塑性与 成瘾行为的发展。然而，人们对这些分子机制知之甚少， 精神兴奋剂改变PV+抑制性中间神经元功能，以及这如何促成成瘾行为。一 有前途的机制靶点是神经元周围网络蛋白Brevican（Bcan），它在细胞自主调控中发挥作用。 在稳定PV+中间神经元的兴奋性输入中的作用。本提案的首要目标是测试 重复的精神兴奋剂暴露通过调节PV+中间神经元活性的假设 Bcan表情。在目的1中，我将描述Bcan在NAc PV+中间神经元中表达的调节， AMPH CPP的开发。在目标2中，我将测试如何操纵Bcan表达影响突触 输入到这些神经元。在目标3中，我将测试在NAc PV+细胞中操作Bcan对阈值的影响。 发展CPP。这些研究将探讨细胞转录和突触可塑性机制 PV+中间神经元内，以及它们如何影响成瘾相关行为的表达。