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

项目摘要 滥用精神刺激性药物会导致神经奖赏回路的持续性功能变化 这是成瘾发展的基础。这些区域包括伏隔核(NAC)，这是 毒品奖励。越来越多的证据表明，NAC中改变的中间神经元功能对 药物诱导的回路适应导致成瘾行为。我们已经证明了NAC小白蛋白- 表达(PV)抑制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)诱导的运动敏感化和条件性位置偏爱(CPP)。其他人则有 结果表明，可卡因自身给药加强了杏仁基底外侧核到NAC PV的兴奋性输入 中间神经元，并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在行为上与 成瘾性行为的发展。然而，人们对其分子机制知之甚少。 精神刺激剂改变PV抑制中间神经元的功能，以及这如何有助于成瘾行为。一个 有希望的机制靶点是发挥细胞自主性作用的神经周网络蛋白brevican(Bcan)。 在稳定兴奋性输入到PV中间神经元中的作用。这项提案的首要目标是测试 心理刺激剂反复暴露通过调节PV中间神经元活性的假说 BCAN表达。在目标1中，我将描述在NAC PV中间神经元上bcan表达的调节。 AMPH CPP的发展。在目标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。在目标3中，我将测试操纵NAC光伏电池中的BCAN对阈值的影响 开发CPP。这些研究将探讨细胞转录和突触可塑性的机制。 以及它们如何影响成瘾相关行为的表达。

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.