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 PV+细胞中的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。 在PV+中间神经元内，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.