Interrogating maladaptive serotonin raphe-striatal plasticity in L-DOPA-induced dyskinesia

项目摘要/摘要： L-多巴仍是治疗帕金森病(PD)的黄金标准药物。不幸的是，在十年内 从L-多巴开始，近九成的帕金森氏症患者会出现难治性的异常不自主运动，称为L- 多巴诱发的运动障碍(LID)，严重影响生活质量。研究表明5-羟色胺(5-HT)神经元 作为LID的来源，因为它们可以吸收L-多巴，将其转化为多巴胺(DA)，并将DA释放为不受监管的 “虚假神经递质”导致运动障碍表型。尽管旨在缓解眼睑的治疗方法已经 出现这种情况时，只有少数患者因其成本、副作用和/或侵入性而受益。此外，我们 尚未找到防止眼罩发展的方法，部分原因是对L-DOPA如何 治疗会引起适应不良的5-羟色胺重组和异常纹状体输出。我们的研究团队已经 最近使用新的方法收集了初步数据，这些方法为 5-羟色胺的神经可塑性机制将对基础和临床科学有所启发。这些一致的发现 这让我们假设我们的中心假设是适应性不良的5-羟色胺-中缝-纹状体神经回路可塑性 沉淀并保持盖子。我们多名调查员团队的首要目标是确定 在中缝-纹状体回路驱动盖内结构和功能适应不良发展的基础上， 这反过来可能导致新的、优化的干预目标。我们将通过以下方式填补这一知识空白 追求3个既独立又相互关联的具体目标。我们的3个具体目标将：1)定义 DA去神经和/或L多巴治疗导致5-羟色胺中缝的解剖和功能重组。 帕金森病和实验性帕金森病的纹状体通路，2)使用投射特异性化学发生调节 确定5-羟色胺中缝-纹状体活动对L-多巴诱导的抗帕金森病疗效的影响 运动障碍，以及3)确定调节5-羟色胺中缝纹状体神经元的DA释放如何防止 LID的发展和相关的适应不良的神经元变化。拟议的跨物种调查将 在5-羟色胺中缝-纹状体环路内建立神经可塑性作为发育和表达的首要因素 在这样做的过程中，确定最佳的治疗策略，以改善数百万当前和 未来的帕金森病患者。

PROJECT SUMMARY/ABSTRACT: L-DOPA remains the gold-standard treatment for Parkinson’s disease (PD). Unfortunately, within a decade of commencing L-DOPA, nearly 90% of PD patients develop intractable abnormal involuntary movements known as L- DOPA-induced dyskinesias (LID), severely impacting quality of life. Research implicates serotonin (5-HT) neurons as a source of LID as they can take up L-DOPA, convert it to dopamine (DA), and release DA as an unregulated “false neurotransmitter” leading to a dyskinesogenic phenotype. Although treatments aimed at alleviating LID have emerged, only a minority of patients benefit due to their cost, side effects and/or invasiveness. Moreover, we have yet to find a way to prevent LID development, in part due to major gaps in knowledge on how L-DOPA treatment instigates maladaptive 5-HT reorganization and aberrant striatal output. Our research team has recently collected preliminary data using novel approaches that provide exciting new insights into the mechanisms of 5-HT neuroplasticity that will enlighten both basic and clinical science. These convergent findings led us to postulate our Central Hypothesis that maladaptive 5-HT-raphe-striatal neurocircuit plasticity precipitates and maintains LID. The overarching goal for our multi-investigator team is to identify the mechanisms underlying the development of structural and functional maladaptation within the raphe-striatal circuit driving LID, which in turn could lead to novel, optimized targets for intervention. We will fill this knowledge gap through the pursuit of 3 independent, but inter-related Specific Aims. Our 3 Specific Aims will: 1) define the extent to which DA denervation and/or L-DOPA treatment results in anatomical and functional reorganization of the 5-HT raphe- striatal pathway in PD and experimental parkinsonism, 2) use projection-specific chemogenetic modulations to determine the impact of the 5-HT raphe-striatal activity on L-DOPA-induced anti-parkinsonian efficacy and dyskinesia, and 3) establish how regulating DA release from 5-HT raphe-striatal neurons prevents the development of LID and associated maladaptive neuronal changes. The proposed cross-species investigation will establish neuroplasticity within the 5-HT raphe-striatal circuit as a foremost factor in the development and expression of LID and in so doing, identify optimal treatment strategies to improve the quality of life for millions of current and prospective PD patients.