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

项目总结/摘要： 左旋多巴仍然是帕金森病（PD）的金标准治疗。不幸的是，在十年内， 开始使用左旋多巴时，近90%的PD患者会出现难治性异常不自主运动，称为L- 多巴诱导的运动障碍（LID），严重影响生活质量。研究暗示5-羟色胺（5-HT）神经元 作为LID的来源，因为它们可以摄取L-DOPA，将其转化为多巴胺（DA），并释放DA作为不受调节的多巴胺。 “假神经递质”导致皮肤发育不良表型。尽管旨在缓解LID的治疗方法 然而，由于其成本、副作用和/或侵入性，只有少数患者受益。而且我们 我还没有找到一种方法来防止LID的发展，部分原因是对L-DOPA如何 治疗引起适应不良的5-HT重组和异常的纹状体输出。我们的研究团队 最近使用新颖的方法收集了初步数据，为人类提供了令人兴奋的新见解 5-HT神经可塑性的机制，将启发基础和临床科学。这些趋同的发现 导致我们假设我们的中枢假说，即适应不良的5-HT-中缝-纹状体神经回路可塑性 沉淀并保持LID。我们的多研究者团队的首要目标是确定 在中缝-纹状体回路驱动LID的结构和功能适应不良的基础上， 这反过来又可能导致新的、优化的干预目标。我们将通过以下方式填补这一知识空白： 三个独立但相互关联的目标。我们的三个具体目标将：1）确定在多大程度上 DA去神经和/或L-DOPA治疗导致5-HT中缝核的解剖和功能重组， PD和实验性帕金森综合征纹状体通路，2）使用投射特异性化学发生调节， 确定5-HT中缝-纹状体活性对L-DOPA诱导的抗帕金森病疗效的影响， 运动障碍，以及3）建立如何调节DA释放5-HT中缝-纹状体神经元阻止 LID的发展和相关的适应不良神经元变化。拟议的跨物种调查将 在5-HT中缝-纹状体回路中建立神经可塑性，作为发育和表达的首要因素 的LID，并在这样做，确定最佳的治疗策略，以改善生活质量的数百万目前和 预期PD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.