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

探讨 L-DOPA 引起的运动障碍中血清素适应不良的中缝纹状体可塑性

• 批准号: 10366348
• 负责人: CHRISTOPHER R BISHOP
• 金额: $ 69万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366348
• 关键词: Anatomy; Animal Disease Models; Antiparkinson Agents; Automobile Driving; Autopsy; Autoreceptors; Basic Science; Behavior; Behavioral; Brain; Brain Diseases; Cells; Clinical; Clinical Sciences; Corpus striatum structure; Data; Denervation; Development; Dopamine; Dyskinetic syndrome; Electrophysiology (science); Experimental Parkinsonism; Fiber; Goals; Gold; Homeostasis; Human; Hyperactivity; Intervention; Investigation; Knowledge; L-DOPA induced dyskinesia; Lead; Levodopa; Link; Mediating; Methods; Microdialysis; Microscopy; Midbrain structure; Minority; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitters; Output; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Photometry; Pre-Clinical Model; Quality of life; Rattus; Research; Research Personnel; Serotonin; Source; Synapses; TPH2; Techniques; Technology; Testing; Time; Tissues; abnormal involuntary movement; cost; designer receptors exclusively activated by designer drugs; dopamine replacement therapy; gain of function; genetic approach; improved; in vivo; innovation; insight; interest; neurochemistry; neurotransmission; neurotransmitter release; novel; novel strategies; optimal treatments; pre-clinical; prevent; prospective; side effect; standard care; stem; tool; treatment strategy

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.

项目摘要/摘要： L-DOPA仍然是帕金森氏病（PD）的金标准治疗方法。不幸的是，在十年之内 conconconting l-dopa，几乎90％ DOPA引起的运动障碍（盖），严重影响生活质量。研究暗示5-羟色胺（5-HT）神经元 作为盖子的来源，他们可以占用L-DOPA，将其转换为多巴胺（DA），并释放DA作为不受监管的 “假神经递质”导致了动力障碍表型。尽管旨在减轻盖子的治疗 出现了，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 尚未找到防止盖子开发的方法 治疗促进了适应不良的5-HT重组和异常的纹状体输出。我们的研究团队有 最近使用新颖的方法收集了初步数据，这些方法为您提供了令人兴奋的新见解 5-HT神经塑性的机制将启发基础科学和临床科学。这些收敛的发现 导致我们假设我们的中心假设是适应不良的5-HT-Raphe-raphe-raphe神经环状可塑性 沉淀并保持盖子。我们的多投影团队的总体目标是确定机制 在raphe-raphe电路驱动盖上的结构和功能不良的发展基础 反过来，这可能导致新颖，优化的干预目标。我们将通过 追求3个独立但相互关联的特定目的。我们的3个具体目标将：1）定义在多大程度上 DA去神经和/或L-DOPA治疗导致5-HT Raphe-的解剖和功能重组 PD和实验性帕金森氏症中的纹状体途径，2）使用投影特异性的化学调制调节 确定5-HT Raphe-纹状体活性对L-DOPA诱导的抗Parkinsonian效率的影响 运动障碍和3）确定如何从5-HT Raphe-纹状体神经元中释放DA 盖子的发展和相关的不良运动神经元变化。拟议的跨物种调查将 在5-HT Raphe-纹状体回路中建立神经可塑性，作为发育和表达的外国因素 盖子和这样做，确定最佳治疗策略，以改善数百万当前和 前瞻性PD患者。