Interrogating Maladaptive Serotonin Raphe-Striatal Plasticity in L-DOPA-Induced Dyskinesia

探讨左旋多巴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: 10531913
• 负责人: CHRISTOPHER R BISHOP
• 金额: $ 65.12万
• 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/10531913
• 关键词: Anatomy; Animal Disease Models; 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; Genetic; Goals; Homeostasis; Human; Hyperactivity; Intervention; Investigation; Knowledge; L-DOPA induced dyskinesia; Levodopa; Link; Mediating; Methods; Microdialysis; Microscopy; Midbrain structure; Minority; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitters; Output; Parkinson Disease; Parkinsonian Disorders; 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.

项目概要/摘要： 左旋多巴仍然是治疗帕金森病 (PD) 的金标准。不幸的是，十年之内 开始使用 L-DOPA 后，近 90% 的 PD 患者会出现顽固性异常不自主运动，称为 L- 多巴引起的运动障碍（LID），严重影响生活质量。研究涉及血清素 (5-HT) 神经元 作为 LID 的来源，因为它们可以吸收 L-DOPA，将其转化为多巴胺 (DA)，并以不受管制的形式释放 DA “假神经递质”导致运动障碍表型。尽管旨在减轻 LID 的治疗已 出现后，由于其成本、副作用和/或侵入性，只有少数患者受益。此外，我们 尚未找到预防 LID 发展的方法，部分原因是对于左旋多巴如何发挥作用的知识存在重大差距 治疗会引发适应不良的 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，这些数据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科学和临床科学。这些趋同的发现 引导我们提出我们的中心假设：适应不良的 5-HT-中缝纹状体神经回路可塑性 沉淀并维持 LID。我们的多研究者团队的首要目标是确定机制 驱动 LID 的中缝-纹状体回路内结构和功能适应不良的发展的基础， 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： 追求 3 个独立但相互关联的具体目标。我们的 3 个具体目标将： 1) 定义 DA 去神经术和/或 L-DOPA 治疗导致 5-HT 中缝的解剖和功能重组 PD 和实验性帕金森病中的纹状体通路，2) 使用投射特异性化学遗传学调节 确定 5-HT 中缝纹状体活性对 L-DOPA 诱导的抗帕金森病功效的影响和 运动障碍，3) 确定调节 5-HT 中缝纹状体神经元释放 DA 如何预防运动障碍 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 建立 5-HT 中缝纹状体回路内的神经可塑性作为发育和表达的最重要因素 LID 的研究，并在此过程中确定最佳治疗策略，以改善数以百万计的当前和 潜在的 PD 患者。