权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘: