Dopaminergic Modulation of Corticostriatal Plasticity

皮质纹状体可塑性的多巴胺能调节

基本信息

批准号：
7162102
负责人：
THOMAS Hugh MCNEILL
金额：
$ 30.51万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-15 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162102
关键词：
Adult Agonist Area Arts Axon Behavioral Biological Assay Brain Brain Injuries Brain-Derived Neurotrophic Factor CREB1 gene Cell Survival Chromosome Pairing Clinical Contralateral Corpus striatum structure Cyclic AMP Data Development Dopamine Dopamine Agonists Dopamine Antagonists Dopamine Receptor Electron Microscopy Event Forelimb Gene Expression Growth Growth Associated Protein 43 Immunoglobulin G In Situ Hybridization Infusion procedures Injury Intervention Laboratories Lead Lesion Maintenance Measures Mediating Mediator of activation protein Methods Modeling Molecular Motor Neuraxis Neurites Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Numbers Pathway interactions Pattern Pharmaceutical Preparations Play Presynaptic Terminals Process Proteins Rattus Recovery Recovery of Function Regulation Reporting Research Personnel Role SCG10 protein Sensorimotor functions Signaling Molecule Site Synapses Synaptic Vesicles Testing Tn receptor Translating Up-Regulation axonal sprouting base interdisciplinary approach neural circuit neurotrophic factor receptor response synaptogenesis synaptosomal-associated protein 25 treatment effect

项目摘要

DESCRIPTION (provided by applicant): The studies proposed use a multidisciplinary approach (i.e. anatomical, pharmacological, molecular and behavioral) to further our understanding of the cellular events that underlie neural plasticity in the CMS by investigating the roles that dopamine and BDNF play in the modulation of axonal sprouting and synapse replacement in the striatum. The rationale for the study is based on previous reports from our laboratory, as well as those of others, showing that: 1) axon terminals from contralateral corticostriatal neurons reinnervate denervated synaptic sites in the striatum after a unilateral cortex lesion; 2) synapse replacement involves the differential regulation of growth associated proteins and neurotrophins that are lesion-specific; and 3) depletion of striatal dopamine in combination with a unilateral cortex lesion results in an aberrant pattern of neurotrophin and growth associated protein gene expression and synapse replacement in the striatum that slows the recovery of motor function. The overarching hypotheses to be tested are: 1) that dopamine acts through specific subtypes of dopamine receptors to up-regulate candidate molecules known to participate in the regulation of neurite outgrowth and synaptogenesis after brain injury, and 2) that a key mediator in the compensatory response to a unilateral cortex lesion is the induction of BDNF in contralateral corticostriatal neurons. We will use the rat unilateral cortex lesion model and selective dopamine agonist and antagonist drug treatments to define the roles that specific subtypes of dopamine receptors play in the regulation of reactive synaptogenesis after brain injury. We will use intra-striatal infusions of the neurotrophin antagonist trkB-IgG to test the hypothesis that neurite outgrowth and synapse formation after the cortex lesion is mediated through BDNF and the trkB receptor. We will assess lesion- and treatment effect on: 1) upregulation of candidate molecules known to participate in the regulation of neurite outgrowth, synaptogenesis and cell survival after brain injury; and 2) synapse loss and replacement. Molecular and anatomical changes will be correlated with the recovery of sensorimotor function, as measured by the rotorod, forelimb-use asymmetry and forelimb placing tests. Data from our studies are fundamental for broadening our understanding of the capacity of the brain to compensate for injury, and central to the development of new treatment strategies that can translate the basic principles of neuroplasticity into effective clinical interventions.

描述（由申请人提供）：拟议的研究使用多学科方法（即解剖学，药理，分子和行为），以进一步了解CMS中神经可塑性构成的细胞事件，通过研究多巴胺和BDNF在轴突萌芽和同步替代中的作用。该研究的基本原理基于我们实验室的先前报告以及其他实验室的报告，表明：1）单侧皮层病变后对侧皮层神经元的轴突末端重新巩固了纹状体中纹状体中的突触部位； 2）突触替代涉及针对病变特异性的生长蛋白和神经营养蛋白的差异调节； 3）纹状体多巴胺与单侧皮层病变的耗竭导致神经营养蛋白的异常模式和生长相关的蛋白基因表达和突触替代在纹状体中，从而减弱了运动功能的恢复。 The overarching hypotheses to be tested are: 1) that dopamine acts through specific subtypes of dopamine receptors to up-regulate candidate molecules known to participate in the regulation of neurite outgrowth and synaptogenesis after brain injury, and 2) that a key mediator in the compensatory response to a unilateral cortex lesion is the induction of BDNF in contralateral corticostriatal神经元。我们将使用大鼠单侧皮层病变模型和选择性多巴胺激动剂和拮抗剂药物处理来定义多巴胺受体特定亚型在调节脑损伤后反应性突触发生中起作用的作用。我们将使用神经营养素拮抗剂TRKB-IGG的静脉内输注来检验以下假设：神经突生长和突触形成皮层病变后通过BDNF和TRKB受体介导。我们将评估以下病变和治疗效果：1）已知参与神经突生长，突触发生和脑损伤后细胞存活的候选分子的上调； 2）突触丧失和替代。分子和解剖学的变化将与rotorod，前肢使用的不对称性和前肢放置测试测量的感觉运动功能的恢复相关。来自我们的研究的数据是扩大我们对大脑能力补偿伤害能力的理解的基础，这是发展新治疗策略的核心，这些策略可以将神经可塑性的基本原理转化为有效的临床干预措施。