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）：建议的研究使用多学科方法（即解剖学、药理学、分子和行为），通过研究多巴胺和 BDNF 在 CMS 中发挥的作用，进一步了解 CMS 神经可塑性背后的细胞事件。纹状体中轴突萌芽和突触替换的调节。这项研究的基本原理是基于我们实验室以及其他实验室之前的报告，表明：1）单侧皮质损伤后，对侧皮质纹状体神经元的轴突末端重新支配纹状体中去神经支配的突触位点； 2) 突触替换涉及损伤特异性的生长相关蛋白和神经营养素的差异调节； 3）纹状体多巴胺的消耗与单侧皮质损伤相结合，导致纹状体中神经营养蛋白和生长相关蛋白基因表达和突触替换的异常模式，从而减慢运动功能的恢复。要测试的总体假设是：1）多巴胺通过多巴胺受体的特定亚型发挥作用，上调已知参与脑损伤后神经突生长和突触发生调节的候选分子，2）对单侧皮质损伤的反应是在对侧皮质纹状体神经元中诱导 BDNF。我们将使用大鼠单侧皮质损伤模型和选择性多巴胺激动剂和拮抗剂药物治疗来确定多巴胺受体的特定亚型在脑损伤后反应性突触发生调节中所起的作用。我们将使用神经营养蛋白拮抗剂 trkB-IgG 的纹状体内输注来检验皮层损伤后神经突生长和突触形成是通过 BDNF 和 trkB 受体介导的假设。我们将评估以下方面的损伤和治疗效果：1）已知参与脑损伤后神经突生长、突触发生和细胞存活调节的候选分子的上调； 2）突触丢失和替换。分子和解剖学的变化将与感觉运动功能的恢复相关，通过旋转杆、前肢使用不对称性和前肢放置测试来测量。我们的研究数据对于扩大我们对大脑补偿损伤能力的理解至关重要，并且对于开发新的治疗策略至关重要，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。