Dopaminergic Modulation of Corticostriatal Plasticity

描述(申请人提供)：建议的研究采用多学科方法(即解剖学、药理学、分子和行为学)，通过研究多巴胺和脑源性神经营养因子在纹状体轴突萌发和突触替换中所扮演的角色，进一步了解CMS神经可塑性背后的细胞事件。这项研究的基本原理是基于我们实验室和其他实验室之前的报告，表明：1)来自对侧皮质纹状体神经元的轴突终末在单侧皮质损伤后重新支配纹状体的失神经突触位置；2)突触替换涉及损伤特有的生长相关蛋白和神经营养因子的差异调节；3)纹状体多巴胺的耗竭与单侧皮质损伤联合导致神经营养因子和生长相关蛋白基因表达的异常以及纹状体中突触的替换，从而减缓运动功能的恢复。有待检验的主要假设是：1)多巴胺通过特定亚型的多巴胺受体上调已知的参与脑损伤后轴突生长和突触形成的候选分子；2)对侧皮质损伤的代偿反应中的一个关键中介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特定亚型的多巴胺受体在脑损伤后反应性突触发生的调节中所起的作用。我们将使用纹状体内注射神经营养因子拮抗剂TrkB-Ig G来验证这一假说，即皮质损伤后轴突生长和突触形成是通过BDNF和TrkB受体介导的。我们将评估损伤和治疗效果：1)脑损伤后参与调节轴突生长、突触发生和细胞存活的候选分子上调；2)突触丢失和替换。分子和解剖学上的变化将与感觉运动功能的恢复相关，如通过旋转杆、前肢使用不对称和前肢放置试验来测量。我们研究的数据是扩大我们对大脑补偿损伤能力的理解的基础，也是开发新的治疗策略的核心，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。

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.