Functional Adaptation of Neural Circuits After Exercise and Basal Ganglia Injury

描述(由申请者提供)：证据表明，锻炼的类型和进行方式会导致大脑中不同的运动神经回路的招募。运动训练(ET)与脑功能重组的关系缺乏系统的研究。目前的建议集中在内毒素在基底节损伤大鼠模型中引起的代偿性脑反应。具体地说，我们讨论了大脑的哪些回路发生功能重组，以及受损和非受损大脑中运动改善、组织学/生化变化和神经功能变化之间的关系。运动挑战期间的脑功能图被用来研究运动在基底节-丘脑-皮质(BGTC)和小脑-丘脑-皮质(CBTC)环路以及副感觉运动区中所起的作用。我们团队开发了一种新型的植入式微泵，用于在自由活动的动物体内远程激活脑血流(CBF)示踪剂[14C]-碘安替比林。与脑血流相关的局部组织放射性通过放射自显影进行量化，并在三维重建的大脑中进行分析。感兴趣区分析和统计参数图(SPM)提供了关于大脑局部变化的信息，而有效的连通性分析解决了特定大脑回路水平上的变化。血管内皮生长因子和血管密度的区域性测量可以检查血管生成在ET反应中所起的作用，而GAP-43的测量将提供运动相关的神经萌发和突触可塑性的评估。运动技能评估将跟踪神经恢复情况，而酪氨酸羟化酶免疫组织化学和细胞计数将提供损伤程度的衡量标准。在项目结束时，我们将知道ET的特定参数(复杂性、强度、持续时间、被迫或自愿参与以及ET停止)在多大程度上决定了脑功能的局部变化，以及基底节损伤对这些变化的影响。此外，我们将知道ET在多大程度上恢复受损电路的功能，以及补充交替电机和非电机电路的相对重要性。总之，这些研究对我们理解健康和受损大脑中基于经验的功能重组具有广泛的影响。该提案响应了在大脑回路水平上了解神经可塑性的更大需求(NIH神经科学研究蓝图)，优化特定的神经康复策略(NCMRR任务)，以及提高我们对帕金森氏病的理解(NINDS帕金森研究议程)。 与公共健康相关：运动有助于改善脑损伤后的运动障碍，然而，人们对这些影响在大脑层面上的活跃程度知之甚少。该项目使用脑损伤的动物模型来解决神经康复研究中的这一空白。具体地说，它将检查运动对大脑的哪些神经回路产生影响，运动的作用是通过对神经的直接影响还是通过将营养物质输送到受损区域的血管的增殖来调节的，哪些参数构成了“有效”的运动，以及在停止运动后任何变化的持久性。

DESCRIPTION (provided by applicant): Evidence suggests that the type of exercise and the way it is performed results in the recruitment of different motor circuits in the brain. A systematic investigation on the relationship between exercise training (ET) and functional brain reorganization is lacking. The current proposal focuses on the compensatory cerebral responses elicited by ET in a rat model of basal ganglia injury. Specifically, we address in what circuits of the brain does functional reorganization occur, and what is the relationship between motor improvement, histologic/biochemical changes and changes in neural function in the lesioned and nonlesioned brain. Functional brain mapping during a locomotor challenge is used to examine the role exercise plays in the basal ganglia-thalamic-cortical (BGTC) and the cerebellar-thalamic-cortical (CbTC) circuits, as well as in accessory sensorimotor areas. A novel, implantable, minipump developed by our team is used for timed injection of the cerebral blood flow (CBF) tracer [14C]-iodoantipyrine by remote activation in the freely moving animal. Regional CBF-related tissue radioactivity is quantified by autoradiography and analyzed in the three-dimensionally reconstructed brain. Region-of-interest analysis and statistical parametric mapping (SPM) provide information on regional cerebral changes, while effective connectivity analyses addresses changes at the level of specific brain circuits. Regional measurements of vascular endothelial growth factor and vascular density allow the examination of the role played by angiogenesis in response to ET, while measurement of GAP-43 will provide an assessment of exercise-related neural sprouting and synaptic plasticity. Motor skill assessment will track neurologic recovery, while tyrosine hydroxylase immunohistochemistry and cell counts will provide a measure of lesion extent. At the end of the project, we will know to what extent specific parameters of ET (complexity, intensity, duration, forced or voluntary engagement, and ET cessation) determine regional changes in brain function, and what the impact is of basal ganglia injury on such changes. In addition, we will know to what extent ET restores functionality of damaged circuits, and the relative importance of the recruitment of alternate motor and nonmotor circuits. Together, these studies have a wide-ranging impact for our understanding of experience-based functional reorganization in the healthy and injured brain. The proposal is responsive to a greater need to understand neural plasticity at the level of circuits in the brain (NIH Blueprint for Neuroscience Research), to optimize specific neurorehabilitation strategies (NCMRR mission), and to improve our understanding of Parkinson's disease (NINDS Parkinson's Research Agenda). PUBLIC HEALTH RELEVANCE: Exercise is helpful in improving the motor deficits after brain injury, however, little is known to what extent these effects are active at the level of the brain. This project uses an animal model of brain injury to address this gap in neurorehabilitation research. Specifically, it will examine what neural circuits of the brain are affected by exercise, whether its actions are mediated by direct effects on the nerves or through proliferation of blood vessels that carry nutrients to the areas of damage, what parameters constitute 'effective' exercise, and what is the persistence of any changes upon discontinuing exercise.