Functional Adaptation of Neural Circuits After Exercise and Basal Ganglia Injury

描述（由申请人提供）：有证据表明，运动的类型和执行方式会导致大脑中不同运动回路的招募。运动训练与脑功能重组的关系尚缺乏系统的研究。目前的建议集中在基底节损伤大鼠模型中ET引起的代偿性脑反应。具体来说，我们解决了什么样的大脑回路功能重组发生，以及什么是运动改善，组织学/生化变化和神经功能的变化在病变和非病变的大脑之间的关系。在运动挑战过程中的功能性脑映射被用来检查运动在基底神经节-丘脑-皮质（BGTC）和小脑-丘脑-皮质（CbTC）回路以及辅助感觉运动区中所起的作用。我们的团队开发了一种新型的植入式微型泵，用于通过远程激活自由移动动物的脑血流（CBF）示踪剂[14 C]-碘安替比林的定时注射。通过放射自显影术定量局部CBF相关组织放射性，并在三维重建的大脑中进行分析。感兴趣区域分析和统计参数映射（SPM）提供了有关区域大脑变化的信息，而有效的连接分析则解决了特定大脑回路水平的变化。血管内皮生长因子和血管密度的区域测量允许检查血管生成对ET的反应所起的作用，而GAP-43的测量将提供与运动相关的神经萌芽和突触可塑性的评估。运动技能评估将跟踪神经功能恢复，而酪氨酸羟化酶免疫组织化学和细胞计数将提供病变程度的测量。在项目结束时，我们将知道ET的具体参数（复杂性，强度，持续时间，强迫或自愿参与以及ET停止）在多大程度上决定了脑功能的区域变化，以及基底神经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回路的功能，以及备用运动和非运动回路的招募的相对重要性。总之，这些研究对我们理解健康和受伤大脑中基于经验的功能重组产生了广泛的影响。该提案是响应更大的需要，以了解神经可塑性在大脑回路的水平（NIH蓝图神经科学研究），优化特定的神经康复策略（NCMRR使命），并提高我们对帕金森氏病的理解（NINDS帕金森氏病研究议程）。 公共卫生相关性：运动有助于改善脑损伤后的运动缺陷，然而，人们对这些影响在大脑水平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。具体来说，它将研究大脑的神经回路受到运动的影响，其行动是否是通过对神经的直接影响或通过将营养物质运送到受损区域的血管增殖来介导的，什么参数构成“有效”运动，以及停止运动后任何变化的持续性。

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.