Functional Adaptation of Neural Circuits After Exercise and Basal Ganglia Injury

运动和基底神经节损伤后神经回路的功能适应

• 批准号: 8278581
• 负责人: DANIEL PHILIPP HOLSCHNEIDER
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278581
• 关键词: Acute; Address; Adopted; Affect; Angiogenic Factor; Animal Model; Animals; Area; Autoradiography; Basal Ganglia; Bilateral; Biochemical; Blood Vessels; Brain; Brain Injuries; Brain Mapping; Brain region; Cell Count; Cells; Cerebellum; Cerebrovascular Circulation; Cerebrum; Complex; Corpus striatum structure; Data; Dose; Educational Intervention; Equation; Equilibrium; Exercise; Gait; Growth Associated Protein 43; Hippocampus (Brain); Histologic; Image; Immunohistochemistry; Injection of therapeutic agent; Injury; Intervention; Investigation; Joints; Lesion; Limb structure; Maintenance; Maps; Measurement; Measures; Mediating; Medicine; Mission; Modality; Modeling; Motor; Motor Activity; Motor Cortex; Motor Skills; National Institute of Neurological Disorders and Stroke; Nerve; Neuraxis; Neurologic; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurorehabilitation; Neurosciences Research; Neurotransmitters; Nutrient; Outcome; Outcome Measure; Overlearning; Oxidopamine; PECAM1 gene; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pattern; Perfusion; Play; Protocols documentation; Publishing; Radioactivity; Rattus; Recovery; Regimen; Rehabilitation therapy; Relative (related person); Research; Role; Running; Sensorimotor functions; Speed; Staging; Structure; Synaptic plasticity; System; Thalamic structure; Tissues; Tracer; Training; Translating; Tyrosine 3-Monooxygenase; United States National Institutes of Health; Vascular Endothelial Growth Factors; angiogenesis; base; density; dopaminergic neuron; experience; flexibility; functional outcomes; functional restoration; improved; injured; interest; motor control; motor deficit; muscle strength; neural circuit; neurogenesis; neurotrophic factor; novel; prevent; programs; public health relevance; relating to nervous system; response; somatosensory; synaptogenesis; time use

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.

描述（由申请人提供）：有证据表明，运动的类型和进行的方式会导致大脑中不同运动回路的募集。目前缺乏对运动训练（ET）与大脑功能重组之间关系的系统研究。目前的提案重点关注 ET 在基底神经节损伤大鼠模型中引起的代偿性大脑反应。具体来说，我们研究大脑的哪些回路发生功能重组，以及病变和非病变大脑的运动改善、组织学/生化变化和神经功能变化之间的关系。运动挑战期间的功能性脑图谱用于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域中的作用。我们团队开发的新型植入式微型泵用于通过远程激活在自由活动的动物体内定时注射脑血流 (CBF) 示踪剂 [14C]-碘安替比林。通过放射自显影术对区域 CBF 相关的组织放射性进行量化，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）提供有关区域大脑变化的信息，而有效的连接分析则解决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可以检查血管生成对 ET 的反应所起的作用，而 GAP-43 的测量将提供对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系统恢复情况，而酪氨酸羟化酶免疫组织化学和细胞计数将提供病变程度的测量。在项目结束时，我们将了解 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）在多大程度上决定大脑功能的区域变化，以及基底神经节损伤对这样的变化。此外，我们还将了解 ET 在多大程度上恢复受损回路的功能，以及补充备用运动和非运动回路的相对重要性。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具有广泛的影响。该提案响应了对了解大脑回路水平的神经可塑性（NIH 神经科学研究蓝图）、优化特定神经康复策略（NCMRR 任务）以及提高我们对帕金森病的了解（NINDS 帕金森病研究）的更大需求。议程）。 公共健康相关性：运动有助于改善脑损伤后的运动缺陷，但是，人们很少知道这些影响在大脑水平上的活跃程度。该项目使用脑损伤动物模型来弥补神经康复研究中的这一空白。具体来说，它将检查大脑的哪些神经回路受到运动的影响，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增殖来介导，哪些参数构成“有效”运动，停止锻炼后持续发生的变化是什么？