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; 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）：证据表明，锻炼类型及其执行方式会导致大脑中不同运动电路的募集。缺乏对运动训练（ET）与功能性脑重组之间关系的系统研究。当前的提案着重于基底神经节损伤大鼠模型中ET引起的补偿性脑反应。具体而言，我们解决了发生功能重组的大脑电路，以及运动改善，组织学/生化变化与病变和非赋予大脑中神经功能的变化之间的关系。运动挑战期间的功能性大脑映射用于检查运动在基底神经节 - 丘脑 - 皮层（BGTC）和小脑 - 丘脑 - 丘脑（CBTC）电路中的角色，以及辅助感官区域。我们的团队开发的一种新颖的，可植入的微型木材，用于定时注射大脑血流（CBF）示踪剂[14C] - 碘antipyrine，通过自由移动的动物中的远程激活。通过放射自显影对区域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。利益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，而有效的连通性分析解决了特定脑电路水平上的变化。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的作用，而GAP-43的测量将评估与运动相关的神经发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，而酪氨酸羟化酶免疫组织化学和细胞计数将提供病变范围的量度。在项目结束时，我们将知道ET的特定特定参数（复杂性，强度，持续时间，强迫或自愿互动，而及等等）决定了大脑功能的区域变化，以及基础神经节损伤对此类变化的影响。此外，我们将知道ET在多大程度上恢复受损电路的功能，以及替代电动机和非运动电路的募集的相对重要性。总之，这些研究对我们对健康和受伤大脑中基于经验的功能重组的理解产生了广泛的影响。该提案是对在大脑中电路水平上了解神经可塑性的更大需求（NIH蓝图的神经科学研究），以优化特定的神经康复策略（NCMRR任务），并提高我们对帕克森氏病（Ninds Parkinson's Research's Research's Research's Research's Contarta）的理解。 公共卫生相关性：锻炼有助于改善脑损伤后的运动缺陷，但是，这些影响在大脑水平上几乎不知所任何程度。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差距。具体而言，它将检查大脑的神经回路受运动的影响，无论是通过对神经的直接影响还是通过将养分携带营养成分的血管扩散到损害区域的血管，哪些参数构成“有效”运动以及任何变化对中断运动时的持续性是什么是什么是什么是什么。