Primate Model of Stroke and Recovery in Aging

灵长类动物中风和衰老恢复模型

• 批准号: 7528701
• 负责人: TARA L MOORE
• 金额: $ 20.72万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528701
• 关键词: Affect; Age; Aging; American Heart Association; Animal Model; Animal Testing; Animals; Area; Behavioral; Blood Vessels; Boxing; Brain; Centers for Disease Control and Prevention (U.S.); Contralateral; Data; Development; Digit structure; Disease; Disruption; Electrophysiology (science); Event; Exclusion; FOS Protein; FOS gene; Food; Forearm; Forelimb; Future; Gene Activation; Goals; Grant; Hand; Hour; Human; Human Resources; Immediate-Early Genes; Impairment; Individual; Injury; Intervention; Ipsilateral; Ischemia; Lesion; Licensing; Limb structure; Literature; Localized; Macaca mulatta; Maps; Marshal; Measures; Methods; Modeling; Monkeys; Motor; Motor Activity; Motor Cortex; Movement; Nature; Neurobiology; Neurons; Numbers; Occupational; Occupational Therapist; Occupational Therapy; Operative Surgical Procedures; Outcome; Patients; Pattern; Performance; Personal Satisfaction; Pharmacologic Substance; Pilot Projects; Plexiglas; Plexiglass; Population; Postoperative Period; Primates; Process; Proto-Oncogene Proteins c-fos; Public Health; Range; Rate; Recovery; Recovery of Function; Rehabilitation therapy; Research; Research Personnel; Rewards; Shapes; Stroke; Study models; Surveys; Techniques; Testing; Therapeutic Intervention; Time; Training; Treatment Efficacy; United States; Upper Extremity; Videotape; Week; Wrist; age group; aged; aging brain; base; behavior test; day; experience; insight; internal control; ischemic lesion; juvenile animal; middle age; motor control; motor deficit; neurobiological mechanism; nonhuman primate; pressure; retinal rods; senescence; stroke recovery; tool

DESCRIPTION (provided by applicant): Stroke, primarily a disease-state observed in late middle age and early senescence, results in cortical injury that frequently affects motor activity of the extremities. Given the number of individuals that experience a stroke each year there is a critical need to understand the neurobiological basis of functional recovery in the aging brain. The development of a non-human primate model of cortical ischemia with older animals with small, focal unilateral lesions in the area of the motor cortex that controls the upper extremity provides a unique opportunity to not only develop coordination and strength tools to assess impairment and recovery, but also to establish the extent of cortical reorganization in this age group. In the current proposal we plan to use rhesus monkeys to develop a model of cortical ischemia and reorganization that allows for the quantifiable assessment of motor function recovery in young and middle-aged animals. Three newly developed wrist/digit coordination and strength tasks will be used with monkeys that have small, focal unilateral lesions in the area of the motor cortex that controls the forearm, wrist and digits. Once the monkey reaches asymptotic levels of performance, a unilateral lesion will be made in the area of the motor cortex identified as controlling the digits, hand and forearm. The lesion will produce impairment in the use of the contralateral hand. Monkeys will be retested post-operatively. Following completion of testing a subset of monkeys will receive one final intense training session and then will be perfused. Brains will be processed for cFos activation to quantify the expression of the c-fos protein, a marker of immediate early gene activation and cortical activity. This will allow us to conduct a global survey for differentially activated cortical and subcortical regions in each animal resulting from the final testing session. A second group of animals will undergo a second surgery that will consist of electrophysiological techniques used to identify the areas of reorganization of the cortical representation of the forearm, wrist and digits. A second small, focal lesion will then be made in this area of re-organization in order to establish that this area was in fact facilitating the functional recovery observed during post-operative testing. These animals will be re-tested on all tasks for four weeks to establish the presence and extent of a motor deficit similar in magnitude to the deficit recorded after the first surgery. This proposal will develop a model of stroke that allows for the quantitative assessment of hand/digit motor performance following a localized cortical stroke and can be used in future studies to quantify the efficacy of therapeutic treatments aimed at facilitating recovery of motor function. PUBLIC HEALTH RELEVANCE: Stroke, primarily a disease-state observed in late middle age and early senescence, results in cortical injury that frequently affects motor activity of the extremities. Given the number of individuals that experience a stroke each year there is a critical need to understand the neurobiological basis of functional recovery in the aging brain. This grant proposes the development of a rhesus monkey model of stroke using young and middle-aged animals that involves creating focal unilateral damage in the area of the motor cortex that controls the forearm, hand and digits. It will provide a unique opportunity to assess impairment and spontaneous recovery of hand/digit coordination and strength and for the assessment of the areas of cortical reorganization that may be responsible for recovery. Finally, the establishment of this model and the acquisition of extensive baseline data, will allow for a future RO1 application to investigate various pharmaceutical and occupational therapeutic interventions in a middle-aged and aged non-human primates with motor functions and cortical organization most like those of humans.

描述（由申请人提供）：中风，主要是在中年晚期和早期衰老中观察到的一种疾病状态，导致皮质损伤，经常影响四肢的运动活动。考虑到每年经历中风的人数，迫切需要了解衰老大脑功能恢复的神经生物学基础。非人灵长类动物模型的皮层缺血与老年动物的小，局灶性单侧病变的运动皮层，控制上肢的区域的发展提供了一个独特的机会，不仅开发协调和力量的工具，以评估损伤和恢复，但也建立在这个年龄组的皮质重组的程度。在目前的提案中，我们计划使用恒河猴开发一个模型的皮质缺血和重组，允许定量评估的运动功能恢复在年轻和中年动物。三个新开发的手腕/手指协调和力量任务将用于猴子，这些猴子在控制前臂，手腕和手指的运动皮层区域中具有小的局灶性单侧病变。一旦猴子达到渐近水平的性能，将在确定为控制手指、手和前臂的运动皮层区域中进行单侧损伤。病变将导致对侧手的使用障碍。术后将对猴进行重新试验。完成测试后，一部分猴子将接受最后一次高强度训练，然后进行灌注。将处理大脑以进行cFos激活，以量化c-fos蛋白的表达，c-fos蛋白是立即早期基因激活和皮质活动的标志物。这将使我们能够对每只动物在最终测试阶段产生的差异激活的皮质和皮质下区域进行全面调查。第二组动物将接受第二次手术，该手术将包括用于识别前臂、手腕和手指的皮质表示的重组区域的电生理技术。然后在该重组区域制作第二个小的局灶性病变，以确定该区域实际上促进了术后测试期间观察到的功能恢复。对这些动物进行为期四周的所有任务重新测试，以确定是否存在与首次手术后记录的缺陷程度相似的运动缺陷及其程度。该提案将开发一种中风模型，允许定量评估局部皮质中风后的手/手指运动性能，并可用于未来的研究，以量化旨在促进运动功能恢复的治疗效果。 公共卫生关系：中风，主要是在中年晚期和早期衰老中观察到的疾病状态，导致经常影响肢体运动活动的皮质损伤。考虑到每年经历中风的人数，迫切需要了解衰老大脑功能恢复的神经生物学基础。该基金建议使用年轻和中年动物开发中风的恒河猴模型，该模型涉及在控制前臂，手和手指的运动皮层区域造成局灶性单侧损伤。它将提供一个独特的机会来评估手/手指协调和力量的损伤和自发恢复，并评估可能负责恢复的皮质重组区域。最后，该模型的建立和广泛的基线数据的采集，将允许未来的RO 1应用程序，以调查各种药物和职业治疗干预的中年和老年非人灵长类动物的运动功能和皮质组织最像人类。