Primate Model of Stroke and Recovery in Aging

描述(申请人提供)：中风，主要是在中年后期和衰老早期观察到的一种疾病状态，导致皮质损伤，经常影响肢体的运动能力。考虑到每年经历中风的人数，迫切需要了解老化大脑功能恢复的神经生物学基础。在控制上肢的运动皮质区域有小的、局灶性单侧损害的老年动物建立了非人类灵长类动物的皮质缺血模型，这提供了一个独特的机会，不仅可以开发协调和力量工具来评估损伤和恢复，而且还可以确定这个年龄段的皮质重组的程度。在目前的提案中，我们计划使用恒河猴来开发一种皮质缺血和重组的模型，该模型允许对幼年和中年动物的运动功能恢复进行量化评估。三项新开发的手腕/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质区域有小的、局限性的单侧损伤。一旦猴子的表现达到渐近水平，就会在控制手指、手和前臂的运动皮质区域造成单侧损害。这种损伤会对对侧手的使用造成损害。猴子将在手术后进行重新测试。测试完成后，一部分猴子将接受最后一次高强度训练，然后进行灌流。大脑将被处理以进行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。这将使我们能够对最终测试过程中每个动物的不同激活的皮质和皮质下区域进行全球调查。第二组动物将接受第二次手术，手术将包括电生理技术，用于识别前臂、手腕和手指皮质代表的重组区域。然后，将在这个重组区域进行第二个小的局灶性损伤，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。这些动物将接受为期四周的所有任务的重新测试，以确定运动缺陷的存在和程度，其程度与第一次手术后记录的缺陷类似。这项建议将开发一种卒中模型，允许对局限性皮质卒中后的手/指运动能力进行定量评估，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方法的疗效。公共卫生相关性：中风主要是在中年晚期和衰老早期观察到的一种疾病状态，会导致皮质损伤，经常影响肢体的运动能力。考虑到每年经历中风的人数，迫切需要了解老化大脑功能恢复的神经生物学基础。这笔赠款建议使用年轻和中年动物建立中风的恒河猴模型，包括在控制前臂、手和手指的运动皮质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害和自发恢复，并为评估可能导致恢复的皮质重组区域提供一个独特的机会。最后，这个模型的建立和广泛的基线数据的获取，将允许未来的RO1应用程序来研究中老年非人类灵长类动物的各种药物和职业治疗干预措施，这些灵长类动物的运动功能和皮质组织与人类最相似。

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.