Primate Model of Stroke and Recovery in Aging

描述（由申请人提供）：中风，主要是在中年晚期和早期衰老时观察到的一种疾病状态，导致皮层损伤，经常影响四肢的运动活动。鉴于每年经历中风的人数，我们迫切需要了解衰老大脑功能恢复的神经生物学基础。非人类灵长类动物皮质缺血模型的发展，老龄动物在控制上肢的运动皮质区域有小的、局灶性的单侧病变，这不仅为开发评估损伤和恢复的协调和力量工具提供了一个独特的机会，而且还建立了该年龄组皮层重组的程度。在目前的建议中，我们计划使用恒河猴来开发一个皮层缺血和重组的模型，该模型允许对青年和中年动物的运动功能恢复进行量化评估。三个新开发的手腕/手指协调和力量任务将用于控制前臂，手腕和手指的运动皮质区域有小的局部单侧病变的猴子。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产生单侧病变。病变会对对侧手的使用产生损害。术后将对猴子进行重新测试。测试完成后，一组猴子将接受最后一次高强度训练，然后进行灌注。将对大脑进行cFos激活处理，以量化c-fos蛋白的表达，c-fos蛋白是早期基因激活和皮层活动的标志。这将使我们能够对每只动物在最终测试阶段产生的皮层和皮层下区域的差异激活进行全球调查。第二组动物将接受第二次手术，该手术将包括电生理技术，用于识别前臂，手腕和手指皮层表征的重组区域。然后在这个重组区域做第二个小的局灶性病变，以确定这个区域实际上促进了术后测试中观察到的功能恢复。这些动物将在四周内接受所有任务的重新测试，以确定是否存在与第一次手术后记录的运动缺陷程度相似的运动缺陷。该提案将开发一个中风模型，允许定量评估局部皮质中风后的手/手指运动表现，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治疗的疗效。公共卫生相关性：中风主要是在中年晚期和早期衰老时观察到的一种疾病状态，导致皮层损伤，经常影响四肢的运动活动。鉴于每年经历中风的人数，我们迫切需要了解衰老大脑功能恢复的神经生物学基础。这项拨款建议发展恒河猴中风模型，使用年轻和中年动物，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基线数据的获取，将允许未来的RO1应用于研究具有与人类最相似的运动功能和皮层组织的中老年非人类灵长类动物的各种药物和职业治疗干预。

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.