Primate Model of Stroke and Recovery in Aging

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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.