The main goal of this dissertation was to investigate if rehabilitative training after ischemic damage can increase cell proliferation and encourage the differentiation and maintenance of newly formed neurons. For all studies, I utilized a rehabilitative training task which has repeatedly been found to enhance behavioral performance after ischemic lesions of the sensorimotor cortex. Training was focused on the impaired forelimb in order to (1) target forelimb deficits induced by the lesions and (2) engage remaining cortex in potential plastic events. The level of cell proliferation was investigated by measuring and phenotyping cells labeled with a mitotic marker (bromodeoxyuridine) in the peri-lesion area and various other regions. First, in an animal model of cortical ischemia, the level of cell proliferatoin measured in rehabilitated animals after ischemic damage was significantly decreased in peri-lesion cortex compared to non-rehabilitated animals. In order to investigate which component of cell generation, proliferation or maintenance, was affected by rehabilitative training, pulse labeling of new cells followed by short or long term training periods was accomplished. This study revealed thatrehabilitative training had increased cell proliferation that occurred early after ischemic damage and the maintenance of these early generated cells were significantly increased in the peri-lesion cortex of rehabilitated animals compared to controls. Lastly, in order to verify the results of the first study (experience induced reduction of new cells in periinfarct tissue) pulse labeling of new cells during a mid-time point of rehabilitation period after ishemic lesions was employed and resulted in the same significantly reduced level of new cells in peri-infarct tissue of rehabilitated animals compared to controls. In all studies, the proportion of the neuronal and astrocyte phenotype of newly generated cells was not significantly affected by rehabilitative training after ischemic damage. However, a significant increased accumulation of new microglia was seen in rehabilitated animals, but reactive microglia produced early after ischemic damage were not significantly maintained which indicates a possible dual role that microglia during post-operative rehabilitative training. Together these studies indicate that functionally beneficial behavioral experience can affect cell proliferative responses, and mainitenance of newly generated non-neuronal cells early after ischemic damage. / text

In adult rats, following unilateral stroke-like injury to the motor cortex, there is significant loss of function in the forelimb contralateral to the ischemic damage. In the remaining motor cortex, changes in neuronal activation patterns and connectivity are induced following motor learning and rehabilitation in the brains of adult animals. Rehabilitative training promotes functional recovery of the impaired forelimb following motor cortical strokes; however, its benefits are most efficacious when coupled with other rehabilitative treatments. Multiple lines of evidence suggest that focal cortical electrical stimulation (CS) enhances the effectiveness of rehabilitative training (RT) and promotes changes in neural activation and plasticity in the peri-lesion motor cortex. Specific examples of plastic events include increases in dendritic and synaptic density in the peri-lesion cortex following CS/RT compared to rehabilitative training alone. The objective of these studies was to investigate which conditions, such as timing and method of delivery of CS, when coupled with RT, are most efficacious in promoting neuronal plasticity and functional recovery of the impaired forelimb following ischemic cortical injury in adult animals. The central hypothesis of these dissertation studies is that, following unilateral stroke-like injury, CS improves the functional recovery of the impaired forelimb and promotes neural plasticity in remaining motor cortex when combined with RT. This hypothesis was tested in a series of experiments manipulating post-ischemic behavioral experience with the impaired forelimb. Adult rats were proficient in a motor skill (Single Pellet Retrieval Task) and received ischemic motor cortex lesion that caused impairments in the forelimb. Rats received daily rehabilitative training on a tray reaching task with or without concurrent cortical stimulation. Epidural cortical stimulation, when paired with rehabilitative training, resulted in enhanced reaching performance compared to RT alone when initiated 14 days after lesion. These results were found to be maintained well after the treatment period ended. Rats tested 9-10 months post-rehabilitative training on the single pellet retrieval task continued to have greater reaching performance compared to RT alone. However, delayed onset of rehabilitative training (3 months post-infarct) indicated that CS does not further improve forelimb function compared to RT along. It was further established that CS delivered over the intact skull (transcranial stimulation) of the lesioned motor cortex was not a beneficial adjunct to rehabilitative training. Together these dissertation studies provide insight into the effectiveness and limitations of CS on behavioral recovery. The findings in these studies are likely to be important for understanding how post-stroke behavioral interventions and adjunct therapies could be used to optimize brain reorganization and functional outcome. / text