Neuronal Plasticity and Recovery of Function After Stroke

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Stroke is a devastating disorder that leads to neuronal death and neurologic disability. We have shown that the brain's inherent ability to form new neuronal connections and restore lost function after stroke can be enhanced by neutralizing the inhibitory nature of the adult CNS through antibody therapy that neutralizes the protein Nogo-A. We now plan to study the ability of anti-Nogo-A immunotherapy to enhance functional recovery and neuronal plasticity in the chronic stroke impaired rat. This is an exciting and novel area of research and may benefit many more patients who suffer with chronic neurologic disabilities, even those resulting from causes other than stroke. In addition, understanding changes in plasticity-related molecules underlying anti-Nogo-A immunotherapy given at a chronic stage of stroke could lead to improved therapeutic approaches for future clinical use. Therefore, we hypothesize that anti-Nogo-A immunotherapy when given to chronic stroke-impaired aged rats will result in improved functional outcome, enhanced anatomical plasticity, and specific genomic changes in brain regions important for sensorimotor recovery. We will test our hypothesis in the following specific aims: Specific Aim #1- Determine whether treatment with anti-Nogo- A immunotherapy results in behavioral recovery when given two months after ischemic stroke in the aged rat. We will use behavioral tests of sensorimotor recovery in the aged animal and study long term outcomes in order to enhance the translation of these results to clinical use. Specific Aim #2- Determine whether treatment with anti-Nogo-A immunotherapy results in neuroanatomical plasticity when given two months after ischemic stroke in the aged rat. This aim will employ neuroanatomical tract tracing and Golgi-Cox staining to examine axonal and dendritic plasticity in areas important for sensorimotor recovery. Specific Aim #3- Determine whether the contralesional forelimb cortex mediates behavioral recovery when anti-Nogo-A immunotherapy is given two months after stroke in the aged rat. This aim will investigate the importance of the contralesional cortex and other subcortical connections in improving functional outcome after anti-Nogo-A therapy when given at two months after stroke. Specific Aim #4- Examine genomic changes in ipsilesional and contralesional cortical regions and pertinent subcortical areas in aged rats given anti-Nogo-A immunotherapy two months after stroke. Understanding changes in plasticity-related molecules underlying anti-Nogo-A immunotherapy given at a chronic stage of stroke could lead to improved therapeutic approaches for future clinical use.