Stroke is a devastating clinical problem which leads to neuronal death and functional loss. Interestingly, similar brain damage in the perinatal period often results in better functional outcome. This improved recovery is thought to be due to the inherent """"""""plasticity"""""""" of the young brain, with the formation of new neuroanatomical connections from spared neural tissue replacing damaged pathways. The main goal of the present proposal is to promote neuroanatomical plasticity following adult brain damage, and thereby improve functional outcome. We have recently shown that a powerful technique to induce adult plasticity is by blockade of the myelin associated neurite inhibitory protein Nogo-A. We now plan to use a clinically relevant model of focal ischemic stroke to determine if Nogo-A blockade results in neuroanatomical plasticity and functional recovery and Hypothesize that: following focal ischemic brain damage, blockade of the myelin associated neurite inhibitory protein Nogo-A with the monoclonal antibody IN-1 will result in cortico-efferent plasticity from the spared, unlesioned cortex and improved functional outcome. This hypothesis will be tested in the following Specific Aims:
Specific aim #1 will determine if blockade of Nogo-A following stroke leads to structural plasticity of corticofugal fibers from the spared, unablated cortex using neuroanatomical tracing techniques.
Specific aim #2 will determine if blockade of Nogo-A following stroke leads to behavioral recovery in forelimb performance affected by the stroke using specific tests for forelimb motor and sensory function.
Specific aim #3 will determine if improved recovery in forelimb use is directly related to the new structural plasticity from the spared cortex using electrophysiological methods to define the new neuronal pathways. The results of these studies may lead to new therapeutic approaches to return lost functions to patients suffering from ischemic as well as other causes of brain damage by enhancing the inherent ability of the brain to use undamaged tissue to repair and recover.
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