Neurobehavioral recovery processes after focal injury may involve the resolution of dysfunction in remote brain regions not structurally damaged, as well as spared regions taking on functions previously performed by the damaged tissue. In this Project, we propose to use a well-controlled focal cortical thrombosis model to investigate mechanisms of remote dysfunction and recovery that may be targeted for therapeutic intervention. In Part 1 of the proposal, the importance of cortical spreading depression in the early induction of functional and neurochemical changes in remote cortical regions will be investigated. We have recently shown that repetitive waves of cortical spreading depression propagate into normal cortical regions following cortical infarction. Proposed studies will clarify the importance of cortical spreading depression in the genesis of remote metabolic depression as well as the neurobehavioral consequences of remote cortical dysfunction. In Part 2, evidence for somatosensory circuit reorganization weeks after cortical infarction will be determined using metabolic, biochemical and molecular probes. Using three-dimensional assessment of autoradiographic images, we will determine whether alternate patterns of circuit activation occur during vibrissae stimulation after chronic infarction. To obtain evidence for anatomical reorganization at sites of altered circuit activation, the immunocytochemical visualization of the presynaptic proteins synaptophysin and GAP-43 and early immediate genes will be used to provide morphological evidence for synaptic remodeling. Based on previous data showing amphetamine-induced accelerated functional recovery in this model, we will assess the effects of amphetamine treatment on patterns of metabolic activation in the post- infarcted brain and the effect of amphetamine on the up-regulation of synaptic proteins. These studies should provide a unique opportunity to both better define mechanisms underlying brain dysfunction after focal injury and to find rational therapeutic strategies with which to promote recovery processes.
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