Anatomical plasticity, for example the sprouting of spared axons after a lesion, is likely to play a critical role in functional recovery after brain injury or neurodegeneration. However the mechanisms of anatomical plasticity in the adult brain remain poorly understood. Recent experimental results demonstrated a lesion-specific axonal sprouting from the homotypic contralateral cortex in the dorsolateral (motor) striatum of adult rats after lesions of the sensorimotor cortex. This axonal sprouting was observed after lesions induced by thermocoagulation of pial blood vessels, which produce a local ischemia in the cortex, but not after aspiration lesions. The goal of the present study is to determine the cellular and molecular mechanisms involved in this sprouting of corticospinal axons. We will take advantage of the fact that comparable cortical lesions made either by thermocoagulation or by aspiration have different effects on axonal sprouting in the striatum. This will allow us to identify those cellular and molecular mechanisms that are specifically associated with the robust anatomical plasticity seen after ischemic lesions. Recent data from our laboratory have shown that both lesions induce markedly different changes in neuronal activity and patterns of gene expression in the contralateral cortex. In a first set of experiments, we will further identify genes that are likely to be critical for the axonal sprouting by comparing patterns of mRNA expression after the two types of lesions. This will be done first by large scale screening with a DNA micoarray method, followed by confirmation with RT-PCR and mapping at the cellular level with in situ hybridization histochemistry and immunohistochemistry. In a second set of experiments we will block the changes in cellular activity in the cortex contralateral to the lesion to elucidate its role in 1) the molecular changes observed after the lesion 2) axonal sprouting. This multidisciplinary approach will allow us to identify the contribution of key molecular and cellular effects to axonal sprouting in the motor striatum. The results will help to understand the mechanisms responsible for differences in anatomical plasticity after various types of brain injury in the adult. This has relevance for the treatment of stroke and neurodegenerative diseases, two major health concern and leading causes of disability.
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