Stroke is the leading cause of adult disability. Despite this great impact, the mechanisms of recovery after stroke remain poorly understood. Stroke induces neurons near the damage to sprout new connections, a process termed post-stroke axonal sprouting. Post-stroke axonal sprouting correlates in location and magnitude with functional recovery. In patients, recovery after stroke is enhanced by forced overuse of the affected limb—a process termed constraint-induced therapy. We hypothesized that constraint-induced therapy will stimulate an increased degree of axonal sprouting in the brain after stroke. If this hypothesis is correct, the gene systems that are activated by constraint-induced therapy can be identified and used to develop pharmacological treatments that promote axonal spouting. Small strokes were produced near the forelimb motor cortex, causing weakness in the contralateral forelimb. To label axons in the motor cortex, a lentivirus coding for green fluorescent protein (GFP) was injected into the rat forelimb motor cortex at the time of stroke, which leads to integration of the GFP gene into neuronal DNA and expression of GFP throughout the neuronal cell body. After stroke, animals were split into three groups: stroke + Botox, stroke alone, and control (no stroke) groups. Botox was injected into the (good) forelimb ipsilateral to the stroke. Botox produces muscular paralysis without sensory loss and constrains the rat to overuse the affected limb. After 4 weeks, animals' brains were sectioned coronally and tangentially and processed for GFP immunohistochemistry to label neuronal projections and cytochrome oxidase to label the circuits of the rat sensorimotor cortex. Sections will be quantitatively mapped for the extent of labeled axonal projections using computer-assisted brain mapping software. The total length and direction of labeled axons will be statistically compared between stroke-no Botox, stroke-Botox, and control animals.
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