Grant: Project Grant

In the healthy brain, neurons, glia, and vessels work in concert so that blood flow adjusts in proportion to the level of neuronal activity. In stroke, a blockage of a major artery results in a sharp decline in blood flow, damaging the neurons and inducing sudden paralysis, impaired speech, and/or loss of vision. If the blood clot is dissolved rapidly, a complete recovery is possible. However, because the currently available treatments are safe and effective only when applied rapidly following the stroke onset, only ~10% of patients receive them; most suffer significant disabilities, and up to a third are institutionalized. Uncertainty surrounding the cellular changes needed for full recovery of brain function is a major factor preventing the development of more widely applicable therapies. It has become clear that recovery is strongly affected by changes that occur in the neurons, glia and blood vessels in the peri-infarct zone, the impaired, but potentially salvageable brain region surrounding the site of stroke. Using advanced imaging in live rats, we will track the function of peri-infarct neurons, glia, and vessels in the weeks following stroke. We will treat the animals with specific drugs, delivered directly to the perilesional tissue, to raise the activity of the surviving neurons while providing them with increased metabolic support, so as to bolster the remapping of lost function to these neurons. We will develop these interventions first in the young rats and then tailor them to the middle-aged rats suffering from metabolic syndrome (e.g. high cholesterol, diabetes) that are common in humans and known to impede stroke recovery. These experiments will establish the ways by which brain functioning can be affected in the chronic stage of stroke so as to improve recovery. The insights obtained will spur the development of new treatments that are effective in the chronic stage following stroke and thus stand to benefit the vast majority of patients.