Grant: Operating Grant

In the healthy brain, neurons and blood vessels work in concert so that blood flow increases when neurons become active. This neurovascular coupling is compromised in stroke, whereby a blockage of a major artery results in a sharp decline in blood flow, causing damage to the neurons, and inducing sudden paralysis, impaired speech, and/or loss of vision. If the blood clot is dissolved rapidly, the likelihood of a complete recovery is very good. However, due to the very narrow window (3-4.5 hours) for safe and effective treatment, only ~2% of patients receive these drugs; most suffer significant disabilities, and up to a third are institutionalized. Uncertainty surrounding the cellular changes that are needed for full recovery of brain function is a major factor preventing the development of more effective therapies to rehabilitate patients following stroke. It has become clear that recovery is strongly affected by changes that occur in the neurons and blood vessels in the peri-infarct zone, the impaired, but potentially salvageable brain region peripheral to the area directly affected by the loss of blood supply. The goal of the present proposal is to understand the changes in the neurovascular coupling in the peri-infarct zone in the weeks following stroke. This work will be conducted using advanced 3D imaging in live rats that have received stroke. The responses of neurons and blood vessels to sensory stimulation will be contrasted between untreated animals and those treated with specific drugs to restore healthy levels of neuronal activity and vessel tone, in the hope of reestablishing healthy neurovascular coupling. These experiments will interrogate the mechanisms by which changes in the neurons and blood vessels support rehabilitation and thereby guide the development of new treatments that may be applied in the chronic stage following stroke and that thus stand to benefit a vast majority of patients.