Grant: Catalyst Grant: Sex as a Variable in Biomedical Research

Neurons and brain 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 time window (3-4.5 hours) for safe and effective dissolution of the clots, only ~2% of patients receive these drugs; most suffer significant disabilities, and up to a third are institutionalized. Furthermore, while premenopausal women have far fewer strokes than men of the same age; post-menopause, women suffer greater post-stroke disability than do men. A major factor preventing the development of more effective therapies is the uncertainty surrounding the cellular changes needed for full recovery of brain function, particularly in the peri-infarct zone, the impaired, but potentially salvageable brain region adjacent 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 in women vs. men. This work will be conducted using advanced 3D imaging post stroke in live male rats, premenopausal female rats, and postmenopausal female rats administered either placebo or put on estrogen replacement therapy. The neurons and blood vessel functioning will be contrasted between untreated animals and those treated with a compound that provides an alternate source of energy to the brain. These experiments will interrogate the mechanisms by which changes in the neurons and blood vessels support rehabilitation as a function of sex and estrogen levels and thereby guide the development of new treatments that may be applied in the chronic stage following stroke in both sexes.