Migraine is the most common debilitating neurological disorder. Once considered relatively benign, it is now known to increase the risk for stroke, especially in women, accounting for 1500 excess deaths a year. The reason for this significant clinical problem is unknown. We will attempt to understand it by focusing on features that link the disorders. Cortical spreading depression (CSD) and peri-infarct depolarization (PID) are nearly identical waves of excitation that move across the brain surface. CSD is the likely mechanism of the migraine aura, and both CSD and PID worsen stroke. Susceptibility to migraine is associated with a susceptibility to CSD: we have shown that female mice have a lower threshold for induction of CSD, in line with the 3:1 ratio of women to men with migraine. And mice expressing genes that cause severe variants of migraine also have lower CSD thresholds. Our proposal is that the same factors which increase the risk of CSD also favor PID, and thus may account for the increased rate of stroke in migraine. We will test this assumption with two related sets of experiments. The first will examine the possibility that CSD, considered benign in isolation, may actually be harmful on a chronic basis, especially when paired with sex-based and genetic predisposition to migraine. We will compare female to male mice, and migraine transgenic mice to controls, to see whether long term CSD causes stroke-like damage. If it does, it could explain the high rate of subclinical stroke-like changes seen on imaging of migraine patients. The second set of experiments will test the proposition that the tendency to migraine (and thus CSD) also confers an increased risk of PID with stroke. We will induce stroke in female, male, migraine transgenic, and wild type mice to see if migraine susceptibility increases the number and severity of PID, increases stroke size, and worsens stroke recovery. We will also test whether memantine, a drug that inhibits CSD, and that we have identified as a migraine preventive, can also protect against PID and stroke related damage. We will use a combination of advanced imaging, neuronal recordings, behavior, and tissue examination to address all of these clinically important questions. PUBLIC HEALTH RELEVANCE: This proposal directly addresses a serious clinical problem with techniques that should provide both mechanistically specific and clinically-actionable information. Our experiments should advance the understanding of both migraine and stroke, especially the hormonal and genetic factors that increase risks in women, and in doing so generate concrete recommendations for the treatment of at-risk patients.