Each year, ~700,000 Americans have a new or recurrent ischemic stroke. Here, ~10% of stroke survivors have a recurrent stroke in the following year, the investigation of both recovery and resilience to further injury. Stroke incidence is rising in reproductive aged people and at present, ~4 million American stroke survivors live with stroke-associated deficits. Younger stroke survivors live longer with deficits, have increased risk of recurrence, and create novel challenges (i.e. pre-menopausal stroke). Given the prevalence of stroke, even rare stroke presentations impact many people. Hippocampal stroke triggers unique devastating symptoms, including transient or permanent amnesia, impaired spatial navigation, and disorientation. In our recent study, deleterious peri-infarct and independent beneficial SD in remote contralesional tissue occurred in the same brain following a focal unilateral stroke. Beneficial contralesional spreading depolarizations (SDs) were more prevalent in female mice. We hypothesize that these beneficial SDs are regulated by female sex hormones and may not only benefit stroke recovery, but also protect against primary or recurrent strokes. This conceptually innovative proposal looks beyond the stroke core to explore how SD impacts well-perfused tissue distal to the emerging stroke. Plenty of attention has been placed on cortical stroke, however, here, using innovative technological approaches, we ask how SD impacts deeper brain structures in the absence of anesthetics (known to protect the brain). In our previous work, we induce focal unilateral stroke and monitor neuronal Ca2+ influx (ie. SD) in behaving mice of both sexes expressing a fluorescent genetically encoded neuronal Ca2+ biosensor, GCaMP6f, by delivering and collecting light through chronic bilateral fiberoptic implants. The ipsilesional fiber is used for stroke induction (photothrombosis, photo-oxidation of Rose Bengal dye circulating in vessels), while bilateral fibers monitor neuronal Ca2+ (GCaMP6f fluorescence) in ipsilesional stroke core and well-perfused contralesional tissue. The impact of stroke on hippocampal functions will be assessed in male and female mice in several complementary ways (including acute spatial navigation in an open field arena, spatial memory using the Barnes maze, contextual memory using fear conditioning, and working memory using the touch screen-based assays.