Seizure propagation triggers a protective contralesional spreading depolarization during focal hippocampal stroke predominantly in freely behaving female mice

Abstract

Following stroke, women have worse functional outcomes than men, due in part to more frequent non-focal symptoms, leading to misdiagnosis and lack of treatment. Understanding changes in peri-stroke behavior is critical to improving outcomes. During an ischemic stroke, energy loss in tissue fed by a blocked cerebral vessel induces rapid neuronal death. Next, large depolarizing waves (spreading depolarization, SD) emanate from this ischemic core. While SD in nearby hypoperfused tissue is deleterious, its impact on remote structures is unclear. Behavioural and cognitive symptoms may mirror this biphasic nature of cell death. We present a model for delivering and monitoring focal stroke in awake freely behaving mice, using bilateral fiberoptic cannulas to induce hippocampal stroke (unilateral photothrombosis) and monitor both ipsi- and contralesional neuronal Ca2+dysregulation/dynamics via GCaMP6f photometry. Ipsilesional Ca2+dysregulation, which correlated with lesion size, was indistinguishable between sexes, yet females had larger, more frequent contralesional SD-associated Ca2+waves, with increased acute exploration. Hippocampal stroke generated retrograde and anterograde amnesia, yet anterograde amnesia was absent in mice that had SD-associated Ca2+waves. Fiber photothrombosis with paired photometry offers flexibility to induce and monitor stroke in any brain region in freely behaving mice, allowing interrogation of previously inaccessible stroke biology.