Contralesional hippocampal spreading depolarization promotes functional recovery after stroke

Abstract

Ischemic stroke, brain tissue infarction following obstructed cerebral blood flow, leads to long-term neurological deficits and death. While neocortex is a commonly affected region with established preclinical models, less is known about deeper brain strokes, despite having unique neurological outcomes. We induced focal ischemic stroke while simultaneously monitors neuronal activity in awake behaving Thy1-GCaMP6f mice by delivering and collecting light through bilateral fiberoptic implants. Unilateral hippocampal stroke resulted in atypical mouse behavior coincident with ipsilesional terminal spreading depolarization (sustained increase in GCaMP6f fluorescence). Ischemia induced seizures that propagated to the contralesional hippocampus triggering a transient spreading depolarization (SD), predominantly in females. Hippocampal stroke impaired contextual fear conditioning acquired pre-stroke. Yet, 7 days post-stroke, contextual fear conditioning was only improved in mice with evidence of contralesional SD. Here, recovery of hippocampal function was lost by blunting peri-stroke SD with NMDAR antagonism, indicating that contralesional SD improves recovery following hippocampal stroke.