Aberrant Hippocampal Neurogenesis Is a Conserved Response to Stroke in Mice: A Multicenter Multimodel Study

Adult hippocampal neurogenesis is altered after cerebral ischemia. Although stroke increases newborn neuron production, many cells display aberrant morphological and positional features that may impair functional integration and contribute to long-term cognitive deficits. Given the clinical heterogeneity of ischemic stroke and limited translational success of preclinical studies relying on single models, it remains unclear whether poststroke neurogenic alterations are conserved across experimental paradigms. This study aimed to identify common and model-specific features of hippocampal neurogenesis across focal ischemia models.

We conducted a multicenter, multimodel analysis within the Stroke-IMPaCT consortium using permanent and transient middle cerebral artery occlusion paradigms, including distal middle cerebral artery occlusion under normoxic or hypoxic conditions (distal middle cerebral artery occlusion+hypoxia), and filament-based transient middle cerebral artery occlusion, across 6 sites. Adult C57BL/6J mice were analyzed at 3 days, 7 days, and 2 months after ischemia, sham, or naïve conditions. Hippocampal proliferation (Ki67) and neuroblasts (DCX [doublecortin]) were quantified; morphological maturation of newborn neurons was assessed through high-resolution analyses of dendritic architecture and somatodendritic polarity.

Across all stroke models, ischemia induced a robust bilateral increase in hippocampal proliferation, most pronounced at 3 days and still elevated at 7 days, returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized over time. Despite recovery in cell number, long-term analyses revealed a consistent reduction in apical dendrite length and increased proportion of neurons with aberrant features, including ectopic positioning, polarity defects, and abnormal lateral growth, across models and centers.

Aberrant hippocampal neurogenesis represents a robust hallmark of poststroke pathology in mice, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across models. Our findings underscore the importance of considering structural quality, and not only quantity, of newborn neurons when evaluating poststroke plasticity and developing therapeutic strategies.