Zera, K. | Search bioRxiv

bioRxiv2026

ABERRANT HIPPOCAMPAL NEUROGENESIS IS A CONSERVED RESPONSE TO STROKE IN MICE: A MULTI-CENTER MULTIMODEL STUDY

BackgroundAdult hippocampal neurogenesis is markedly altered after cerebral ischemia. Although stroke increases the production of newborn neurons, many of these cells display aberrant morphological and positional features that impair their functional integration and contribute to long-term cognitive decline. Given the clinical heterogeneity of ischemic stroke and the persistent translational failures of preclinical approaches relying on single-model studies it remains unknown whether post-stroke neurogenic alterations are conserved across different experimental paradigms. This study aimed to define common and model-specific features of hippocampal neurogenesis across complementary focal ischemia models. MethodsWe performed a multi-center, multimodel analysis within the STROKE-IMPaCT consortium using permanent and transient middle cerebral artery occlusion (MCAO) paradigms (MCAO via ligation or cauterization under normoxic (dMCAO) or hypoxic conditions (dMCAO+Hypoxia); and filament-based tMCAO across six international sites. Brains from adult C57BL/6J mice were collected 3 days, 7 days, or 2 months after ischemia, sham, or naive conditions. Hippocampal cell proliferation (Ki67) and neuroblast density (DCX) were quantified, and the morphological maturation of newborn neurons was evaluated using high-resolution analyses of dendritic architecture and somatodendritic polarity. All analyses were performed blind to experimental group. ResultsAcross all stroke models, ischemia induced a robust bilateral increase in hippocampal cell proliferation, most pronounced at 3 days and still elevated at 7 days, with levels returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized by 2 months. Despite recovery in cell number, long-term morphological analysis revealed a consistent reduction in apical dendrite length and a higher proportion of neurons exhibiting aberrant features including ectopic localization, multipolar or inverted polarity, and abnormal lateral growth across all models. These abnormalities were observed both when pooling data across sites and when analyzing each model or center individually. ConclusionsIschemia induces an early, transient increase in hippocampal neurogenesis across diverse stroke paradigms, but the newborn neurons generated after stroke consistently display maladaptive morphological features. These cross-model, cross-site abnormalities indicate that aberrant hippocampal neurogenesis represents a robust hallmark of post-stroke pathology within the investigated species, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across experimental stroke models. Our findings support the concept that maladaptive neurogenesis may contribute to chronic post-stroke cognitive impairment and underscore the need to consider the quality not only the quantity of newborn neurons when developing therapeutic strategies.

animal behavior and cognition↗

bioRxiv2025

Juvenile mice are susceptible to infarct-induced neurodegeneration that causes delayed cognitive decline in a new model of pediatric ischemic stroke

Over half of pediatric stroke survivors have permanent neurologic and cognitive deficits, and some children develop new or worsening cognitive impairment late after stroke. Their cognitive symptoms are associated with chronic alterations of brain structure in regions distant from the infarct, including in the uninjured hemisphere. However, the mechanisms that cause childrens late cognitive symptoms and disrupted brain growth outside the infarcted tissue remain unknown. We therefore developed and validated a mouse model of pediatric ischemic stroke that causes infarct-induced, delayed cognitive decline accompanied by chronic innate and adaptive neuroinflammation in the infarct and in uninjured subcortical regions that are connected to the infarct. MethodsMale and female C57BL/6J mice were randomized to stroke or sham surgery at p28 to model stroke in late childhood and compared to adult 6-month-old mice. We used permanent distal MCAO followed by 60 minutes of hypoxia, an established model for focal ischemia that generates a purely cortical stroke. Mice underwent behavioral testing at 1- and 7-weeks post stroke Barnes Maze protocol adapted for reversal learning. We performed immunostaining to quantify stroke size, atrophy, and innate and adaptive neuroinflammation at 3 days and 7 weeks after surgery. ResultsAt 7 weeks post-stroke, juvenile stroke mice performed significantly worse on reversal learning on Barnes Maze testing than sham mice (n = 7 stroke, 7 sham, p = 0.0265 2-way ANOVA with repeated measures). At 3 days after stroke, juvenile mice had greater innate immune cell activation at subcortical sites of secondary neurodegeneration; however, by 7 weeks after surgery, this relationship was reversed, and adults had greater chronic innate immune cell activation at these uninjured subcortical sites (corpus callosum, corticospinal tract, thalamus). Like adult mice, pediatric mice exhibited chronic innate and adaptive neuroimmunity in the infarct scar; the inflammation in the stroke scar did not differ by age. ConclusionsIn a model of pediatric ischemic stroke, juvenile mice develop a delayed cognitive deficit that is associated with chronic innate and adaptive neuroinflammation in uninjured subcortical structures that undergo secondary neurodegeneration. Our results suggest that infarct-induced neurodegeneration occurs after stroke in juvenile mice and that juvenile and adult mice have divergent trajectories in the innate immune response to stroke.

neuroscience↗