Paper

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

Berchtold, Daniel, Anrather, Josef, Pena-Martinez, Carolina C, Rodriguez-Llave, Adrian, Allan, Stuart M, De Castro-Millan, Francisco Javier, Nieto-Vaquero, Carmen, Vazquez-Reyes, Sandra, Garcia-Culebras, Alicia, Cuartero, Maria Isabel, Loppi, Sanna, Zera, Kristy, Dames, Claudia, Doyle, Kristian Paul, Becktel, Danielle, Mccoll, Barry W, Fowler, Jill, Frye, Jennifer, Goertz, Jennifer, Buckwalter, Marion S, Parra-Perez, Carlos, Meisel, Andreas, Brezzo, Gaia, Straus, Dana, Maria Angeles Moro, Crumpacker, Rachel

2026

Overview

Background: Adult hippocampal neurogenesis is altered after cerebral ischemia. Although stroke increases newborn neuron production, many cells show aberrant morphology and positioning that may impair integration and contribute to cognitive decline. It remains unclear whether these alterations are conserved across focal ischemia paradigms. We aimed to define shared and model-specific features of hippocampal neurogenesis across stroke models. Methods: We performed a multi-center, multimodel analysis within the STROKE-IMPaCT consortium using permanent and transient middle cerebral artery occlusion (MCAO): distal MCAO by ligation or cauterization under normoxia (dMCAO) or hypoxia (dMCAO+Hypoxia), and filament-based tMCAO. Adult C57BL/6J mouse brains were collected 3 days, 7 days, or 2 months after ischemia, sham, or naive conditions. Hippocampal proliferation (Ki67) and neuroblast density (DCX) were quantified, and newborn neuron maturation assessed by high-resolution analyses of dendritic architecture and somatodendritic polarity. Analyses were blinded. Results: Across all models, ischemia induced a robust bilateral increase in hippocampal proliferation, highest at 3 days and still elevated at 7 days, returning to baseline by 2 months. Neuroblast density similarly increased at 7 days, particularly ipsilaterally, but normalized by 2 months. Despite recovery in cell number, long-term analysis revealed reduced apical dendrite length and more neurons with aberrant features including ectopic localization, multipolar or inverted polarity, and abnormal lateral growth. These abnormalities were consistent across sites and within each model. Conclusions: Ischemia induces an early, transient increase in hippocampal neurogenesis across diverse stroke paradigms, but newborn neurons consistently display maladaptive morphological features. Aberrant hippocampal neurogenesis is therefore a robust hallmark of post-stroke pathology, independent of ischemia type or surgical approach. These findings support the concept that impaired neuronal integration may contribute to chronic post-stroke cognitive decline and highlight the need to consider the quality, not only the quantity, of newborn neurons in therapeutic strategies.Competing Interest StatementThe authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press
• Subject: Cell number / Cerebral blood flow / Cognitive ability / Doublecortin protein / Hippocampus / Hypoxia / Ischemia / Neuroblasts / Neurogenesis / Neurons / Stroke