Aberrant Hippocampal Neurogenesis Is a Conserved Response to Stroke in Mice: A Multicenter Multimodel Study
Year: 2026
Type: article
Abstract: ABSTRACT Background Adult 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. Methods We 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. Results Across 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. Conclusions Ischemia 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.
Source: Stroke
Authors: Francisco J. De Castro-Millán, Sandra Vázquez-Reyes, Carolina Peña-Martínez, Adrián Rodríguez-Llave, Carlos Parra-Pérez, Carmen Nieto-Vaquero, Gaia Brezzo, Kristy A. Zera, Dana Straus, Jennifer E. Goertz, Sanna H. Loppi, Rachel R. Crumpacker, Jennifer B. Frye, Danielle A. Becktel, Claudia Dames, Daniel Berchtold, Jill H. Fowler, Andreas Meisel, Josef Anrather, Kristian P. Doyle, Stuart M. Allan, Marion S. Buckwalter, Barry W. McColl, Alicia García-Culebras, María Isabel Cuartero, María Ángeles Moro
Institutions: Universidad Complutense de Madrid, Spanish National Centre for Cardiovascular Research, Universidad Rey Juan Carlos, UK Dementia Research Institute, University of Edinburgh, Stanford Medicine, Stanford University, Weill Cornell Medicine, University of Arizona, Humboldt-Universität zu Berlin, Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, University of Manchester, Research Institute Hospital 12 de Octubre
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7169061997