Explore the vast range of titles available.

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.

The aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis and had higher levels of serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery. The findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer’s disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.