Extracellular vesicle-mediated spinal cord-brain crosstalk induces hippocampal neurogenesis impairment and cognitive deficits post-spinal cord injury.

Spinal cord injury (SCI) is well-documented for its devastating impact on motor and sensory functions. However, its potential effects on cognitive function remain underexplored. This study aims to investigate the mechanisms of SCI-induced cognitive dysfunction, focusing on spinal cord-hippocampal communication mediated by extracellular vesicles (EVs). Cognitive function and hippocampal neurogenesis were assessed in mice subjected to either SCI or sham surgery. EVs were isolated from spinal cord tissues of SCI and sham groups and stereotactically injected into the hippocampus to evaluate their effects on cognition and neurogenesis. Cx3cr1-CreERT2 transgenic mice combined with AAV-CD63-EGFP injection were used to confirm the source of EVs. High-throughput sequencing was performed to identify differentially expressed miRNAs in EVs from SCI versus sham groups, with miR-152-3p selected for further analysis. RNA sequencing and dual-luciferase reporter assays were used to confirm whether miR-152-3p regulates cognition and neurogenesis via the WNT10b pathway. Finally, stereotactic injection of a WNT agonist was performed to assess its potential for restoring cognition and neurogenesis post-SCI. This study demonstrates that SCI induces cognitive decline and impairs hippocampal neurogenesis in the dentate gyrus (DG) of mice. microglia-derived EVs were identified as critical mediators of communication between the spinal cord and hippocampus. Specifically, microglia-derived EVs were found to carry miR-152-3p, which inhibits WNT10b signaling, disrupts neurogenesis in the DG, and contributes to post-SCI cognitive deficits. Notably, activation of the WNT pathway in hippocampal neural stem cells (NSCs) after SCI promoted neurogenesis and significantly improved cognitive function in SCI mice. This study uncovers a novel microglia-derived EV-mediated communication axis between the spinal cord and hippocampus following SCI. It identifies the miR-152-3p/WNT10b axis as a key regulator of SCI-induced cognitive dysfunction and impaired neurogenesis. Activation of the WNT pathway was shown to restore neurogenesis and cognitive function, providing valuable insights into therapeutic strategies for SCI-associated cognitive impairments.