Exercise-Induced Changes in Aging Mouse Hippocampus: A Single-Cell Transcriptomic Analysis

Background This study aimed to investigate the effects of physical exercise on learning, memory, and cellular dynamics in the hippocampus of aged mice, exploring the potential of exercise as a non-pharmacological intervention to mitigate age-related cognitive decline. Methods Eighteen 15-month-old C57BL/6J mice were divided into an aging group (O-Ctrl) and an aging exercise group (O-Ex), with 3-month-old young mice serving as controls (Y-Ctrl). The O-Ex group underwent an 8-week low-intensity exercise protocol. Post-exercise, all groups were assessed using the Barnes maze test for spatial learning and memory. Single-cell transcriptomic sequencing was performed on hippocampal tissues to identify changes in cell populations and gene expression. Results Exercise significantly reduced escape latency in the O-Ex group compared to O-Ctrl, indicating improved learning and memory. Sequencing revealed ten distinct cell types in the hippocampus with exercise reversing aging-induced alterations in astrocytes/neural stem cells (AST/NSCs) and neuronal populations. Differential gene expression analysis highlighted changes in key genes such as Apoe, Fkbp5, Ccnd3, AKT3, Zbtb16, and SIc24a4. Immunofluorescence assays corroborated these findings, showing a decrease in GFAP-positive astrocytes in exercised-aged mice Conclusion Our findings demonstrate that exercise can significantly improve cognitive functions in aged mice, potentially through modulating hippocampal cell populations and gene expression profiles. These results suggest that physical activity could be a viable strategy to delay or prevent age-related cognitive decline, offering insights into the underlying molecular mechanisms.