Abstract: BACKGROUND: The hippocampus is crucial for cognitive function, and exercise holds promise for enhancing cognition and alleviating cognitive decline. However, the molecular mechanisms underlying these effects remain unclear. Bioinformatics, by analyzing the impact of exercise on molecular expression in the hippocampus, helps reveal key mechanisms, providing new insights into how exercise promotes cognition and informing the development of intervention strategies.
OBJECTIVE: Using bioinformatics methods to conduct an in-depth analysis of the gene expression profiles of hippocampal tissue in mice subjected to voluntary exercise interventions and by examining the biological functions of differentially expressed genes and their potential regulatory networks to elucidate the molecular mechanisms by which exercise modulates neural function in the hippocampus.
METHODS: Gene expression microarray datasets (GSE42904 and GSE29075) from the Gene Expression Omnibus (GEO) database were obtained for hippocampal tissue in mice subjected to voluntary exercise interventions. Strict differential gene analysis was performed using the Limma and DESeq2 packages in R, and the results were visually presented using volcano plots generated by the ggplot2 package. Common differentially expressed genes were identified using the FunRich software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the clusterProfiler package in R. Protein-protein interaction networks of differentially expressed genes were analyzed using the online tool STRING, and core targets were further screened using Cytoscape software. 
RESULTS AND CONCLUSION: In the GSE42904 dataset, voluntary exercise intervention led to the differential expression of 123 genes in the hippocampus of mice, primarily involved in rhythmic processes, glycosylation, and other GO biological processes. These genes were also associated with multiple KEGG pathways, including interleukin-17, calcium, and ethanol signaling. Key hub genes identified in the protein-protein interaction network included Npy, Mapk3, Mapk11, and Chgb. In the GSE29075 dataset, voluntary exercise resulted in the differential expression of 455 genes in the hippocampus, mainly involved in the positive regulation of cellular projection organization, negative regulation of apoptotic signaling, and other GO biological processes. These genes were significantly enriched in pathways related to neurodegenerative diseases. Key hub genes identified in the protein-protein interaction network included Eed, Bptf, and Nedd8. To conclude, voluntary exercise significantly regulates the expression of key genes such as Chrm1, Eed, Npy, Mapk3, Mapk11, and Map2k1 in the hippocampus of mice. These genes play a core regulatory role in biological processes such as neurodegenerative diseases and calcium signaling. Voluntary exercise may promote cognitive function by influencing neurogenesis and synaptic plasticity.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: voluntary exercise, mouse, hippocampus, differentially expressed genes, signaling pathways, protein-protein interaction network, GEO database, bioinformatics