Effects of Aerobic Exercise on Depression-Like Behaviors and Hippocampal Transcriptomics in CSDS-Induced Adolescent Mice

Background: Adolescence is a critical period of vulnerability to depression, yet most evidence for the antidepressant effects of exercise derives from adult models. This study aims to investigate the effects of aerobic exercise and identify its associated molecular changes in the adolescent depression mouse model. Methods: A chronic social defeat stress (CSDS) model was established in adolescent male C57BL/6J mice to induce depression-like behaviors. Thirty-six mice were randomly assigned to three groups: control (CG), model (MG), and model plus exercise (ME). MG and ME mice were subjected to CSDS for two weeks (days 7–20), while ME mice additionally received three weeks of aerobic treadmill training covering the whole CSDS period (days 0–20). Behavioral tests were conducted on days 21–26, followed by the collection of serum and hippocampal tissues for molecular, histological, and transcriptomic analyses. Results: CSDS induced significant depression-like behaviors in adolescent male mice, including social avoidance, anhedonia, and behavioral despair, all of which were effectively alleviated by aerobic exercise. Aerobic exercise appeared to mitigate CSDS-induced neural damage and maintain hippocampal tissue integrity. Moreover, aerobic exercise increased serum levels of serotonin. Transcriptomic analysis identified 587 differentially expressed genes (DEGs). Among these genes, 59 overlapping DEGs were regulated by both CSDS and exercise, and were enriched in carbohydrate metabolism and cholinergic signaling pathways. Conclusions: Aerobic exercise alleviates depression-like behaviors in adolescent male mice, possibly by modulating hippocampal gene expression – especially in cholinergic and carbohydrate metabolism pathways – which provides potential clues to how exercise could influence peripheral monoamine levels and hippocampal structural integrity. These putative mechanisms require further investigation. Overall design: This study used RNA-seq to characterize hippocampal transcriptomic alterations induced by chronic social defeat stress (CSDS) and their modulation by aerobic exercise in adolescent male C57BL/6J mice. Animals were randomly assigned to three experimental groups: control (CG), CSDS model (MG), and CSDS with aerobic exercise intervention (ME), with six independent biological replicates per group. Following completion of behavioral testing, hippocampal tissues were collected from each mouse, and total RNA was extracted for RNA-seq analysis. Gene-level expression profiles were generated and used for differential gene expression analysis to identify CSDS-associated transcriptional changes and exercise-responsive molecular pathways.