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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE315740 | GEO | 2026/02/02

REPOSITORIES: GEO

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Project description:Despite depression being one of the most prevalent and debilitating disorders worldwide, it has been difficult to understand its pathophysiology and to develop more effective treatments. Maladaptive transcriptional regulation within limbic neural circuits, including reward processing regions such as the nucleus accumbens (NAc), in response to chronic stress is thought to be a major contributor to the development of the syndrome. Epigenetic events?in particular, histone writers and erasers?that alter chromatin structure to regulate programs of gene expression have increasingly been associated with depression-related behavioral abnormalities in animal models and in depressed humans examined postmortem. However, very little is known about the ATP-dependent chromatin remodelers that control nucleosome positioning and the packing state of chromatin. Here we show that the ACF complex, part of the ISWI family of chromatin remodelers, is persistently and selectively upregulated in the NAc of mice that are susceptible to chronic social stress, as well as in the NAc of depressed human. We further establish that ACF induction is both necessary and sufficient for susceptibility to stress-induced depressive-like behaviors. Using ChIP-seq, we demonstrate that altered ACF binding after chronic stress is strongly correlated with altered nucleosome positioning, in particular, around the transcriptional start sites of affected genes. These alterations in ACF binding and nucleosome repositioning are associated with repressed expression of a subset of genes in animals that are susceptible to chronic stress. Together, these findings establish that active ATP-dependent chromatin remodeling by the ACF complex is a key regulator in the repression of genes that mediate susceptibility to social stress, and provide novel candidate targets for improved therapeutics of depression and other stress-related disorders. c57bl/6 mice underwent chronic social defeat stress (CSDS), and social interaction test was used to separate animals into control, susceptible and resilient groups. Nucleus accumbens (NAc) tissue was collected 48 hours after the last defeat session, and then Acf1, SNF2H ChIP-seq or H3 MNase-seq were performed based on the control, susceptible, and resilient groups. Three sequencing replicates were performed on each group.

Project description:Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein cohorts of CSDS versus CON(CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p<0.05. The protein cluster 1, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion and synapses. Further GO analysis of the common proteins for NORCSDS-IMICSDS groups and NORCSDS-CSDSCON groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the shared protein cohorts of NORCSDS-IMICSDS and NORCSDS-CSDSCON, revealing an enrichment of the proteins associated with the mitochondrial and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that several proteins related to mitochodrial function, including Cox7c, Mrp142, Naa30, Ighm, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group. Additionally, proteins associated with synaptic function, such as Dcx, Arid1b, Rnf112, Apoa4 and Fam3c, were also observed to undergo modulation in the NOR-treated groups. These findings suggest that the proteins involved in depression treatment exert differential effects the mitochondrial and synaptic regulation of the mice prefrontal proteome. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.

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

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