To explore the synergistic antidepressant effects of music therapy combined with exercise and to elucidate the underlying mechanisms.

A depressive-like mouse model was established using the chronic restraint stress (CRS) paradigm. The effects of exercise alone and exercise combined with music were assessed. Behavioral alterations were evaluated using the elevated plus maze and forced swim tests. Hippocampal transcriptomic sequencing was performed to investigate potential molecular mechanisms by which music enhanced the antidepressant efficacy of exercise. Microglial activation was examined via immunofluorescence staining. Systemic inflammatory changes were quantified using RT-qPCR. Neuronal injury and synaptic plasticity were assessed using Nissl staining and Golgi staining, respectively.

Behavioral assessments showed that CRS induced distinct depressive-like behaviors, which were reversed by exercise and improved by the combined music-exercise intervention. Transcriptomic analysis suggested that music could enhance the antidepressant effects of exercise by modulating neuroinflammatory pathways. Immunofluorescence and RT-qPCR results indicated that the combined intervention could more significantly reduce levels of peripheral inflammatory cytokines and ameliorate systemic inflammation than exercise alone. Nissl and Golgi staining revealed that music combined with exercise more effectively mitigated depression-related neuronal damage, as evidenced by increased Nissl body abundance and enhanced dendritic spine density in the hippocampus.

The combination of music and exercise can more effectively improve depressive-like behaviors in CRS mice than exercise alone. This enhanced benefit may be associated with attenuation of neuroinflammation and improved recovery of neuronal integrity and synaptic plasticity.