Age-associated cognitive decline, characterized by progressive memory and executive function impairment without dementia, poses challenges to elderly health. While aerobic exercise and environmental enrichment training may improve cognitive function, the underlying neural mechanisms remain unclear. In this study, we developed a novel intervention combines aerobic exercise (AE) with multisensory stimulation environment training (MSET). This combined training (CT) was more effective in mitigating cognitive decline in aged mice than either individual component or controls, aligning with increased neuronal activity and synaptic plasticity in the hippocampus (HPC) and prefrontal cortex (PFC). Using neural circuit tracing and chemogenetics, we explored the importance of the HPC-PFC circuit. Inhibiting the HPC-PFC circuit reduced the improvement effect of combined training (CT) on cognitive function, whereas activating this circuit enhanced cognitive function. We found candidate molecules responsive to CT in the HPC and PFC using single-cell sequencing. We identified that AE component modulated the expression levels of proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N) and lymphocyte antigen 6 family member H (LY6H) in neurons in the HPC and PFC. At the same time, MSET component influenced the expression levels of dipeptidyl peptidase like 6 (DPP6) and glutamate ionotropic receptor NMDA type subunit associated protein 1 (GRINA) in neurons of the HPC and PFC. CT was linked to the upregulation of these molecular targets, which correlated with its beneficial effects. These findings provide insight into the mechanism underlying cognitive improvement associated with CT, suggesting a potential basis for exploring strategies aimed at mitigating cognitive decline through interventions like CT.
