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Objectives Cognitive decline is one of the most prevalent health problems and is associated with increased healthcare utilization and economic burden. Physical and cognitive training both have positive effects on cognition but have been less applied in combination. We hypothesized that simultaneous cognitive-physical components would yield greater cognitive benefits than single-domain interventions in rats.Methods A total of 40 male Wistar rats were divided into four treatment groups: the control, enriched environment (EE), exercise (EX), and EE + EX. Animals in EE groups housed in the large cages (50 × 50 × 50 cm) contained differently shaped objects for 3 weeks. EX animals were forced to run on a treadmill once daily for 3 consecutive weeks. Morris water maze test was used for the assessment of spatial learning and memory. Real-time PCR was performed to assess the expression of nestin, and Sox2 in the hippocampus.Results EX and EE animals separately did not show a significantly enhanced function in spatial memory in comparison with the control group. When animals were treated with EE and EX simultaneously, they exhibited significantly superior performance in spatial memory than control, EX, or EE groups separately. The hippocampal expression of Sox2 was significantly higher in EE + EX group than in the control, EX, and EE alone.Conclusions These results may have clinical implications for behavioral interventions in conditions with cognitive deficiencies.

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