Combined long-term enriched environment and caffeine supplementation improve memory function in C57Bl6 mice

Abstract Regular physical activity has been associated with healthy brain aging, reflected by beneficial effects on cognition and learning and memory. Nutritional supplements such as caffeine have been shown to act as cognitive enhancers and may possess neuroprotective properties. Interestingly, caffeine also improves athletic capabilities and is widely used by athletes because of its performance-enhancing effect, while information on potential additive beneficial effects of physical activity and caffeine on cognitive performance is scarce. In the present study, the effects of caffeine supplementation in combination with prolonged physical and cognitive stimulation in the form of the enriched environment (EE) housing for a duration of 4 months were analyzed. We demonstrate that caffeine supplementation together with prolonged environmental enrichment led to enhanced memory function, resulting in improved recognition and spatial working memory in behavioral paradigms such as the novel object recognition task or the Morris water maze in C57Bl6 wild-type mice. Mice housed under EE conditions showed increased gene expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. The present findings underscore the potential impact of continuous physical activity in the prevention of age-related cognitive decline and may offer new options for combinatorial approaches.