Exercise-induced Citrate Enhances Associative Memory Formation by Modulating Histone Acetylation in a Sex-dependent manner

Abstract

Exercise stimulates the release of metabolites from the liver and muscles known as "exercise factors" into the circulation. The benefits of exercise on cognition are mediated by an increase in brain-derived neurotrophic factor (BDNF) levels in the hippocampus. Identifying these exercise-related factors could provide a detailed insight on the processes by which exercise exerts its positive effects on cognition. Previous work has shown that the levels of citrate, a Kreb’s cycle intermediate, are increased in the circulation upon exercise. In this study, we tested whether exogenous administration of citrate enhances learning and memory formation in a sex-dependent manner and elucidated the underlying molecular mechanisms. Our results show that citrate enhances associative memory formation in male mice, but not female mice. In males. citrate is released by the muscles during exercise, crosses the blood-brain barrier and induces TrkB overexpression in the hippocampus. In fact, we found that citrate-dependent enhancement of learning and memory is linked to an increase in hippocampal histone acetylation, specifically acetylation of histone H4. This increase is accompanied with a decrease in hippocampal HDAC2, leading to the expression of immediate early genes involved in synaptic plasticity. Overall, our findings suggest that citrate may be an endogenous molecule that mediates exercise-induced memory formation in male mice.