Exercise-induced a-ketoglutarate enhances spatial learning by modulating hippocampal levels of BDNF in a sex-specific manner

Abstract

Exercise promotes the release of proteins and metabolites known as exercise factors from the muscles, liver, and bones into the blood. The exercise factors increase hippocampal levels of brain-derived neurotrophic factor (BDNF) which mediates the benefits of exercise on cognition. Identifying these exercise factors would elucidate the mechanisms underlying the benefits of exercise. In this study we examined the effects of the tricarboxylic acid cycle intermediate a-ketoglutarate (aKG) onacognition in both males and females to uncover any sex differences considering theanew NIH guidelines to factor sex as a variable in research. We report that aKG isareleased in the serum of males following forced resistance exercise and voluntary endurance exercise. In contrast, aKG is released in the serum of females only following voluntary endurance exercise. We used the Morris water maze test to investigate the effects of aKG on spatial learning and memory formation. We report that the administration of exogenous aKG enhances spatial learning but not memory in both males and females. This enhanced learning is associated with an increase in hippocampal BDNF and FNDC5 levels in females only. In males, aKG does not to induce hippocampal FNDC5/BDNF, and therefore promotes learning through a yet unknown mechanism. Overall, our results reveal one of the mechanism through which exercise enhances BDNF and promotes learning in females.