Lactic acid mediates the effects of physical exercise on learning and memory through SIRT1-dependent activation of hippocampal BDNF. (c2018)

Abstract

Exercise promotes learning and memory formation. These effects are dependent in part on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate induction of Bdnf gene expression in the hippocampus will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is increased during exercise, induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in hippocampal BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, previously shown to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for central nervous system diseases in which BDNF signaling is disrupted.