Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

Abstract

Exercise promotes learning and memory formation. These effects depend 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 hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in 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, known 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 CNS diseases in which BDNF signaling is disrupted.It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."

Exogenous L-lactate promotes astrocyte plasticity but is not sufficient for enhancing striatal synaptogenesis or motor behavior in mice

“…In addition, we found that daily peripheral IP injections of 10mM L-lactate to mice significantly increased the expression of these same NTF transcripts (Bdnf, Gdnf, Cntf) within the STR compared to saline treated mice. Studies from others have also shown that Llactate can lead to the increased expression of BDNF within the hippocampus, leading to increased neurogenesis and memory and learning (El Hayek et al, 2019). Our study is one of the first to report the differential effect of L-lactate on NTF expression, including Bdnf, within the STR.…”

Genetic and metabolic links between the murine microbiome and memory

“…Lactate administration has also been found to enhance neuronal activity in vivo [44]. A recent study has shown that during exercise, lactate is released by the muscles, and crosses the blood-brain barrier to induce Bdnf expression and TRKB signaling in the hippocampus [45]. This enforces the hypothesis that a direct link from lactate to neurons exists that bypasses the need for glycogen energy storage in astrocytes [41].…”

Acute Sprint Interval Exercise Increases Both Cognitive Functions and Peripheral Neurotrophic Factors in Humans: The Possible Involvement of Lactate

“…Similarly, Ferris et al (2007) found that the increased blood LA level induced by acute exercise correlated with blood BDNF level. Furthermore, it has been pointed out, that LA is the "missing exercise factor" inducing BDNF synthesis (El Hayek et al, 2019). Very recently, El Hayek et al (2019) observed that LA modulates the redox status of neurons by altering the NAD + /NADH ratio which leads to SIRT1 activation and in turn engages the hippocampal PGC1-α/FNDC5 pathway to induce BDNF expression (Koltai et al, 2010;Wrann et al, 2013).…”