Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)
Open accessAbstract
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. SIGNIFICANCE STATEMENT 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.”
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Glucose hypometabolism could be responsible for decreased ATP levels in the brain as observed, a drop in cognitive performances, and an upregulation of the main pathological markers in Alzheimer's disease.
“This glucose hypometabolism could be responsible for decreased ATP levels in the brain (Rossi et al., 2020) as we observed in our study, a drop in cognitive performances (El Hayek et al., 2019) and an upregulation of the main pathological markers in AD (Fu et al., 2015; Liu et al., 2004).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as El Hayek et al., 2019
The section “Lactate enhances learning and memory formation” reports that lactate-treated mice performed better on spatial learning and memory tests, supporting a link between a metabolic factor and cognitive performance. It does not test whether glucose hypometabolism causes cognitive decline. The ATP and Alzheimer’s-marker claims are attached to other citations, not El Hayek et al.; page numbers were unavailable in our copy. (LLM, conf=0.84)
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- Authors
- El Hayek, L., Khalifeh, M., Zibara, V., Abi Assaad, R., Emmanuel, N., Karnib, N., El-Ghandour, R., Nasrallah, P., Bilen, M., Ibrahim, P., Younes, J., Abou Haidar, E., Barmo, N., Jabre, V., Stephan, J. S., & Sleiman, S. F.
- Affiliations
- Lebanese American University (LB)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2019-01-28
- Volume
- 39
- Issue
- 13
- Pages
- 1661-18
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6435829
- OpenAlex
- W2912250897
- Cited by
- 539
- References
- 8
- Citations by year
- 2026: 64 · 2025: 96 · 2024: 91 · 2023: 94 · 2022: 76 · 2021: 61 · 2020: 41 · 2019: 16
- FWCI
- 23.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- lactate, physical activity, learning and memory, hippocampus, brain-derived neurotrophic factor, SIRT1, TrkB signaling, PGC-1α, FNDC5, blood-brain barrier, spatial memory, neurodegenerative diseases
- MeSH terms
- Animals, Cells, Cultured, Fibronectins, Hippocampus, Learning, Male, Memory, Mice, Inbred C57BL, Physical Conditioning, Animal, Signal Transduction, Brain-Derived Neurotrophic Factor, Lactic Acid, Sirtuin 1
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