Exercise and Sodium Butyrate Transform a Subthreshold Learning Event into Long-Term Memory via a Brain-Derived Neurotrophic factor-Dependent Mechanism
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We demonstrate that exercise enables hippocampal-dependent learning in conditions that are normally subthreshold for encoding and memory formation, and depends on hippocampal induction of brain-derived neurotrophic factor (BDNF) as a key mechanism. Using a weak training paradigm in an object location memory (OLM) task, we show that sedentary mice are unable to discriminate 24 h later between familiar and novel object locations. In contrast, 3 weeks of prior voluntary exercise enables strong discrimination in the spatial memory task. Cognitive benefits of exercise match those attained with post-training sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor previously shown to enable subthreshold learning. We demonstrate that the enabling effects of exercise and NaB on subthreshold OLM learning are dependent on hippocampal BDNF upregulation, and are blocked by hippocampal infusion of BDNF short-interfering RNA. Exercise and NaB increased bdnf transcripts I and IV, and the increases were associated with BDNF promoter acetylation on H4K8 but not H4K12. These data provide support for the concept that exercise engages epigenetic control mechanisms and serves as a natural stimulus that operates in part like NaB and potentially other HDAC inhibitors, placing the brain into a state of readiness for plasticity.
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SCFAs modulate neurotrophic factors such as NGF, GDNF, and BDNF, which regulate the growth, survival and differentiation of neurons and synapses in the CNS and play important parts in learning and memory and in a range of brain disorders.
“Neurotrophic factors, such as nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and BDNF that regulate the growth, survival and differentiation of neurons and synapses in the CNS also play important parts in learning and memory and in a range of brain disorders have been also shown to be modulated by SCFAs (120–123).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [122]
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- Authors
- Intlekofer, K. A., Berchtold, N. C., Malvaez, M., Carlos, A. J., McQuown, S. C., Cunningham, M. J., Wood, M. A., & Cotman, C. W.
- Affiliations
- University of California, Irvine (US)
- University of Vermont (US)
- Corresponding author
- Berchtold, Nicole C
- Venue
- Neuropsychopharmacology
- Published
- 2013-04-24
- Volume
- 38
- Issue
- 10
- Pages
- 2027-2034
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3746687
- OpenAlex
- W2065413869
- Cited by
- 190
- References
- 46
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 17 · 2023: 22 · 2022: 11 · 2021: 12 · 2020: 12 · 2019: 20 · 2018: 7 · 2017: 12 · 2016: 28 · 2015: 17 · 2014: 9 · 2013: 1
- FWCI
- 10.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG000538, R01AG034667, T32AG9629, AG 00538, AG34667)
- National Institute of Mental Health (R01MH081004, MH081004)
- National Institute on Drug Abuse (F31DA29368, F31DA029368)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- physical activity, sodium butyrate, brain-derived neurotrophic factor, long-term memory, hippocampus, object location memory, histone deacetylase inhibition, histone acetylation, epigenetic regulation, neuroplasticity, sedentary behavior, memory consolidation
- MeSH terms
- Acetylation, Animals, Discrimination Learning, Hippocampus, Male, Microinjections, Physical Conditioning, Animal, Promoter Regions, Genetic, Up-Regulation, Brain-Derived Neurotrophic Factor, Butyric Acid, RNA, Small Interfering, Mice, Histone Deacetylase Inhibitors, Memory, Long-Term
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