title: Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism.
abstract: 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.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA.
authors.forename: Karlie A
authors.initials: KA
authors.lastname: Intlekofer
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Berchtold
authors.forename: Melissa
authors.initials: M
authors.lastname: Malvaez
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Carlos
authors.forename: Susan C
authors.initials: SC
authors.lastname: McQuown
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cunningham
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Wood
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D000107:Acetylation; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020148:Butyric Acid / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008845:Microinjections; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D020148:Butyric Acid