Exercise and Sodium Butyrate Transform a Subthreshold Learning Event into Long-Term Memory via a Brain-Derived Neurotrophic factor-Dependent Mechanism

We demonstrate that exercise enables hippocampal-dependent learning in conditions thatare normally subthreshold for encoding and memory formation, and depends on hippocampalinduction of brain-derived neurotrophic factor (BDNF) as a key mechanism. Using a weaktraining paradigm in an object location memory (OLM) task, we show that sedentary mice areunable to discriminate 24 h later between familiar and novel object locations. Incontrast, 3 weeks of prior voluntary exercise enables strong discrimination in the spatialmemory task. Cognitive benefits of exercise match those attained with post-training sodiumbutyrate (NaB), a histone deacetylase (HDAC) inhibitor previously shown to enablesubthreshold learning. We demonstrate that the enabling effects of exercise and NaB onsubthreshold OLM learning are dependent on hippocampal BDNF upregulation, and are blockedby hippocampal infusion of BDNF short-interfering RNA. Exercise and NaB increased bdnftranscripts I and IV, and the increases were associated with BDNF promoter acetylation onH4K8 but not H4K12. These data provide support for the concept that exercise engagesepigenetic control mechanisms and serves as a natural stimulus that operates in part likeNaB and potentially other HDAC inhibitors, placing the brain into a state of readiness forplasticity.