Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism - PubMed (original) (raw)
Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism
Karlie A Intlekofer et al. Neuropsychopharmacology. 2013 Sep.
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.
Figures
Figure 1
Experimental design. (a) Sedentary (Sed) or exercised (EX) mice were given a 3-min acquisition trial (as a subthreshold learning task as shown previously; Stefanko et al, 2009; McQuown_et al_, 2011), followed immediately with an i.p. injection of sodium butyrate (NaB) or vehicle (veh), and returning all animals to clean home cages without access to running wheels. Twenty-four hours or 7 days later, a 5-min object location memory (OLM) retention test was administered where one object was moved to a novel location. Time spent exploring the identical objects was recorded and a discrimination index (DI) was calculated to determine preference for the object in the novel location. (b) To determine whether a brain-derived neurotrophic factor (BDNF)-dependent mechanism was involved in the enhancement of subthreshold learning, short-interfering RNA (siRNA) against bdnf, or control siRNA, were infused to the hippocampus 2 days before OLM acquisition. Mice were given a 3-min acquisition trial, followed 24 h later by a 5-min OLM retention test. Animals were killed 1 h after the OLM test, and hippocampi were removed for molecular assays.
Figure 2
In a subthreshold object location memory (OLM) paradigm, exercise (Ex) improves learning equivalent to sedentary (Sed) mice injected with post-acquisition sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor. (a) Twenty-four hours after a 3-min acquisition trial, vehicle-treated Sed animals do not show preference for the novel location over the familiar location, as measured by the discrimination index ratio (DI). Following 3 weeks voluntary exercise, Ex animals show marked preference for the novel location to a similar extent as post-acquisition injection of NaB. (b) Quantitative reverse transcription PCR (RT-qPCR) revealed that hippocampal brain-derived neurotrophic factor (bdnf) mRNA levels are increased by exercise and NaB, in parallel with the cognitive enhancement. (c) Effects of NaB on cognition persist 7 days after the acquisition trial, whereas the exercise effects on spatial memory in the subthreshold paradigm eventually decay after daily physical activity ceases. (d) RT-qPCR revealed that bdnf mRNA expression patterns at the 7-day timepoint paralleled the cognitive data across the treatment groups, remaining elevated after NaB treatment but not with exercise. Data are expressed as means±SEM. For the 24-h timepoint: **p<0.01 vs sedentary. For the 7-day timepoint:σ_p_<0.05;σσσ_p_<0.001 vs sedentary.
Figure 3
Exercise (Ex) and sodium butyrate (NaB) increase acetylation of histone H4, specifically acetylation at H4K8 of promoters for (a) brain-derived neurotrophic factor (bdnf) I and (b) bdnf IV, but not (c) bdnf VI. Acetylation at H4K12 was not significantly increased by Ex or NaB at either promoters (d)bdnf I, (e) bdnf IV, or (f) bdnf VI. Comparing sedentary (Sed) animals with or without object location memory (OLM) testing, behavioral testing had a small effect on H4K8 acetylation on bdnf promoters I and IV, and H4K12 acetylation in bdnf promoter IV. Data are expressed as means±SEM, *p<0.05 vs Sed+Veh (OLM tested),#p<0.05, vs baseline acetylation level in sedentary unhandled animals (indicated by dotted line).
Figure 4
Preventing increased brain-derived neurotrophic factor (bdnf) mRNA expression with intrahippocampal short-interfering RNA (siRNA) blocks the cognitive benefits of exercise (Ex) and sodium butyrate (NaB) in a subthreshold object location memory (OLM) learning task. (a) Exercise-dependent improvements in the subthreshold OLM paradigm were abolished by intrahippocampal infusion of bdnf siRNA, but not by control siRNA. Intrahippocampal bdnf siRNA blocked induction of (b) bdnf mRNA and (c) BDNF protein expression by exercise and decreased levels of mRNA and protein below baseline. (d) Cognitive improvements in the subthreshold OLM paradigm with NaB treatment were blocked by intrahippocampal infusion of bdnf siRNA, but not control siRNA. Data are expressed as means±SEM. *p<0.05; **p<0.01; ***p<0.001.
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