D-β-Hydroxybutyrate and lactate mediate the positive effects of exercise on chronic stress by changing the histone modification profile in the hippocampus

Abstract

Depression is a very common mental illness and the leading cause of disability worldwide. Some people are more vulnerable than others; however, the underlying mechanisms behind this vulnerability are not well understood. Exercise has long been studied as a lifestyle factor that can be used to counteract the effect of stress. Our objective was to investigate whether two well-established exercise factors, D-β-Hydroxybutyrate and lactate, mediate its positive effects on resilience to chronic stress and social behavior. For that reason, we first blocked the transport of these metabolites to the brain during exercise and assessed whether this blockage abolished the positive effects of exercise on social behavior. Next, we assessed the effects of D-β-Hydroxybutyrate and lactate and determined whether they promote resilience to chronic stress. To that effect, we induced stress in mice using the chronic social defeat stress paradigm. Mice were subjected to chronic social defeat stress while receiving either D-β-Hydroxybutyrate or lactate. Mice that were subjected to chronic social defeat stress exhibited depressive-like behavior, showed increased susceptibility to stress, and displayed increased social avoidance behavior. D-β-Hydroxybutyrate and lactate promoted resilience to stress and rescued social avoidance behavior. The rescue by D-β-Hydroxybutyrate was associated with an increase in histone H3 β-Hydroxybutyrylation levels in the hippocampus. Furthermore, we examined the antidepressant properties of these two exercise factors. To assess that, we subjected the mice to chronic social defeat stress, and then administered our treatments. Both D-β-Hydroxybutyrate and lactate acted as antidepressants when administered after the establishment of a depressive phenotype. Finally, we found that a ketogenic diet known to increase the levels of D-β- Hydroxybutyrate in the brain also mimics the effects of these exercise factors and promotes resilience to stress and rescues social avoidance behavior. The molecular basis behind the rescue effect of D-β-Hydroxybutyrate is still being studied.