Lactic acid mediates resistance to stress through class I HDAC induction in a chronic social defeat model of depression. (c2017)

Abstract

Depression is one of the most common psychiatric disorders and a leading cause of disability worldwide. Environmental factors, mainly stress, play an important role in promoting this disorder by inducing changes in gene expression that are sustained by epigenetic modifications, particularly in the hippocampal brain regions. Transcriptional profiling of the hippocampus revealed a downregulation in the Brain- Derived Neurotrophic Factor (Bdnf) gene expression in animal models of stress, and this downregulation was reversed by antidepressant treatment and physical exercise. In our study, we use a chronic social defeat paradigm, a validated model of depression in mice, to study the antidepressant effect of the endogenous molecule lactate that is released after physical exercise. We used multiple behavioral tests including open field, T-maze and social interaction tests to show that lactate rescues depression phenotypes such as defeat and anxiety behavior We also report that lactate activates independent pathways to affect two separate processes: promotion of resilience to stress and protection from depression. Our results reveal an antidepressant-like activity of an endogenous molecule lactate, produced after physical exercise and known to accumulate in the hippocampal regions of the brain and illustrate a novel mechanism that can explain the positive effects of exercise on mood disorders.