Epigenetic mechanisms underlying stress-induced depression

Abstract

Stressful life events are a major contributor to the development of major depressive disorder. Environmental perturbations like stress change gene expression in the brain, leading to altered behavior. Gene expression is ultimately regulated by chromatin structure and the epigenetic modifications of DNA and the histone proteins that make up chromatin. Studies over the past two decades have demonstrated that stress alters the epigenetic landscape in several brain regions relevant for depressive-like behavior in rodents. This chapter will discuss epigenetic mechanisms of brain histone acetylation, histone methylation, and DNA methylation that contribute to adult stress-induced depressive-like behavior in rodents. Several biological themes have emerged from the examination of the brain transcriptome after stress such as alterations in the neuroimmune response, neurotrophic factors, and synaptic structure. The epigenetic mechanisms regulating these processes will be highlighted. Finally, pharmacological and genetic manipulations of epigenetic enzymes in rodent models of depression will be discussed as these approaches have demonstrated the ability to reverse stress-induced depressive-like behaviors and provide proof-of-concept as novel avenues for the treatment of clinical depression.

Keywords: DNA methylation; DNMT; Depression; Epigenetic; HDAC; Histone acetylation; Histone methylation; Sirtuin; Stress; TET.

Figure 1.. Changes in epigenetic enzymes, histone modifications, and DNA methylation in various brain regions of rats and mice after chronic stress.

A drawing of a sagittal view of the rodent brain showing the main brain regions that have been studied for epigenetic alterations after chronic stress protocols (i.e. chronic mild stress, social defeat stress) that result in depressive-like behavior in susceptible animals. Ventricles are shown as yellow areas. Proteins are in all capital letters and mRNA or gene names are italicized. Green and red arrows indicate an increase or decrease, respectively, in the associated epigenetic enzyme or modification after chronic stress. Two arrows in the opposite direction indicate that an increase and a decrease have been observed in studies employing different chronic stress protocols and/or different species. If changes have been observed at a specific gene, the gene name is indicated in parenthesis after the arrow. *Indicates modifications at the Gdnf gene in the same study (Uchida et al, 2011). Abbreviations: PFC, prefrontal cortex; NAc, nucleus accumbens; HPC, hippocampus, PVN, paraventricular nucleus of the hypothalamus; H3Kcr, histone H3 lysine crotonylation; H3K27me3, histone H3 lysine 27 trimethylation; H3ac, histone H3 acetylation; H3K14ac, histone H3 lysine 14 acetylation; H3K9ac, histone H3 lysine 9 acetylation; H4K12ac, histone H4 lysine 12 acetylation; H3K27me2, histone H3 lysine 27 dimethylation.