# Role of Repressive Histone Lysine Demethylases and Methylases in Susceptibility to Depression Using a Novel Progressive Social Defeat Stress Mouse Model

## TL;DR

This study explores how epigenetic changes in mice brains during stress may lead to depression-like behaviors.

## Contribution

A novel progressive social defeat stress model was developed to study epigenetic changes in depression susceptibility.

## Key findings

- H3K9me2 marks were consistently downregulated in the hippocampus and DG after four days of stress.
- H3K27me2 showed early upregulation in the hippocampus and late downregulation in the DG after five days of stress.
- Early increases in phf8 and phf2 genes were observed in the hippocampus and DG, respectively.

## Abstract

Major depressive disorder (MDD) results from repeated and constant exposure to stress over prolonged periods. The highly variable response to stress and the low heritability suggests that MDD has a strong epigenetic basis. Studies show global dysregulation of histone modifications in both susceptible and resilient animals after chronic stress suggesting involvement of epigenetics in stress response in the brain. Given that the hippocampus and dentate gyrus (DG) show epigenetic changes in neurogenesis in Rodent models of stress that is known to be highly affected in MDD, we hypothesized that epigenetic changes might be involved in the advent of depressive phenotype during the progressive stress paradigm. To study the stress progression into the depression-like phenotype at the molecular level, we designed a novel progressive social defeat stress (PSDS) paradigm based on the popular chronic social defeat stress (CSDS) paradigm but involving only 5 days of defeat stress. Our molecular studies revealed consistent downregulation of H3K9me2 marks in the hippocampus and DG after the 4th day of stress while H3K27me2 showed an early upregulation in the hippocampus and a late downregulation after the 5th day of stress in the DG. In parallel, an early increase in phf8 and phf2 in hippocampus and DG, respectively, was observed. These findings of variable changes like repressive histone methylation marks and expression of corresponding demethylase genes after different durations of defeat stress, led to better understanding of the important role epigenetics play in stress progression into depression at molecular level in establishing resilient and susceptible phenotypes.

The online version contains supplementary material available at 10.1007/s10571-025-01597-3.