The Changes of Histone Methylation Induced by Adolescent Social Stress Regulate the Resting-State Activity in mPFC

Jiesi Wang; Wei Zhang; Hang Xu; Bart Ellenbroek; Jiajie Dai; Li Wang; Chaogan Yan; Weiwen Wang

doi:10.34133/research.0264

The Changes of Histone Methylation Induced by Adolescent Social Stress Regulate the Resting-State Activity in mPFC

Research (Wash D C). 2023 Oct 31:6:0264. doi: 10.34133/research.0264. eCollection 2023.

Authors

Jiesi Wang¹, Wei Zhang^{1

2}, Hang Xu¹, Bart Ellenbroek³, Jiajie Dai^{1

2}, Li Wang^{1

2}, Chaogan Yan^{2

4

4}, Weiwen Wang^{1

2

4}

Affiliations

¹ CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
² Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
³ School of Psychology, Victoria University of Wellington, Kelburn, Wellington 6012, New Zealand.
⁴ CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.

Abstract

Early-life stress can lead to sustained alterations in regional resting-state brain functions, but the underlying molecular mechanism remains unclear. Stress can also induce sustained changes in epigenetic modifications across brain regions, which are not limited to a few genes; rather, they often tend to produce global levels of change. The functional implication of these changes also remains to be elucidated. We hypothesize that global epigenetic changes may partly modulate the resting-state functions of brain regions to influence behavior. To test this hypothesis, we used an adolescent social stress (ASS) model in mice and examined the relationship between epigenetic modifications and regional resting-state brain activity using resting-state functional magnetic resonance imaging (rs-fMRI). The results showed that, compared to the control mice, the stressed mice showed increased anxiety and social avoidance behaviors and greater levels of dimethylation of histone H3 at lysine 9 (H3K9me2) in the medial prefrontal cortex (mPFC). In addition, the resting-state activity represented by the amplitude of low-frequency fluctuation (ALFF) was significantly lower in the mPFC of stressed mice. To verify the relationship of H3K9me2 and ALFF, the specific inhibition of H3Kme2 was performed by using the drug UNC0642, which reversed the anxiety behavior induced by ASS and significantly increase the ALFF value of mPFC in both normal and ASS animals. Our study is the first to report an association between histone modifications and rs-fMRI findings, providing a new perspective for understanding of the significance of regional brain epigenetic changes and a possible molecular explanation for rs-fMRI findings.