Histone H1x in mouse ventral hippocampus associates with, but does not cause behavioral adaptations to stress

TL;DR

This study finds that higher levels of a protein called H1x in a specific brain region are linked to stress susceptibility in mice, but increasing H1x levels alone does not cause stress-related behavioral changes.

Contribution

The study demonstrates that elevated H1x in the ventral hippocampus is associated with stress susceptibility but does not directly cause behavioral adaptations to stress.

Findings

Elevated H1x protein levels in the ventral hippocampus are uniquely expressed in stress-susceptible mice.

Overexpression of H1x in the ventral hippocampus does not lead to behavioral adaptations in mice.

H1x levels are associated with stress susceptibility but are not sufficient to drive behavioral changes.

Abstract

Prior research has identified differential protein expression levels of linker histone H1x within the ventral hippocampus (vHipp) of stress-susceptible versus stress-resilient mice. These mice are behaviorally classified based on their divergent responses to chronic social stress. Here, we sought to determine whether elevated vHipp H1x protein levels directly contribute to these diverging behavioral adaptations to stress. First, we demonstrated that stress-susceptible mice uniquely express elevated vHipp H1x protein levels following chronic stress. Given that linker histones coordinate heterochromatin compaction, we hypothesize that elevated levels of H1x in the vHipp may impede pro-resilience transcriptional adaptations and prevent development of the resilient phenotype following social stress. To test this, 8–10-week-old male C57BL/6 J mice were randomly assigned to groups undergoing 10 days of chronic social defeat stress (CSDS) or single housing, respectively. Following CSDS, mice were classified as susceptible versus resilient based on their social interaction behaviors. We synthesized a viral overexpression (OE) vector for H1x and transduced all stressed and single housed mice with either H1x or control GFP within vHipp. Following viral delivery, we conducted social, anxiety-like, and memory-reliant behavior tests on distinct cohorts of mice. We found no behavioral adaptations following H1x OE compared to GFP controls in susceptible, resilient, or single housed mice. In sum, although we confirm elevated vHipp protein levels of H1x associate with susceptibility to social stress, we observe no significant behavioral consequence of H1x OE. Thus, we conclude elevated levels of H1x are associated with, but are not singularly sufficient to drive development of behavioral adaptations to stress.

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