Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior

Ashley E. Lepack, Rosemary C. Bagot, Catherine J. Peña, Yong Hwee E. Loh, Lorna A. Farrelly, Yang Lu, Samuel K. Powell, Zachary S. Lorsch, Orna Issler, Hannah M. Cates, Carol A. Tamminga, Henrik Molina, Li Shen, Eric J. Nestler, C. David Allis, Ian Maze

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Human major depressive disorder (MDD), along with related mood disorders, is among the world's greatest public health concerns; however, its pathophysiology remains poorly understood. Persistent changes in gene expression are known to promote physiological aberrations implicated in MDD. More recently, histone mechanisms affecting cell type- and regional-specific chromatin structures have also been shown to contribute to transcriptional programs related to depressive behaviors, as well as responses to antidepressants. Although much emphasis has been placed in recent years on roles for histone posttranslational modifications and chromatin-remodeling events in the etiology of MDD, it has become increasingly clear that replication-independent histone variants (e.g., H3.3), which differ in primary amino acid sequence from their canonical counterparts, similarly play critical roles in the regulation of activity-dependent neuronal transcription, synaptic connectivity, and behavioral plasticity. Here, we demonstrate a role for increased H3.3 dynamics in the nucleus accumbens (NAc) - a key limbic brain reward region - in the regulation of aberrant social stress-mediated gene expression and the precipitation of depressive-like behaviors in mice. We find that molecular blockade of these dynamics promotes resilience to chronic social stress and results in a partial renormalization of stressassociated transcriptional patterns in the NAc. In sum, our findings establish H3.3 dynamics as a critical, and previously undocumented, regulator of mood and suggest that future therapies aimed at modulating striatal histone dynamics may potentiate beneficial behavioral adaptations to negative emotional stimuli.

Original languageEnglish (US)
Pages (from-to)12562-12567
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


  • Chronic social defeat stress
  • Depression
  • H3.3
  • Histone dynamics
  • Nucleus accumbens


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