title: Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior.
abstract: 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 stress-associated 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.
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Ashley E
authors: AE
authors: Lepack
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Rosemary C
authors: RC
authors: Bagot
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Catherine J
authors: CJ
authors: Peña
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Yong-Hwee E
authors: YE
authors: Loh
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Lorna A
authors: LA
authors: Farrelly
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Yang
authors: Y
authors: Lu
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Samuel K
authors: SK
authors: Powell
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Zachary S
authors: 0000-0002-3152-9287
authors: ZS
authors: Lorsch
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Orna
authors: O
authors: Issler
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Hannah M
authors: HM
authors: Cates
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75235.
authors: Carol A
authors: CA
authors: Tamminga
authors: The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY 10065.
authors: Henrik
authors: H
authors: Molina
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Li
authors: L
authors: Shen
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Department of Pharmacological Sciences, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Department of Psychiatry, Icahn School of Medicine, Mount Sinai, New York, NY 10029.
authors: Eric J
authors: EJ
authors: Nestler
authors: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065.
authors: C David
authors: CD
authors: Allis
authors: Department of Neuroscience, Icahn School of Medicine, Mount Sinai, New York, NY 10029; ian.maze@mssm.edu.|Friedman Brain Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Department of Pharmacological Sciences, Icahn School of Medicine, Mount Sinai, New York, NY 10029.|Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065.
authors: Ian
authors: I
authors: Maze
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D003866:Depressive Disorder / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009714:Nucleus Accumbens / Q000378:metabolism / Q000503:physiopathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics / Q000503:physiopathology*
chemical_list: D006657:Histones; D020033:Protein Isoforms
keywords: H3.3; chronic social defeat stress; depression; histone dynamics; nucleus accumbens