Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior
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Significance: Human major depressive disorder is a chronic remitting syndrome that affects millions of individuals worldwide; however, the molecular mechanisms mediating this syndrome remain elusive. Here, using a unique combination of epigenome-wide and behavioral analyses, we demonstrate a role for histone variant dynamics in the nucleus accumbens (NAc)—a critical brain center of reward and mood—contributing to stress susceptibility in mice. These studies, which also demonstrate that molecular blockade of aberrant dynamics in the NAc promotes resilience to chronic stress, promise to aid in the identification of novel molecular targets (i.e., downstream genes displaying altered expression as the result of stress-induced histone dynamics) that may be exploited in the development of more effective pharmacotherapeutics.
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Expression of activity-dependent histone variant H3.3 (H3f3b) is increased in the NAc in postmortem MDD tissue, after early life stress, and in CSDS-susceptible mice, an effect prevented in mice by environmental enrichment.
“Expression of activity-dependent histone variant H3.3 (H3f3b) is increased in the NAc in postmortem MDD tissue, after early life stress, and in CSDS-susceptible mice, an effect prevented in mice by environmental enrichment [146].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [146]
Stalling histone turnover with viral knockdown of H3.3 produces resilience after CSDS partly due to normalization of transcriptional dysregulation of genes associated with morphology and plasticity.
“Stalling histone turnover with viral knockdown of H3.3 produces resilience after CSDS partly due to normalization of transcriptional dysregulation of genes associated with morphology and plasticity [146].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [146]
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Histone Variants in Neuronal Transcription and Behavioral Regulation
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Epigenetics and pharmacoepigenetics of neuropsychiatric disorders
Cacabelos, R., Cacabelos, N., Iglesias, O.-M., Tellado, I., & Naidoo, V. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-18722-3.00020-7
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Animal models with construct validity for studying epigenetic processes in neurobehavior
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- Authors
- Lepack, A. E., Bagot, R. C., Peña, C. J., Loh, Y.-H. E., Farrelly, L. A., Lu, Y., Powell, S. K., Lorsch, Z. S., Issler, O., Cates, H. M., Tamminga, C. A., Molina, H., Shen, L., Nestler, E. J., Allis, C. D., & Maze, I.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- The University of Texas Southwestern Medical Center (US)
- Rockefeller University (US)
- Corresponding author
- Maze, Ian
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-10-18
- Volume
- 113
- Issue
- 44
- Pages
- 12562-12567
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5098673
- OpenAlex
- W2537624101
- Cited by
- 63
- References
- 25
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 5 · 2022: 8 · 2021: 7 · 2020: 3 · 2019: 9 · 2018: 4 · 2017: 4 · 2016: 1
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (P50 MH096890)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- histone H3.3, nucleus accumbens, major depressive disorder, depression-like behavior, chronic social stress, stress resilience, chromatin regulation, histone dynamics, striatum, mood regulation, gene expression
- MeSH terms
- Adult, Aged, Animals, Depressive Disorder, Female, Gene Expression Regulation, Histones, Humans, Male, Mice, Inbred C57BL, Middle Aged, Nucleus Accumbens, Stress, Psychological, Protein Isoforms, Mice, Gene Knockdown Techniques
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