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Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition
Open accessAbstract
Chronic social defeat stress in mice significantly decreases subsequent social interactions and induces other depression-like behaviors. Here we measured and manipulated levels of acetylated histone H3 (acH3), a chromatin mark of transcriptional activation, in the hippocampus and amygdala after ten continuous days of social defeat stress in male C57/Bl6J mice. This form of social stress causes a transient increase, followed by a persistent decrease, in the levels of acH3 in hippocampus. By comparison, increased acH3 in amygdala was more robust but also highly transient. The persistent decrease in acH3 in hippocampus may be pathological, since it is reversed by chronic fluoxetine administration. Consistent with this hypothesis, infusion of a histone deacetylase (HDAC) inhibitor MS-275 (100 μM) into hippocampus reverses a defeat-induced deficit in sucrose preference, although it does not restore social interaction behavior. Next, different forms of social enrichment were examined with or without hippocampal infusion of MS-275. After social stress, simple pair-housing with another male C57, or female C57, mouse does not reverse social avoidance. However, when HDAC inhibitors are infused into hippocampus during social housing with another male, social avoidance is attenuated. Interestingly, social avoidance is reversed when MS-275 is infused directly into amygdala. Together, these findings further support the antidepressant potential of HDAC inhibitors, and indicate that temporally overlapping environmental and molecular events are required to optimally reverse specific stress-induced behavioral symptoms.
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“Histone acetylation changes, primarily mediated by HDAC, impact the stress response, depression-like behavior, and antidepressant effects.104,127–129”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [127]
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“In depression-related models, reduced acetylation at sites such as H3K9ac and H4K12ac has been associated with decreased expression of key mood-regulating genes, including brain-derived neurotrophic factor (BDNF) and the serotonin transporter (SLC6A4) (Covington et al., 2011; Schroeder et al., 2007).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Covington et al., 2011
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“the injection of an HDAC inhibitor into the amygdala reversed social avoidance.127”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [127]
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“Transiently increased H3K14 acetylation in the amygdala of mice followed by chronic social defeat stress.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [127]
In the citing paper
“we have shown that susceptible mice also avoid non–aggressive C57BL6/J littermates, and that such social avoidance is essentially permanent—it persists for >6 months—despite housing with non–aggressive littermates, suggesting that it does reflect a maladaptive response36, 38.”
From Neurobiology of resilience (2012) · cites this paper as [38]
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Metadata
- Authors
- Covington, H. E., Vialou, V. F., LaPlant, Q., Ohnishi, Y. N., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Nestler, Eric J.
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 493
- Issue
- 3
- Pages
- 122-126
- ISSN
- 0304-3940 (ISSN-L)
- PMC
- PMC3074929
- OpenAlex
- W2052682553
- Cited by
- 178
- References
- 25
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 15 · 2023: 12 · 2022: 6 · 2021: 17 · 2020: 10 · 2019: 16 · 2018: 13 · 2017: 15 · 2016: 14 · 2015: 10 · 2014: 15 · 2013: 16 · 2012: 8
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (P50MH066172)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- histone deacetylase inhibition, entinostat, acetylated histone H3, chronic social defeat stress, depression-like behavior, social avoidance, hippocampus, amygdala, fluoxetine, social enrichment, antidepressant effects, chromatin acetylation
- MeSH terms
- Animals, Antidepressive Agents, Benzamides, Depression, Female, Hippocampus, Histone Deacetylases, Interpersonal Relations, Male, Mice, Inbred C57BL, Motor Activity, Pyridines, Stress, Psychological, Mice, Histone Deacetylase Inhibitors
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