CoChat
Sign Up
Cited by 178Histone Deacetylase Inhibitors ResearchTreatment of Major DepressionStress Responses and Cortisol

Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition

Open access
Covington, Herbert E., Vialou, Vincent F., LaPlant, Quincey, Ohnishi, Yoshinori N., Nestler, Eric J.·2011·Neuroscience Letters
DOI 10.1016/j.neulet.2011.02.022PMC PMC3074929
Open this paper in CoChat — free account

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.neulet.2011.02.022

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Histone acetylation changes, primarily mediated by HDAC, impact the stress response, depression-like behavior, and antidepressant effects.

    “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]

    The Abstract and Discussion report that social defeat changed histone H3 acetylation in male mice and that HDAC inhibition produced specific antidepressant-like effects. The paper does not establish that histone acetylation changes are primarily mediated by HDACs; its findings are also limited to particular brain regions and behavioral measures. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In depression-related models, reduced acetylation at H3K9ac and H4K12ac is associated with decreased expression of BDNF and SLC6A4.

    “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

    The Discussion reports a prolonged reduction in hippocampal acetylated H3 after repeated social defeat in mice, supporting the general link between a depression-related model and reduced histone acetylation. The Methods specify that the study examined H3K14 acetylation, not H3K9ac or H4K12ac; the paper does not report an associated decrease in BDNF or SLC6A4 expression. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Injection of an HDAC inhibitor into the amygdala reversed social avoidance.

    “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]

  • H3K14 acetylation was transiently increased in the amygdala of mice following chronic social defeat stress.

    “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]

  • Social avoidance in susceptible mice is likely maladaptive because it also occurs toward non-aggressive littermates and persists for more than six months despite housing with non-aggressive littermates.

    “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]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

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.
ORCID
Venue
Neuroscience Letters
Publisher
Elsevier BV
Published
2011-04
Volume
493
Issue
3
Pages
122-126
ISSN
0304-3940 (ISSN-L)
DOI
10.1016/j.neulet.2011.02.022
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
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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 › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review