Epigenetic modulation of chronic anxiety and pain by histone deacetylation
Abstract
Prolonged exposure of the central amygdala (CeA) to elevated corticosteroids (CORT) facilitates long-term anxiety and pain through activation of glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF). However, the mechanisms maintaining these responses are unknown. Since chronic phenotypes can be sustained by epigenetic mechanisms, including histone modifications such as deacetylation, we tested the hypothesis that histone deacetylation contributes to the maintenance of chronic anxiety and pain induced by prolonged exposure of the CeA to CORT. We found that bilateral infusions of a histone deacetylase inhibitor into the CeA attenuated anxiety-like behavior as well as somatic and visceral hypersensitivity resulting from elevated CORT exposure. Moreover, we delineated a novel pathway through which histone deacetylation could contribute to CORT regulation of GR and subsequent CRF expression in the CeA. Specifically, deacetylation of histone 3 at lysine 9 (H3K9), through the coordinated action of the NAD+-dependent protein deacetylase sirtuin-6 (SIRT6) and nuclear factor kappa B (NFκB), sequesters GR expression leading to disinhibition of CRF. Our results indicate that epigenetic programming in the amygdala, specifically histone modifications, is important in the maintenance of chronic anxiety and pain.
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A decrease in the H3K9ac marker is influenced by stressors and may underscore the anxiety phenotype.
“Though brain regions vary between studies, both studies suggest that a decrease in the H3K9ac marker is influenced by stressors and may underscore the anxiety phenotype.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
In a rat model, delivery of increased concentrations of CORTs was shown to induce chronic anxiety.
“In a rat model, delivery of increased concentrations of CORTs was shown to induce chronic anxiety.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
TSA was found to significantly increase H3K9ac and GR expression, while decreasing CRF mRNA levels in the CeA.
“TSA, a previously mentioned HDAC inhibitor of class I and II HDACs, was found to significantly increase H3K9ac and GR expression, while decreasing CRF mRNA levels in the CeA.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
GR-ChIP-seq revealed that CORT administration reduced GR sequestering of transcription factor AP-1, an interaction that would have suppressed CRF expression via the negative feedback loop in the HPA axis.
“GR-ChIP-seq revealed that CORT administration reduced GR sequestering of transcription factor AP-1, an interaction that would have suppressed CRF expression via the negative feedback loop in the HPA axis.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
H3K9ac is a permissive mark for GR expression.
“ChIP of H3K9ac revealed a significant decrease in acetylation at the GR promoter, emphasizing the role of H3K9ac as a permissive mark for GR expression.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
Increased AP-1-mediated CRF expression is observed in CORT animals.
“Instead, increased AP-1-mediated CRF expression is observed in CORT animals (Tran et al., 2015).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
Decreased H3K9ac was observed in animals infused with CORT compared with controls infused with vehicle on staining of CeA slices.
“Decreased H3K9ac was observed in animals infused with CORT compared with controls infused with vehicle on staining of CeA slices (Tran et al., 2015).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
CORT-infused animals expressed lower levels of glucocorticoid receptors, with a 5-7 fold increase in Crf mRNA expression levels.
“This supports the finding that CORT-infused animals expressed lower levels of glucocorticoid receptors, because of the decrease in H3K9ac reported, with a 5–7 fold increase in Crf mRNA expression levels in the study by Tran et al. (2015).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
Antibody binding revealed colocalization of the HDAC sirtuin 6 (SIRT6) with GR, such that an increase in SIRT6 correlated with a decrease in GR expression.
“Further investigation through antibody binding revealed colocalization of the HDAC sirtuin 6 (SIRT6) with GR, such that an increase in SIRT6 correlated with a decrease in GR expression.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
ChIP of H3K9ac revealed a significant decrease in acetylation at the GR promoter.
“ChIP of H3K9ac revealed a significant decrease in acetylation at the GR promoter, emphasizing the role of H3K9ac as a permissive mark for GR expression.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Tran et al., 2015
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SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
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“This was accompanied by rescue of the anxiety phenotype and a reduction in SIRT6 (Tran et al., 2015).”
BackgroundInfluentialAlemany, S., Soler-Artigas, M., Cabana-Domínguez, J., Fakhreddine, D., Llonga, N., Vilar-Ribó, L., Rodríguez-Urrutia, A., Palacio, J., González-Castro, A. M., Lobo, B., et al. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04107-5 · Cited by 20 · see citing works
- Authors
- Tran, L., Schulkin, J., Ligon, C. O., & Greenwood-Van Meerveld, B.
- Affiliations
- University of Oklahoma Health Sciences Center (US)
- Georgetown University (US)
- Venue
- Molecular Psychiatry
- Published
- 2014-10-07
- Volume
- 20
- Issue
- 10
- Pages
- 1219-1231
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2074409078
- Cited by
- 148
- References
- 6
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 18 · 2020: 14 · 2019: 17 · 2018: 23 · 2017: 15 · 2016: 21 · 2015: 11 · 2014: 1
- FWCI
- 7.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002188)
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- histone deacetylation, chronic anxiety, chronic pain, central amygdala, corticosteroids, glucocorticoid receptor, corticotropin-releasing factor, SIRT6, NF-κB, histone modifications, visceral hypersensitivity, histone deacetylase inhibitors
- MeSH terms
- Adrenal Cortex Hormones, Animals, Anxiety Disorders, Behavior, Animal, Corticotropin-Releasing Hormone, Disease Models, Animal, Histone Deacetylases, Histones, Male, Pain, Rats, Inbred F344, Receptors, Glucocorticoid, Sirtuins, Rats, NF-kappa B p50 Subunit, Epigenomics, Central Amygdaloid Nucleus
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