Histone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli
Open accessAbstract
Previous work has identified alterations in histone acetylation in animal models of drug addiction and depression. However, the mechanisms which integrate drugs and stress with changes in chromatin structure remain unclear. Here, we identify the activity-dependent class II histone deacetylase, HDAC5, as a central integrator of these stimuli with changes in chromatin structure and gene expression. Chronic, but not acute, exposure to cocaine or stress decreases HDAC5 function in the nucleus accumbens (NAc), a major brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. These findings suggest that proper balance of histone acetylation is a crucial factor in the saliency of a given stimulus and that disruption of this balance is involved in the transition from an acute adaptive response to a chronic psychiatric illness.
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Mice exposed to chronic social defeat stress showed decreased HDAC5 expression in the NAc, whereas chronic imipramine increased HDAC5 expression in the NAc.
“mice exposed to chronic social defeat stress showed decreased HDAC5 expression in the NAc, whereas chronic administration of imipramine increased HDAC5 expression in NAc,149”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [149]
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“Though the researchers investigated genes under the regulation of HDAC5 in cocainetreated mice, they did not do so in CSDS mice (Renthal et al., 2007).”
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Self-citation
- Authors
- Renthal, W., Maze, I., Krishnan, V., Covington, H. E., Xiao, G., Kumar, A., Russo, S. J., Graham, A., Tsankova, N., Kippin, T. E., Kerstetter, K. A., Neve, R. L., Haggarty, S. J., McKinsey, T. A., Bassel-Duby, R., Olson, E. N., & Nestler, E. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of California, Santa Barbara (US)
- Harvard University (US)
- Corresponding author
- Nestler, Eric J.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 56
- Issue
- 3
- Pages
- 517-529
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2104261628
- Cited by
- 599
- References
- 55
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 13 · 2023: 17 · 2022: 26 · 2021: 26 · 2020: 19 · 2019: 26 · 2018: 26 · 2017: 37 · 2016: 47 · 2015: 38 · 2014: 55 · 2013: 51 · 2012: 50
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Texas Southwestern Medical Center
- Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
- National Institute on Drug Abuse
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HDAC5, histone acetylation, epigenetic regulation, cocaine, chronic stress, nucleus accumbens, chromatin structure, gene expression, drug addiction, depression, behavioral adaptation, stimulus salience, class II HDACs
- MeSH terms
- Acetylation, Adaptation, Physiological, Animals, Chromatin, Chronic Disease, Cocaine, Disease Models, Animal, Emotions, Histone Deacetylases, Histones, Mice, Inbred C57BL, Nucleus Accumbens, Reward, Stress, Psychological, Gene Expression Regulation, Enzymologic, Dopamine Uptake Inhibitors, Cocaine-Related Disorders, Epigenesis, Genetic, Mice
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