Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens
Open accessAbstract
Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.
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In mice subjected to chronic stress and exhibiting severe depressive behavior, DNMT3A levels were higher in the nucleus accumbens than in controls.
“In mice that were subjected to chronic stress and exhibiting severe depressive behavior, DNMT3A levels were found to be higher in the nucleus accumbens (NAc) than controls.99”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [99]
The Results section (‘DNA methylation in NAc regulates depression-like behavior’; page not provided) reports increased Dnmt3a mRNA in the nucleus accumbens after chronic social defeat stress, a model that induces depressive-like behaviors. It does not say the mice whose levels were measured exhibited severe depressive behavior or that the increase was specific to such mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredManipulation of enzymes that control histone acetylation or deacetylation or DNA methylation in the nucleus accumbens modifies drug behavioral responses, supporting their relevance to drug reward and SUDs.
“Moreover, the manipulation of enzymes that control histone acetylation or deacetylation or DNA methylation in the nucleus accumbens modifies drug behavioral responses, supporting their relevance to drug reward and SUDs 111,112 .”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [112]
Dnmt3a has been implicated in rewarding behavior and neuronal plasticity in the adult mouse nucleus accumbens.
“Dnmt3a has been implicated in rewarding behavior and neuronal plasticity in the adult mouse accumbens [62].”
From Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice (2011) · cites this paper as [62]
Chronic intra-NAc DNMT inhibition restores social interaction.
“CSDS upregulates transcriptional repressor Dnmt3a in the NAc and chronic intra-NAc DNMT inhibition restores social interaction [143].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [143]
CSDS upregulates transcriptional repressor Dnmt3a in the NAc.
“CSDS upregulates transcriptional repressor Dnmt3a in the NAc and chronic intra-NAc DNMT inhibition restores social interaction [143].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [143]
Pro-susceptibility Dnmt3a overexpression or constitutively active IKK both increase MSN spine density.
“Pro-susceptibility Dnmt3a overexpression [143] or constitutively active IκB kinase (IKK) [156, 157] both increase MSN spine density.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [143]
In mice exposed to chronic stress, Dnmt3a levels in the nucleus accumbens were higher than in control animals.
“In mice exposed to chronic stress, Dnmt3a levels in the nucleus accumbens were higher than in control”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [80]
DNMT play a role in depression in animals.
“DNMT play a role in depression in animals.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [80]
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- Authors
- LaPlant, Q., Vialou, V., Covington, H. E., Dumitriu, D., Feng, J., Warren, B. L., Maze, I., Dietz, D. M., Watts, E. L., Iñiguez, S. D., Koo, J. W., Mouzon, E., Renthal, W., Hollis, F., Wang, H., Noonan, M. A., Ren, Y., Eisch, A. J., Bolaños, C. A., Kabbaj, M., Xiao, G., Neve, R. L., Hurd, Y. L., Oosting, R. S., Fan, G., Morrison, J. H., & Nestler, E. J.
- Affiliations
- The University of Texas at Dallas (US)
- Icahn School of Medicine at Mount Sinai (US)
- Florida State University (US)
- The University of Texas Southwestern Medical Center (US)
- Massachusetts Institute of Technology (US)
- Utrecht University (NL)
- University of California, Los Angeles (US)
- Corresponding author
- Nestler, Eric J
- ORCID
- LaPlant, Quincey
- Vialou, Vincent
- Covington, Herbert E
- Dumitriu, Dani
- Feng, Jian
- Warren, Brandon L
- Maze, Ian
- Dietz, David M
- Iñiguez, Sergio D
- Koo, Ja Wook
- Mouzon, Ezekiell
- Renthal, William
- Hollis, Fiona
- Wang, Hui
- Ren, Yanhua
- Eisch, Amelia J
- Kabbaj, Mohamed
- Xiao, Guanghua
- Neve, Rachael L
- Hurd, Yasmin L
- Morrison, John H
- Nestler, Eric J
- Venue
- Nature Neuroscience
- Published
- 2010-08-22
- Volume
- 13
- Issue
- 9
- Pages
- 1137-1143
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2928863
- OpenAlex
- W2121423419
- Cited by
- 612
- References
- 49
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 18 · 2023: 20 · 2022: 36 · 2021: 39 · 2020: 31 · 2019: 47 · 2018: 35 · 2017: 48 · 2016: 46 · 2015: 49 · 2014: 69 · 2013: 54 · 2012: 43
- FWCI
- 19.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (R37AG006647)
- National Institute of Mental Health (F30MH083402, P50MH066172)
- National Institute on Drug Abuse (R33DA027592, R21DA027592, P01DA008227, R01DA014133)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- DNMT3A, DNA methylation, nucleus accumbens, cocaine reward, social defeat stress, dendritic spine plasticity, emotional behavior, depression, antidepressant-like effects, chronic cocaine use
- MeSH terms
- DNA Methyltransferase 3A, Animals, Chronic Disease, Cocaine, Depression, DNA (Cytosine-5-)-Methyltransferases, Dominance-Subordination, Emotions, Gene Expression Regulation, Male, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Nucleus Accumbens, Stress, Psychological, Rats, Sprague-Dawley, Dopamine Uptake Inhibitors, DNA Methylation, Rats, Long-Evans, Dendritic Spines, Mice, Rats
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