Imipramine Treatment and Resiliency Exhibit Similar Chromatin Regulation in the Mouse Nucleus Accumbens in Depression Models
Open accessAbstract
Although it is a widely studied psychiatric syndrome, major depressive disorder remains a poorly understood illness, especially with regard to the disconnect between treatment initiation and the delayed onset of clinical improvement. We have recently validated chronic social defeat stress in mice as a model in which a depression-like phenotype is reversed by chronic, but not acute, antidepressant administration. Here, we use chromatin immunoprecipitation (ChIP)-chip assays--ChIP followed by genome wide promoter array analyses--to study the effects of chronic defeat stress on chromatin regulation in the mouse nucleus accumbens (NAc), a key brain reward region implicated in depression. Our results demonstrate that chronic defeat stress causes widespread and long-lasting changes in gene regulation, including alterations in repressive histone methylation and in phospho-CREB (cAMP response element-binding protein) binding, in the NAc. We then show similarities and differences in this regulation to that observed in another mouse model of depression, prolonged adult social isolation. In the social defeat model, we observed further that many of the stress-induced changes in gene expression are reversed by chronic imipramine treatment, and that resilient mice-those resistant to the deleterious effects of defeat stress-show patterns of chromatin regulation in the NAc that overlap dramatically with those seen with imipramine treatment. These findings provide new insight into the molecular basis of depression-like symptoms and the mechanisms by which antidepressants exert their delayed clinical efficacy. They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress.
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H3K9me2 and H3K27me3 are repressive in the gene promoter region in response to stress.
“Other forms of histone methylation include H3K9me2 and H3K27me3, are repressive in the gene promoter region in response to stress.167,168”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [167]
The Results section reports stress-related changes in dimethylK9/K27-H3 at gene promoters in mouse nucleus accumbens and says increases would be expected to decrease transcription. This supports the repressive-promoter point for H3K9me2, but the paper examines dimethylated K27, not the specifically claimed H3K27me3 (trimethylated K27); it also frames reduced transcription as expected rather than directly demonstrated. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMolecular studies have identified similarities in chromatin remodeling and transcriptional activation between resilient and antidepressant-treated mice, providing new information about therapeutic targets.
“In addition, molecular studies have identified similarities in chromatin remodeling29,30 and transcriptional activation31 between resilient and antidepressant-treated mice, providing new information about therapeutic targets.”
From A standardized protocol for repeated social defeat stress in mice (2011) · cites this paper as [30]
Resilience to chronic social defeat stress is associated with many unique changes in gene expression and chromatin modifications in specific brain regions that are not seen in susceptible animals.
“resilience to chronic social defeat stress is associated with large numbers of unique changes in gene expression and chromatin modifications in specific brain regions that are not seen in susceptible animals24, 57.”
From Neurobiology of resilience (2012) · cites this paper as [57]
There is significant overlap between genes regulated in resilience and those regulated by chronic antidepressant treatment of susceptible individuals.
“there is significant overlap between genes that are regulated in resilience and those that are regulated by chronic antidepressant treatment of susceptible individuals57”
From Neurobiology of resilience (2012) · cites this paper as [57]
Genome-wide studies in the chronic social defeat paradigm have identified gene expression changes and chromatin modifications in the ventral tegmental area and nucleus accumbens that occur uniquely in resilience.
“genome–wide studies in the chronic social defeat paradigm have identified a range of gene expression changes and chromatin modifications in VTA and NAc that occur uniquely in resilience24, 57”
From Neurobiology of resilience (2012) · cites this paper as [57]
There is increased repressive trimethylation along the promoter region of Rac1 after social isolation stress.
“Similarly, there is increased repressive trimethylation along the promoter region of Rac1 after social isolation stress [142].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [142]
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ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses
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- Authors
- Wilkinson, M. B., Xiao, G., Kumar, A., LaPlant, Q., Renthal, W., Sikder, D., Kodadek, T. J., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Central Food Technological Research Institute (IN)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Nestler, E. J.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-06-17
- Volume
- 29
- Issue
- 24
- Pages
- 7820-7832
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2717944
- OpenAlex
- W2064804693
- Cited by
- 262
- References
- 100
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 9 · 2023: 9 · 2022: 13 · 2021: 14 · 2020: 11 · 2019: 11 · 2018: 10 · 2017: 18 · 2016: 23 · 2015: 9 · 2014: 32 · 2013: 16 · 2012: 26
- FWCI
- 19.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (R01MH051399, P50MH066172)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- imipramine, chronic social defeat stress, depression, nucleus accumbens, chromatin regulation, histone methylation, CREB phosphorylation, social isolation, resilience, gene expression, chronic stress, antidepressant mechanism
- MeSH terms
- Animals, Antidepressive Agents, Tricyclic, Behavior, Animal, Chromatin, Depression, Disease Models, Animal, Dominance-Subordination, Histones, Imipramine, Male, Methylation, Mice, Inbred C57BL, Nucleus Accumbens, Social Isolation, Gene Expression, Chromatin Immunoprecipitation, CREB-Binding Protein, Mice, Genome-Wide Association Study
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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.
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