Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors
Open accessAbstract
Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region. We show decreased Tet1 expression in NAc in stress-susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after conditional deletion of Tet1 and found that immune-related genes are the most highly dysregulated. Moreover, many of these genes are also upregulated in the NAc of resilient mice after chronic social defeat stress. These findings reveal a novel role for TET1, an enzyme important for DNA hydroxymethylation, in the brain's reward circuitry in modulating stress responses in mice. We also identify a subset of genes that are regulated by TET1 in this circuitry. These findings provide new insight into the pathophysiology of depression, which can aid in future antidepressant drug discovery efforts.
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Tet1 is decreased in the NAc of susceptible mice.
“Tet1 is decreased in the NAc of susceptible mice.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [145]
Tet1 overexpression induces a resilience-like NAc gene expression profile.
“However, Tet1 overexpression induces a resilience-like NAc gene expression profile [145].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [145]
NAc Tet1 knockout increases sucrose preference and social interaction in stressed mice.
“Paradoxically, NAc Tet1 knockout increases sucrose preference and social interaction in stressed mice.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [145]
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The molecular and cellular mechanisms of depression: a focus on reward circuitry
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- Authors
- Feng, J., Pena, C. J., Purushothaman, I., Engmann, O., Walker, D., Brown, A. N., Issler, O., Doyle, M., Harrigan, E., Mouzon, E., Vialou, V., Shen, L., Dawlaty, M. M., Jaenisch, R., & Nestler, E. J.
- Affiliations
- Florida State University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Albert Einstein College of Medicine (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Nestler, Eric J
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2017-01-11
- Volume
- 42
- Issue
- 8
- Pages
- 1657-1669
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC5518912
- OpenAlex
- W2579741055
- Cited by
- 58
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 10 · 2021: 6 · 2020: 9 · 2019: 9 · 2018: 8
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Hope for Depression Research Foundation
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (P50MH096890, R01MH051399)
- National Institute on Drug Abuse (T32DA007135)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- TET1, nucleus accumbens, depression, anxiety-like behavior, chronic social defeat stress, DNA hydroxymethylation, epigenetics, antidepressant-like effects, immune-related genes, stress response, reward systems, conditional knockout
- MeSH terms
- Animals, Anxiety, Behavior, Animal, Depression, Disease Models, Animal, DNA-Binding Proteins, Male, Nucleus Accumbens, Proto-Oncogene Proteins, Stress, Psychological, Up-Regulation, Gene Expression, Mice, Knockout, Mice
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