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Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus
Open accessAbstract
Exposure to stressful life events during pregnancy exerts profound effects on neurodevelopment and increases the risk for several neurodevelopmental disorders including major depression. The mechanisms underlying the consequences of gestational stress are complex and remain to be elucidated. This study investigated the effects of gestational stress on depressive-like behavior and epigenetic modifications in young adult offspring. Gestational stress was induced by a combination of restraint and 24-hour light disturbance to pregnant dams throughout gestation. Depressive-like and anxiety-like behaviors of young adult offspring were examined. The expression and promoter methylation of brain derived neurotrophic factor (BDNF) were measured using RT-qPCR, Western blot, methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP). In addition, the expressions of histone deacetylases (HDACs) and acetylated histone H3 lysine 14 (AcH3K14) were also analyzed. Our results show that offspring from gestational stress dams exhibited depressive-like and anxiety-like behaviors. Biochemically, stress-offspring showed decreased expression of BDNF, increased expression of DNMT1, HDAC1, and HDAC2, and decreased expression of AcH3K14 in the hippocampus as compared to non-stress offspring. Data from MeDIP and ChIP assays revealed an increased methylation as well as decreased binding of AcH3K14 on specific BDNF promoters. Pearson analyses indicated that epigenetic changes induced by gestational stress were correlated with depressive-like and anxiety-like behaviors. These data suggest that gestational stress may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with depression.
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“Developmental stress paradigms reveal broad reductions in multiple BDNF transcript variants, increased CpG methylation at BDNF promoters, upregulation of HDAC1/2, and decreased H3K14 acetylation (Zheng et al., 2016), forming a coherent repressive chromatin profile that disrupts hippocampal plasticity and increases susceptibility to mood-related dysfunction.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Zheng et al., 2016
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“Developmental stress paradigms reveal broad reductions in multiple BDNF transcript variants, increased CpG methylation at BDNF promoters, upregulation of HDAC1/2, and decreased H3K14 acetylation (Zheng et al., 2016), forming a coherent repressive chromatin profile that disrupts hippocampal plasticity and increases susceptibility to mood-related dysfunction.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Zheng et al., 2016
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BackgroundResultInfluentialProvençal, N., Arloth, J., Cattaneo, A., Anacker, C., Cattane, N., Wiechmann, T., Röh, S., Ködel, M., Klengel, T., Czamara, D., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820842116 · Cited by 209
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“It is associated with reduced expression of the BDNF and AcH3K14 genes and increased expression of histone deacetylases in the hippocampus [395].”
Background
Metadata
- Authors
- Zheng, Y., Fan, W., Zhang, X., & Dong, E.
- Affiliations
- Second Affiliated Hospital of Chongqing Medical University (CN)
- University of Illinois Chicago (US)
- Corresponding author
- Zhang, Xianquan
- Dong, Erbo
- Venue
- Epigenetics
- Publisher
- Informa UK Limited
- Published
- 2016-02-01
- Volume
- 11
- Issue
- 2
- Pages
- 150-162
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC4846107
- OpenAlex
- W2286526924
- Cited by
- 111
- References
- 62
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 15 · 2023: 8 · 2022: 13 · 2021: 16 · 2020: 14 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 4
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epigenetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (NSFC 81271264)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- prenatal stress, maternal stress, offspring depression, anxiety-like behavior, brain-derived neurotrophic factor, epigenetic regulation, DNA methylation, histone acetylation, histone deacetylase, hippocampus, DNMT1, HDAC1, HDAC2, restraint stress, brain development, depression risk
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Acetylation, Animals, Anxiety, DNA (Cytosine-5-)-Methyltransferases, Female, Hippocampus, Histones, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, Stress, Psychological, DNA Methylation, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic, Mice, Histone Deacetylase 1, Histone Deacetylase 2
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