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Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene
Open accessAbstract
Background Childhood maltreatment and early trauma leave lasting imprints on neural mechanisms of cognition and emotion. Using a rat model of infant maltreatment by a caregiver, we investigated whether early-life adversity leaves lasting epigenetic marks at the Brain-derived Neurotrophic Factor (BDNF) gene in the CNS. Methods During the first postnatal week, we exposed infant rats to stressed caretakers that predominately displayed abusive behaviors. We then assessed DNA methylation patterns and gene expression throughout the life span, as well as DNA methylation patterns in the next generation of infants. Results Early maltreatment produced persisting changes in methylation of BDNF DNA that caused altered BDNF gene expression in the adult prefrontal cortex. Furthermore, we observed altered BDNF DNA methylation in offspring of females that had previously experienced the maltreatment regimen. Conclusions These results highlight an epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect.
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“Furthermore, the findings suggested germ-line inheritance because cross-fostering could not completely erase these DNA methylation changes.”
From Biological Embedding of Early-Life Adversity and a Scoping Review of the Evidence for Intergenerational Epigenetic Transmission of Stress and Trauma in Humans (2023) · cites this paper as [73]
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“Other animal findings also suggested ELS/CT-related epigenetic changes in the CNS growth and differentiation-related BDNF gene expression (407), while in a genome-wide blood DNA methylation analysis study by Houtepen et al. (408), a locus in the Kit ligand gene (KITLG;”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [407]
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“Early-life maltreatment of infant rats produced persistent changes in Bdnf DNA methylation that were passed to the next generation by maltreated mothers [73].”
In the citing paper
“Infant maltreatment increases DNA methylation and reduces BDNF gene expression in the PFC (191).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [191]
In the citing paper
“Differential levels of DNA methylation of genes related to stress reactivity have already been associated with PTSD and early life stress [93-95].”
From Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial (2014) · cites this paper as [94]
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“In a related study, adult rats exposed to mistreatment at an early age exhibited higher levels of DNA methylation at CpG sites within the Bdnf promoter as well as decreased levels of Bdnf mRNA.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [124]
In the citing paper
“ELS results in hippocampal hypermethylation at the promoter regions of genes related to the stress axis and brain development, including glucocorticoid receptor (NR3c1) region 17 29–31 and brain derived neurotrophic factor (BDNF) region IV32–34.”
From Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice (2017) · cites this paper as [32]
In the citing paper
“as compared to average reported increases for the same regions resulting from early-life stress of 95%32–34 and 135%29, 30, 47, respectively”
From Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice (2017) · cites this paper as [32]
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“For example, adverse environments early in life result in stable pathological changes in methylation and gene function in the adult [6,7,8,9,10] that are reversible with epigenetic drugs [11,12].”
BackgroundDNA methylation, early life environment, and health outcomes
Mitchell, C., Schneper, L. M., & Notterman, D. A. (2016) · Pediatric Research · doi:10.1038/pr.2015.193 · Cited by 146
Dandi, Ε., Kalamari, A., Touloumi, O., Lagoudaki, R., Nousiopoulou, E., Simeonidou, C., Spandou, E., & Tata, D. Α. (2018) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2018.03.003 · Cited by 154
Stress responses and the mesolimbic dopamine system: Social contexts and sex differences
Trainor, B. C. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.08.013 · Cited by 138
“There is also growing interest in how the social environment during development impacts the brain and behavior (Marler et al. 2003; Roth et al. 2009; Bales et al. 2011).”
Stress and Anxiety Across the Lifespan: Structural Plasticity and Epigenetic Regulation
Hunter, R. G., & McEwen, B. S. (2013) · Epigenomics · doi:10.2217/epi.13.8 · Cited by 142
Learned helplessness and social avoidance in the Wistar-Kyoto rat
Nam, H., Clinton, S. M., Jackson, N. L., & Kerman, I. A. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00109 · Cited by 153
“…1957; Meaney et al., 1989; Viau et al., 1993; Bhatnagar and Meaney, 1995), while MS180 typically elicits several negative behavioral, neuroendocrine, and neurobiological effects in other rat strains (Ladd et al., 2000; Huot et al., 2001; Holmes et al., 2005; Aisa et al., 2009; Roth et al., 2009).”
BackgroundMethodDiverse Epigenetic Mechanisms of Human Disease
Brookes, E., & Shi, Y. (2014) · Annual Review of Genetics · doi:10.1146/annurev-genet-120213-092518 · Cited by 145
Perinatal programming of emotional brain circuits: an integrative view from systems to molecules
Bock, J., Rether, K., Gröger, N., Xie, L., & Braun, K. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00011 · Cited by 152
“As adults the maltreated rats displayed persisting changes in the methylation of BDNF DNA causing alterations in BDNF gene expression (Roth et al., 2009).”
BackgroundGore, A. C., Walker, D. M., Zama, A. M., Armenti, A. E., & Uzumcu, M. (2011) · Molecular Endocrinology · doi:10.1210/me.2011-1210 · Cited by 141
“Lifelong epigenetic changes in Esr1 induced by perinatal EDC Based on our observation of long-lasting effects of MXC and EB on Esr1 gene expression, together with current literature suggesting that expression of Esr1 is epigenetically regulated in the hypothalamus (28, 30, 48, 49), we found that methylation at three s…”
BackgroundPaternal social enrichment effects on maternal behavior and offspring growth
Rahia Mashoodh, A., Franks, B., Curley, J. P., & Champagne, F. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121083109 · Cited by 140
“BNDF plays a critical role in neuronal and behavioral plasticity, and reduced nurturing behaviors in postpartum rats are associated with decreased BDNF mRNA levels (29).”
BackgroundInfluentialRegulation of chromatin structure in memory formation
Roth, T. L., & Sweatt, J. D. (2009) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2009.05.011 · Cited by 138
Self-citationHing, B., Sathyaputri, L., & Potash, J. B. (2018) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32616 · Cited by 137
“Their methylation levels remained significantly higher than those in control offspring (Roth et al., 2009).”
BackgroundInfluentialNeurobiological correlates of illness progression in the recurrent affective disorders
Post, R. M., Fleming, J., & Kapczinski, F. P. (2012) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2012.02.004 · Cited by 142
Transgenerational Epigenetic Effects on Brain Functions
Bohacek, J., Gapp, K., Saab, B. J., & Mansuy, I. M. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.08.019 · Cited by 142
Gapp, K., von Ziegler, L., Tweedie‐Cullen, R. Y., & Mansuy, I. M. (2014) · BioEssays · doi:10.1002/bies.201300116 · Cited by 136
“Epigenetic processes contribute to the transmission of acquired traits Studies in rodents have shown that some epigenetic modifications in chromatin remodeling can persist and be maintained throughout life [4, 20, 21].”
BackgroundEarly Life Stress Effects on Glucocorticoid—BDNF Interplay in the Hippocampus
Daskalakis, N. P., de Kloet, E. R., Yehuda, R., Malaspina, D., & Kranz, T. M. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00068 · Cited by 141
Epigenetics and depression: return of the repressed
Dalton, V. S., Kolshus, E., & McLoughlin, D. M. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.10.028 · Cited by 142
Sánchez, M. M., McCormack, K. M., & Howell, B. (2015) · Social Neuroscience · doi:10.1080/17470919.2015.1087426 · Cited by 138
Epigenetic Mechanisms in Memory and Synaptic Function
Sultan, F. A., & Day, J. J. (2011) · Epigenomics · doi:10.2217/epi.11.6 · Cited by 133
“Epigenetic mechanisms in a several brain regions contribute to stable changes in behavior (see Figure 1 for summary), including learning and memory, drug addiction, depression and long-term responses to maternal care [66–71].”
BackgroundGenome-Wide DNA Methylation Scan in Major Depressive Disorder
Sabunciyan, S., Aryee, M. J., Irizarry, R. A., Rongione, M. A., Webster, M. J., Kaufmann, W. E., Murakami, P. N., Lessard, A., Yolken, R. H., Feinberg, A. P., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034451 · Cited by 139
“For example, early life adversity increased DNAm in Bdnf in rats [12].”
BackgroundChromatin deregulation in disease
Mirabella, A., Foster, B. M., & Bartke, T. (2015) · Chromosoma · doi:10.1007/s00412-015-0530-0 · Cited by 139
“Specifically, the expression levels of neurotrophic factor BDNF were reported to be lower in ELS mouse models (Roth et al. 2009) and in patients affected by mental disorders and exposed to childhood trauma (Ernst et al. 2005; Hashimoto et al. 2005).”
BackgroundDNA Methylation, Behavior and Early Life Adversity
Szyf, M. (2013) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2013.06.004 · Cited by 147
“Exposure of infant rats to abusive stressed caretakers produced long-lasting alterations in the state of methylation of brain derived nerve growth factor (bdnf ) gene promoter in the adult prefrontal cortex (Roth et al., 2009).”
BackgroundFinegersh, A., & Homanics, G. E. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099078 · Cited by 134
“expression [39,40]; therefore, we hypothesized that EtOH exposure alters DNA methylation at the Bdnf exon IXa CpG”
BackgroundDNA methylation analysis of BDNF gene promoters in peripheral blood cells of schizophrenia patients
Ikegame, T., Bundo, M., Sunaga, F., Asai, T., Nishimura, F., Yoshikawa, A., Kawamura, Y., Hibino, H., Tochigi, M., Kakiuchi, C., et al. (2013) · Neuroscience Research · doi:10.1016/j.neures.2013.08.004 · Cited by 129
Cognitive neuroepigenetics: A role for epigenetic mechanisms in learning and memory
Day, J. J., & Sweatt, J. D. (2010) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2010.12.008 · Cited by 137
“, 2008), whereas changes within the cortex may be particularly stable over time (Roth et al., 2009; Miller et al., 2010).”
BackgroundSelf-citationMolteni, R., Cattaneo, A., Calabrese, F., Macchi, F., Olivier, J. D. A., Racagni, G., Ellenbroek, B. A., Gennarelli, M., & Riva, M. A. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.12.014 · Cited by 129
BNDF methylation in mothers and newborns is associated with maternal exposure to war trauma
Kertes, D. A., Bhatt, S., Kamin, H. S., Hughes, D. A., Rodney, N. C., & Mulligan, C. J. (2017) · Clinical Epigenetics · doi:10.1186/s13148-017-0367-x · Cited by 131
“adulthood, the age at testing, the specific tissue source, and the BDNF loci targeted [38, 40, 41, 59].”
BackgroundDuman, E. A., & Canli, T. (2015) · Biology of Mood & Anxiety Disorders · doi:10.1186/s13587-015-0017-x · Cited by 136
“also under investigation [79], making it an ideal gene to investigate its genetic and epigenetic interactions with”
BackgroundEpigenetic Treatments for Cognitive Impairments
Day, J. J., & Sweatt, J. D. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.85 · Cited by 132
“Likewise, differences in maternal care in infants produces enduring changes in DNA methylation at several gene targets and in several brain regions (including the hippocampus) that are maintained well into adulthood (Weaver et al, 2004, 2005; Roth et al, 2009).”
BackgroundSelf-citationZheleznyakova, G. Y., Cao, H., & Schiöth, H. B. (2016) · Behavioral and Brain Functions · doi:10.1186/s12993-016-0101-4 · Cited by 131
“Moreover, the offspring derived from maltreated-females showed hypermethylation of the Bdnf in the prefrontal cortex and hippocampus, suggesting that DNA methylation modifications might be inherited across generations [42, 43].”
BackgroundChoi, C. S., Gonzales, E. L., Kim, K. C., Yang, S. M., Kim, J., Mabunga, D. F. N., Cheong, J. H., Han, S., Bahn, G. H., & Shin, C. Y. (2016) · Scientific Reports · doi:10.1038/srep36250 · Cited by 136
Prescient Human Fetuses Thrive
Sandman, C. A., Davis, E. P., & Glynn, L. M. (2011) · Psychological Science · doi:10.1177/0956797611422073 · Cited by 137
Zhu, Y., Wang, Y., Yao, R., Hao, T., Cao, J., Huang, H., Wang, L., & Wu, Y. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0782-5 · Cited by 128
“gene, and the demethylation function of TSA is not specific to the GR gene [55, 56].”
Epigenetic mechanisms underlying learning and the inheritance of learned behaviors
Dias, B. G., Maddox, S. A., Klengel, T., & Ressler, K. J. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2014.12.003 · Cited by 125
Genetic approaches to understanding post-traumatic stress disorder
Almli, L. M., Fani, N., Smith, A. K., & Ressler, K. J. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713001090 · Cited by 124
Kember, R. L., Dempster, E. L., Lee, T. H. A., Schalkwyk, L. C., Mill, J., & Fernandes, C. (2012) · Brain and Behavior · doi:10.1002/brb3.69 · Cited by 133
“Similar changes following an environmental stressor have been observed in several other genes including Bdnf (Fuchikami et al. 2009; Roth et al. 2009), Crh (Elliott et al. 2010), Dlgap2 (Chertkow-Deutsher et al. 2010), Mecp2, Cnr1, and Crhr2 (Franklin et al. 2010), suggesting that such changes may…”
BackgroundInfluentialBlaze, J., Scheuing, L., & Roth, T. L. (2013) · Developmental Neuroscience · doi:10.1159/000350716 · Cited by 123
Self-citation
Metadata
- Authors
- Roth, T. L., Lubin, F. D., Funk, A. J., & Sweatt, J. D.
- Affiliations
- University of Alabama (US)
- University of Alabama at Birmingham (US)
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 65
- Issue
- 9
- Pages
- 760-769
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3056389
- OpenAlex
- W1965636455
- Semantic Scholar
- 73b25ed907cfc11b7dfd5f2e6c7e3f05afbe7148
- Cited by
- 1,273
- References
- 75
- Citations by year
- 2026: 26 · 2025: 27 · 2024: 37 · 2023: 38 · 2022: 39 · 2021: 68 · 2020: 78 · 2019: 77 · 2018: 90 · 2017: 91 · 2016: 107 · 2015: 100 · 2014: 145 · 2013: 105 · 2012: 91
- FWCI
- 86.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG031722)
- National Institute of Mental Health (MH 57014, R01MH057014)
- National Institute of Neurological Disorders and Stroke (NS048811, F32NS048811)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- childhood adversity, child abuse, brain-derived neurotrophic factor, DNA methylation, epigenetics, transgenerational transmission, prefrontal cortex, gene expression, infant rat model, caregiver abuse, neglect
- MeSH terms
- Animals, Animals, Newborn, Cytidine, Female, Hippocampus, Injections, Intraventricular, Male, Maternal Behavior, Stress, Psychological, Gene Expression, Prefrontal Cortex, DNA Methylation, Brain-Derived Neurotrophic Factor, Rats, Long-Evans, Models, Animal, Epigenesis, Genetic, Rats
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