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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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“Some of the postnatal examples are findings of decreased promotor methylation of rat hippocampal GR exon 17 and hypothalamic estrogen receptor alpha (ERa) genes associated with low levels of maternal care [93,94], increased promotor methylation of GR 1F in fetal blood samples of depressed mothers [95] and increased me…”
BackgroundKordi-Tamandani, D. M., Mojahed, A., Sahranavard, R., & Najafi, M. (2014) · Pharmacology · doi:10.1159/000368083 · Cited by 12
Li, Q., Cui, J., Chen, F., Zhang, X., & Li, L. (2016) · Neuroscience Bulletin · doi:10.1007/s12264-016-0023-z · Cited by 12
Barker, V., Bois, C., Neilson, E., Johnstone, E. C., Owens, D. G. C., Whalley, H. C., McIntosh, A. M., & Lawrie, S. M. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2016.04.028 · Cited by 14
Clinton, S. M., Shupe, E. A., Glover, M. E., Unroe, K. A., McCoy, C. R., Cohen, J. L., & Kerman, I. A. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15158 · Cited by 15
Lauby, S. C., Fleming, A. S., & McGowan, P. O. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.021 · Cited by 14
Dean, D., Madrid, A., Planalp, E. M., Moody, J. F., Papale, L. A., Knobel, K. M., Wood, E. K., McAdams, R. M., Coe, C. L., Goldsmith, H. H., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-91642-0 · Cited by 12
Epigenetic‐Imprinting Changes Caused by Neonatal Fasting Stress Protect From Future Fasting Stress
Jiang, Y., Denbow, C. J., Meiri, N., & Denbow, D. M. (2015) · Journal of Neuroendocrinology · doi:10.1111/jne.12333 · Cited by 12
Environmental influences on the female epigenome and behavior
Keller, S. M., & Roth, T. L. (2016) · Current Zoology · doi:10.1093/eep/dvw007 · Cited by 12
“behavior however was different in females that had been exposed to maltreatment such that previously maltreated dams displayed more anxiety-related behaviors during the last 3 days of pregnancy [119].”
BackgroundInfluentialSelf-citationGibb, R. L., & Kovalchuk, A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804036-2.00001-7 · Cited by 19
Burenkova, O. V., & Grigorenko, E. L. (2024) · Developmental Psychobiology · doi:10.1002/dev.22479 · Cited by 11
Unlocking the epigenome: Stress and exercise induced Bdnf regulation in the prefrontal cortex
Campbell, T. S., Donoghue, K. M., & Roth, T. L. (2024) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2024.107353 · Cited by 13
Self-citationImpact of acute stress exposure on genome-wide DNA methylation
Miller, M., McAfee, C. A., Brown, R., Sears, S., Krautkramer, C., Gogia, R., Wylie, D., Josephs, R. A., & Champagne, F. A. (2025) · Scientific Reports · doi:10.1038/s41598-025-09299-y · Cited by 10
Transgenerational effects of environmental enrichment on repetitive motor behavior development
Bechard, A. R., & Lewis, M. H. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.04.005 · Cited by 11
“Repetitive motor behaviors are most strongly associated with ASD, for which they are diagnostic.”
Oxytocin receptor genes moderate BDNF epigenetic methylation by childhood trauma
Lee, H. S., Kwon, A., & Lee, S. H. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.03.020 · Cited by 12
Gamma-Aminobutyric Acid Involvement in Depressive Illness
Anisman, H., Merali, Z., & Poulter, M. O. (2012) · Frontiers in neuroscience · doi:10.1201/b12215-5 · Cited by 11
Jamshidi, E., Boström, A. E. D., Wilczek, A., Nilsonne, Å., Åsberg, M., & Jokinen, J. (2023) · Cells · doi:10.3390/cells12030350 · Cited by 12
“On the other hand, no differences in circulating BDNF were evinced in a systematic review of studies comparing whole-blood-derived gene expression levels of psychiatric patients with a history of suicidal attempts with non-suicidal controls [24].”
BackgroundIncreased susceptibility to mild neonatal stress in MTHFR deficient mice
Kezurer, N., Galron, D., & Golan, H. M. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.07.037 · Cited by 12
Fear in love: attachment, abuse, and the developing brain.
Sullivan, R. M., & Lasley, E. N. (2010) · Europe PMC (PubMed Central) · Cited by 11
Womersley, J. S., Seedat, S., & Hemmings, S. M. J. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-0062-9 · Cited by 11
“Furthermore, animal studies have suggested that chronic stress impacts the epigenetic regulation of BDNF with a model of infant maltreatment associated with higher BDNF DNA methylation in the prefrontal cortex, persisting into adulthood (Roth et al. 2009).”
BackgroundChampagne, F. A. (2017) · Palgrave Macmillan UK eBooks · doi:10.1057/978-1-137-52879-7_10 · Cited by 11
Psychobiological Consequences of Child Maltreatment
Heim, C. C. (2018) · Child maltreatment solutions network · doi:10.1007/978-3-319-72589-5_2 · Cited by 11
Epigenetics of Aggressive Behavior
Mustafin, R. N., Kazantseva, A. V., Enikeeva, R. F., Davydova, Y. D., Karunas, A. S., Malykh, S. B., & Хуснутдинова, Э. К. (2019) · Russian Journal of Genetics · doi:10.1134/s1022795419090096 · Cited by 11
“Stress exposure of rats within the first week after birth also caused changes in the methylation of the BDNF gene in the prefrontal cortex, and these epigenetic changes were transgenerationally transmitted [31].”
BackgroundDwivedi, Y. (2012) · CRC Press eBooks · doi:10.1201/b12215-10 · Cited by 11
McGowan, P. O. (2014) · Advances in neurobiology · doi:10.1007/978-1-4939-1372-5_17 · Cited by 11
“In the previous section, we discussed evidence from our studies of widespread but specific epigenetic and transcriptional alterations of the GR gene extending far beyond the GR promoter associated with differences in maternal care (McGowan et al. 2011; Murgatroyd et al. 2009; Roth et al. 2009; Zhang et al. 2010).”
BackgroundDevelopmental Neurobiology of the Rat Attachment System and Its Modulation by Stress
Bisaz, R., & Sullivan, R. M. (2012) · Behavioral Sciences · doi:10.3390/bs2020079 · Cited by 12
“In this neonatal stress paradigm rat mothers were stressed by providing them with insufficient bedding to build a nest, resulting in frequent nest building, trampling and rough handling of the pups as well as decreased nursing, which nevertheless manifested in none or only modest reduction in the pups body weight gain…”
BackgroundBreast-Feeding in Infancy and Major Depression in Adulthood: A Retrospective Analysis
Peus, V., Redelin, E., Scharnholz, B., Paul, T., Gass, P., Deuschle, P., Lederbogen, F., & Deuschle, M. (2012) · Psychotherapy and Psychosomatics · doi:10.1159/000331777 · Cited by 11
Balasubramanian, P., Subramanian, M., Nuñez, J. L., MohanKumar, S. M. J., & MohanKumar, P. S. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.12.018 · Cited by 11
Neuroimaging in Adolescents: Post-Traumatic Stress Disorder and Risk for Substance Use Disorders
Etami, Y., Lildharrie, C., Manza, P., Wang, G., & Volkow, N. D. (2023) · Genes · doi:10.3390/genes14122113 · Cited by 11
Rice, R. C., Gil, D. V., Baratta, A. M., Frawley, R. R., Hill, S. Y., Farris, S. P., & Homanics, G. E. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100603 · Cited by 12
“In a maternal maltreatment model of early life stress in rats, increased Bdnf DNA methylation in PFC persisted from early life stress dams to their offspring (Roth et al., 2009).”
Background
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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