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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]
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“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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“…between early life adversity and deficits in safety learning as well as neural alterations related to fear extinction (Kundakovic et al., 2015; Maren and Holmes, 2016; Roth et al., 2009; Wright et al., 2015), it is plausible that early life adversity impairs later fear extinction in humans.”
Neuronal plasticity: A link between stress and mood disorders
Calabrese, F., Molteni, R., Racagni, G., & Riva, M. A. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.05.014 · Cited by 315
“…(exposure of infant rats to a stressed ''abusive'' mother 30 min daily during the first postnatal week) elicited a reduction of BDNF mRNA levels in prefrontal cortex of adult offspring, which was associated with an increased methylation of the Bdnf gene on specific promoters (Roth et al., 2009).”
BackgroundEpigenetic Modifications in Stress Response Genes Associated With Childhood Trauma
Jiang, S., Postovit, L., Cattaneo, A., Binder, E. B., & Aitchison, K. J. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00808 · Cited by 288
The molecular bases of the suicidal brain
Turecki, G. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3839 · Cited by 281
Epigenetic Regulation of the BDNF Gene: Implications for Psychiatric Disorders
Boulle, F., van den Hove, D. L. A., Jakob, S. B., Rutten, B. P., Hamon, M., van Os, J., Lesch, K.-P., Lanfumey, L., Steinbusch, H. W., & Kenis, G. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.107 · Cited by 282
Epigenetic Mechanisms of Depression and Antidepressant Action
Vialou, V., Feng, J., Robison, A. J., & Nestler, E. J. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134540 · Cited by 277
“In a model of early-life stress with impaired maternal care, abnormal DNA methylation and expression patterns of BDNF in the prefrontal cortex are induced for up to two generations (146).”
BackgroundEpigenetic influence of social experiences across the lifespan
Champagne, F. A. (2010) · Developmental Psychobiology · doi:10.1002/dev.20436 · Cited by 273
“Female rat pups exposed to abusive caregiving in infancy engage in abusive caregiving toward their own offspring and F2 offspring of these F1 females had elevated levels of methylation within the BDNF promotor in the PFC and hippocampus (Roth et al., 2009).”
BackgroundNaturalistic rodent models of chronic early‐life stress
Molet, J., Maras, P. M., Avishai‐Eliner, S., & Baram, T. Z. (2014) · Developmental Psychobiology · doi:10.1002/dev.21230 · Cited by 282
The effects of early life stress on the epigenome: From the womb to adulthood and even before
Provençal, N., & Binder, E. B. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2014.09.001 · Cited by 255
Curley, J. P., & Champagne, F. A. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2015.11.001 · Cited by 279
“Lactating females rats that have experienced increased fragmented care during their postnatal development engage in a higher frequency of abusive care toward their own pups (Roth et al., 2009).”
BackgroundInfluentialNrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression
Bouvier, E., Brouillard, F., Molet, J., Claverie, D., Cabungcal, J.-H., Cresto, N., Doligez, N., Rivat, C., Do, K. Q., Bernard, C., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.144 · Cited by 248
Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression
Kang, H.-J., Kim, J.-M., Stewart, R., Kim, S.-Y., Bae, K.-Y., Kim, S.-W., Shin, I.-S., Shin, M.-G., & Yoon, J.-S. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.01.006 · Cited by 254
“Most previous research on associations between stress and epigenetic changes has been carried out in animal models (Roth et al., 2009; Uchida et al., 2011).”
BackgroundDNA methylation: A mechanism for embedding early life experiences in the genome
Szyf, M., & Bick, J. (2013) · Child Development · doi:10.1111/j.1467-8624.2012.01793.x · Cited by 251
Unternaehrer, E., Luers, P., Mill, J., Dempster, E., Meyer, A. H., Staehli, S., Lieb, R., Hellhammer, D. H., & Meinlschmidt, G. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.77 · Cited by 250
“Previous studies found lifelong and transgenerational perpetuation of changes in BDNF methylation after early-life adversity.(32) Fuchikami et al.”
BackgroundMárquez, C., Poirier, G. L., Cordero, M. I., Larsen, M. H., Groner, A., Marquis, J., Magistretti, P. J., Trono, D., & Sandi, C. (2013) · Translational Psychiatry · doi:10.1038/tp.2012.144 · Cited by 245
Roth, T. L., & David Sweatt, J. (2011) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2010.02282.x · Cited by 246
“Altogether, evidence suggests there is some type of relationship between schizophrenia and cytosine methylation (see Roth et al., 2009b for a comprehensive review of epigenetic alterations in schizophrenia).”
BackgroundMethodInfluentialSelf-citationNeurodevelopment, GABA System Dysfunction, and Schizophrenia
Schmidt, M. J., & Mirnics, K. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.95 · Cited by 243
Adverse Childhood Experiences and Suicidal Behavior
Brodsky, B. S., & Stanley, B. (2008) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2008.02.002 · Cited by 238
DNA methylation and childhood maltreatment: From animal models to human studies
Lutz, P.-E., & Turecki, G. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2013.07.069 · Cited by 236
“C IH R A uthor M anuscript C IH R A uthor M anuscript C IH R A uthor M anuscript natal days 1 to 7) to stressed, non-biological mothers (Roth and Sullivan, 2005, Roth et al., 2009).”
BackgroundMethodResultInfluentialPrenatal stress and epigenetics
Cao-Lei, L., de Rooij, S. R., King, S., Matthews, S. G., Metz, G. A. S., Roseboom, T. J., & Szyf, M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.016 · Cited by 253
The Role of Iron in Learning and Memory
Fretham, S. J. B., Carlson, E. S., & Georgieff, M. K. (2011) · Advances in Nutrition · doi:10.3945/an.110.000190 · Cited by 235
“Early life maltreatment reduces BDNF expression in the adult prefrontal cortex, an effect that can be blocked with a methylation inhibitor (77).”
BackgroundEarly adversity and adult health outcomes
Taylor, S. E., Way, B. M., & Seeman, T. E. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000411 · Cited by 249
An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
Millan, M. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.015 · Cited by 229
Comorbidity of Depression with Physical Disorders: Research and Clinical Implications
Kang, H., Kim, S. Y., Bae, K., Kim, S., Shin, I., Yoon, J., & Kim, J. (2015) · Chonnam Medical Journal · doi:10.4068/cmj.2015.51.1.8 · Cited by 240
“Of the various epigenetic mechanisms, DNA methylation is the best studied because it is regarded as a highly stable epigenetic marker.(52) The increased methylation of gene promoters, including 5-HTTLPR and BDNF, is usually associated with lowered gene function and has been associated with depression in general.”
BackgroundEpigenetics of posttraumatic stress disorder: current evidence, challenges, and future directions
Zannas, A. S., Provençal, N., & Binder, E. B. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.04.003 · Cited by 218
Epigenetics of stress adaptations in the brain
Stankiewicz, A. M., Swiergiel, A. H., & Lisowski, P. (2013) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.07.003 · Cited by 220
“…stress (Sterrenburg et al., 2012), or Bdnf promoter methylation in PFC in chronic-social-predator (Roth et al., 2011) and early maltreatment stress (Roth et al., 2009), were done on different strains or species of animals, thus can serve as a confirmation of hypothesis, but not as the strong…”
BackgroundInfluentialEarly life stress alters transcriptomic patterning across reward circuitry in male and female mice
Peña, C. J., Smith, M., Ramakrishnan, A., Cates, H. M., Bagot, R. C., Kronman, H. G., Patel, B., Chang, A. B., Purushothaman, I., Dudley, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13085-6 · Cited by 219
BDNF promoter methylation and suicidal behavior in depressive patients
Kang, H.-J., Kim, J.-M., Lee, J.-Y., Kim, S.-Y., Bae, K.-Y., Kim, S.-W., Shin, I.-S., Kim, H.-R., Shin, M.-G., & Yoon, J.-S. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.08.001 · Cited by 218
A brain-centric model of suicidal behavior
Mann, J. J., & Rizk, M. M. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20081224 · Cited by 214
Enduring psychobiological effects of childhood adversity
Ehlert, U. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.06.007 · Cited by 213
“Keeping the findings of Roth et al. (2009) in mind, it can be hypothesized that epigenetic processes as a consequence of early maltreatment diminish BDNF gene expression, which may contribute to lower cognitive abilities in maltreated children, not only during youth but also during ongoing…”
BackgroundOf sound mind and body: depression, disease, and accelerated aging
Wolkowitz, O. M., Reus, V. I., & Mellon, S. H. (2011) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2011.13.1/owolkowitz · Cited by 214
DNA methylation regulates associative reward learning
Day, J. J., Childs, D. S., Karlsson, M. G., Kibe, M., Moulden, J., Song, E. Y., Tahir, A., & Sweatt, J. D. (2013) · Nature Neuroscience · doi:10.1038/nn.3504 · Cited by 217
Self-citationOxytocin and social motivation
Gordon, I., Martin, C., Feldman, R., & Leckman, J. F. (2011) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2011.07.007 · Cited by 211
Epigenetics and the regulation of stress vulnerability and resilience
Zannas, A. S., & West, A. E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.003 · Cited by 211
“…associated with increased methylation near Bdnf exons IV and IX and reduced Bdnf mRNA expression in the prefrontal cortex but not the hippocampus (Roth et al., 2009), whereas exposure of adult rats to predator stress and social instability leads to increased DNA methylation and decreased mRNA…”
BackgroundLove, O. P., McGowan, P. O., & Sheriff, M. J. (2012) · Functional Ecology · doi:10.1111/j.1365-2435.2012.02040.x · Cited by 216
“A number of other groups have also found evidence of epigenetic regulation in the brain by altered parental care or stress-related early adversity (e.g. Murgatroyd et al. 2009; Roth et al. 2009).”
BackgroundOuellet-Morin, I., Wong, C. C. Y., Danese, A., Pariante, C. M., Papadopoulos, A. S., Mill, J., & Arseneault, L. (2013) · Psychological Medicine · doi:10.1017/s0033291712002784 · Cited by 207
“Additional findings suggest that early-life stress also alters DNA methylation of the arginine vasopressin gene (Murgatroyd et al. 2009) and the brain-derived neurotrophic factor gene (Roth et al. 2009).”
BackgroundStress and trauma: BDNF control of dendritic-spine formation and regression
Bennett, M. R., & Lagopoulos, J. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.10.005 · Cited by 199
“Early life adversity gives rise to DNA methylation of BDNF promoter IV and a decrease in total BDNF mRNA in the prefrontal cortex (Roth et al., 2009).”
Early-life adversity and brain development: Is the microbiome a missing piece of the puzzle?
O’Mahony, S. M., Clarke, G., Dinan, T. G., & Cryan, J. F. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2015.09.068 · Cited by 203
Prenatal Programming of Human Neurological Function
Sandman, C. A., Davis, E. P., Buß, C., & Glynn, L. M. (2011) · International Journal of Peptides · doi:10.1155/2011/837596 · Cited by 220
“These findings and others reporting persisting altered BDNF expression in the prefrontal cortex related to early adversity [76] provide possible routes of maternal influence on fetal and early infant neurological development with profound implications for infant/child adjustments to life challenges.”
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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