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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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“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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“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].”
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“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]
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“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]
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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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“…producing abnormal caregiving behaviors that include a high proportion of rough handling, pup stepping on and dragging, active avoidance (neglect), and decreased LG of pups (Ivy, Brunson, Sandman, & Baram, 2008; Raineki, Cortés, Belnoue, & Sullivan, 2012; Roth et al., 2009; Roth & Sullivan, 2005).”
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“…to be corresponded to an analogous region in rat Bdnf, which was shown to be differentially methylated and associated with Bdnf mRNA expression (Roth et al., 2009) as well as having been investigated in relation to antenatal depressed mood as a marker of SLC6A4 methylation status (Devlin et…”
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“A CpG-rich region of the promoter between 2694 and 2577, relative to the transcriptional start, including seven CpG sites were analyzed as in other studies [18,19].”
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“, stress and neglect), which demonstrate that increased DNA methylation at CpG islands around the Bdnf-IV promoter is associated with long-term repression of hippocampal Bdnf (51, 52).”
BackgroundExposure to dim light at night during early development increases adult anxiety-like responses
Borniger, J. C., McHenry, Z. D., Abi Salloum, B. A., & Nelson, R. J. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.05.012 · Cited by 89
“Changes in adult behavior following modulation of the early life environment have also been linked with altered neurotrophin expression [16,20,21,68].”
BackgroundInfluentialAriffin, H., Azanan, M. S., Abd Ghafar, S. S., Oh, L., Lau, K. H., Thirunavakarasu, T., Sedan, A., Ibrahim, K., Chan, A., Chin, T. F., et al. (2017) · Cancer · doi:10.1002/cncr.30857 · Cited by 99
“In addition, social, traumatic, and psychological experiences associated with having cancer in childhood may become embedded epigenetically and lead to longterm, or even permanent, alterations in gene expression.(36,37) It has been demonstrated that adverse life events at a young age increase the odds of short telomer…”
BackgroundProvençal, N., Booij, L., & Tremblay, R. E. (2015) · Journal of Experimental Biology · doi:10.1242/jeb.111401 · Cited by 101
“The basic concepts of this study were repeated in several other animal models of early-life adversity and found similar epigenetic alterations in genes such as the Bdnf (Roth et al., 2009), Avp (Murgatroyd et al., 2009), Crh (Elliott et al., 2010), Crhr2 (Franklin et al., 2010), Gad1 (Zhang et al., 2010b) and Olfr151…”
BackgroundSzyf, M. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr024 · Cited by 90
“Exposure of infant rats to stressed caretakers that displayed abusive behavior produced persisting changes in methylation of brainderived neurotrophic factor (BDNF) gene promoter in the adult prefrontal cortex (Roth et al., 2009).”
BackgroundSchalinski, I., Elbert, T., Steudte-Schmiedgen, S., & Kirschbaum, C. (2015) · PLOS ONE · doi:10.1371/journal.pone.0136921 · Cited by 88
“Some animal studies show the long-lasting effect of early environments on the neural circuits that control the stress response [46,47], and form an adaptive stress phenotype [10].”
BackgroundRoth, T. L., Matt, S. M., Chen, K., & Blaze, J. (2014) · Developmental Psychobiology · doi:10.1002/dev.21218 · Cited by 98
Self-citationJarić, I., Rocks, D., Cham, H., Herchek, A., & Kundaković, M. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00074 · Cited by 95
DNA methylation-mediated control of learning and memory
Yu, N., Baek, S. H., & Kaang, B. (2011) · Molecular Brain · doi:10.1186/1756-6606-4-5 · Cited by 89
“ECT demethylates the promoter of the coding exon IX [22], which is methylated by early life maltreatment [42].”
BackgroundEarly Childhood Environment and Genetic Interactions: the Diathesis for Suicidal Behavior
Brodsky, B. S. (2016) · Current Psychiatry Reports · doi:10.1007/s11920-016-0716-z · Cited by 86
Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection
Bekdash, R. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032346 · Cited by 96
DNA methylation regulates phenotype-dependent transcriptional activity in Candida albicans
Mishra, P. K., Baum, M., & Carbon, J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109631108 · Cited by 84
“Notably, neurobiological studies have identified gene repression due to intragenic methylation that appears to be correlated with stressful early life experiences (34, 35).”
BackgroundBranchi, I., Karpova, N. N., D’Andrea, I., Castrén, E., & Alleva, E. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.03.038 · Cited by 87
BDNF genetic variants and methylation: effects on cognition in major depressive disorder
Ferrer, A., Labad, J., Salvat-Pujol, N., Barrachina, M., Costas, J., Urretavizcaya, M., de Arriba-Arnau, A., Crespo, J. M., Soriano-Mas, C., Carracedo, Á., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0601-8 · Cited by 84
Smarr, B. L., Grant, A. D., Perez, L., Zucker, I., & Kriegsfeld, L. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-03406-4 · Cited by 86
Sharp, G. C., Arathimos, R., Reese, S. E., Page, C. M., Felix, J. F., Küpers, L. K., Rifas‐Shiman, S. L., Liu, C., The Cohorts for Heart and Aging Research in Genomic Epidemiology plus (CHARGE +) methylation alcohol working group, Burrows, K., et al. (2017) · Epigenomics · doi:10.2217/epi-2017-0095 · Cited by 86
Wang, A., Nie, W., Li, H., Hou, Y.-H., Yu, Z., Fan, Q., & Sun, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094394 · Cited by 85
Kyzar, E. J., Zhang, H., Sakharkar, A. J., & Pandey, S. C. (2016) · Addiction Biology · doi:10.1111/adb.12404 · Cited by 85
“It has been shown that Bdnf exon IV expression is regulated by epigenetic mechanisms in the brain (Roth et al. 2009; Moonat et al. 2013; Pandey et al. 2015; Sakharkar et al. 2016), and its expression is decreased in the amygdala after AIE in adulthood (Pandey et al. 2015).”
BackgroundEpigenetic memory in response to environmental stressors
Vineis, P., Chatziioannou, A. A., Cunliffe, V. T., Flanagan, J. M., Hanson, M. A., Kirsch‐Volders, M., & Kyrtopoulos, S. Α. (2017) · The FASEB Journal · doi:10.1096/fj.201601059rr · Cited by 87
Na, K.-S., Won, E., Kang, J., Chang, H. S., Yoon, H.-K., Tae, W. S., Kim, Y.-K., Lee, M.-S., Joe, S.-H., Kim, H., et al. (2016) · Scientific Reports · doi:10.1038/srep21089 · Cited by 84
The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review
Webb, L. M., Phillips, K. E., Ho, M. C., Veldic, M., & Blacker, C. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030826 · Cited by 84
Nieratschker, V., Massart, R., Gilles, M., Luoni, A., Suderman, M. J., Krumm, B., Meier, S., Witt, S. H., Nöthen, M. M., Suomi, S. J., et al. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.75 · Cited by 83
Long-lasting and transgenerational effects of an environmental enrichment on memory formation
Arai, J. A., & Feig, L. A. (2010) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2010.11.003 · Cited by 87
“Another example of somatic inheritance of epigenetic marks on DNA acquired from the environment is BDNF gene methylation regulated by early-life adversity [47].”
BackgroundKofink, D., Boks, M. P. M., Timmers, H. T. M., & Kas, M. J. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.03.020 · Cited by 83
Beery, A. K., McEwen, L. M., MacIsaac, J. L., Francis, D. D., & Kobor, M. S. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.05.022 · Cited by 81
“, 2015) or other peripheral tissues, while most behaviorally relevant epigenetic changes have been documented in the brain (e.g. Weaver et al., 2004; Roth et al., 2009; Miller et al., 2010).”
BackgroundEpigenetic legacy of parental experiences: Dynamic and interactive pathways to inheritance
Champagne, F. A. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000808 · Cited by 81
Epigenomic mechanisms of early adversity and HPA dysfunction: considerations for PTSD research
McGowan, P. O. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00110 · Cited by 83
“Other groups have provided evidence that additional genes in neural pathways mediating the stress response are epigenetically regulated in association with early life stress, including arginine vasopressin in the hypothalamus (19), and BDNF in the prefrontal cortex and hippocampus (20).”
BackgroundThe early care environment and DNA methylome variation in childhood
Garg, E., Chen, L., Nguyen, T. T. T., Pokhvisneva, I., Chen, L. M., Unternaehrer, E., MacIsaac, J. L., McEwen, L. M., Mah, S. M., Gaudreau, H., et al. (2018) · Development and Psychopathology · doi:10.1017/s0954579418000627 · Cited by 82
“…stress responses as well as synaptic function (Bagot et al., 2012; Klengel et al., 2013; Lam et al., 2012; Murgatroyd et al., 2009; O’Donnell et al., 2018; Roth, Lubin, Funk, & Sweatt, 2009; Weaver et al., 2004; Wu, Patchev, Daniel, Almeida, & Spengler, 2014; Zhang et al., 2010).”
Environmental regulation of the neural epigenome
Caldji, C., Hellstrom, I. C., Zhang, T.-Y., Diorio, J., & Meaney, M. J. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.03.032 · Cited by 82
“BDNF is associated with synaptic remodeling.”
BackgroundMaternal separation is associated with DNA methylation and behavioural changes in adult rats
Anier, K., Malinovskaja, K., Pruus, K., Aonurm‐Helm, A., Zharkovsky, A., & Kalda, A. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.07.012 · Cited by 86
“Several studies have demonstrated that stressful experiences during early life may cause both DNA hypo- and hypermethylation of specific gene promoters (Franklin et al., 2010; Fuchikami et al., 2009; Murgatroyd et al., 2009; Roth et al. 2009; Weaver et al., 2004).”
BackgroundSocial environmental effects on gene regulation
Tung, J., & Gilad, Y. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1357-6 · Cited by 85
“, chronic social defeat and early adversity; [56, 65, 66, 71]).”
BackgroundAdvance in Stress for Depressive Disorder
Ding, Y., & Dai, J. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9271-0_8 · Cited by 86
Epigenetics and Social Context: Implications for Disparity in Cardiovascular Disease
Saban, K. L. (2014) · Aging and Disease · doi:10.14336/ad.2014.0500346 · Cited by 85
“Convincing evidence indicates that prior life adversity, such as low SES, contributes to DNA methylation levels [67,81,82] and may influence the regulation of the proinflammatory response to stress [79,80].”
BackgroundBlaze, J., & Roth, T. L. (2013) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2013.10.001 · Cited by 86
“Previously, we found that exposing infant rats to an adverse caregiving environment produces DNA methylation alterations that are present in both the developing and adult whole (Roth et al., 2009) and medial (Blaze et al., 2013) prefrontal cortex.”
BackgroundMethodSelf-citationEpigenetics applied to psychiatry: Clinical opportunities and future challenges
Kular, L., & Kular, S. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12634 · Cited by 90
“Studies of stress-induced depression and PTSD models in the rat have shown that childhood or adult trauma induces long-lasting repressive epigenetic marks of the Bdnf gene in the brain, these modifications being associated with lower levels of Bdnf expression and depressive-like behavior.(26,27) Experience-induced epi…”
BackgroundBehavior-related gene regulatory networks: A new level of organization in the brain
Sinha, S., Jones, B. M., Traniello, I. M., Bukhari, S. A., Halfon, M. S., Hofmann, H. A., Huang, S., Katz, P. S., Keagy, J., Lynch, V. J., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1921625117 · Cited by 80
Numata, S., Ishii, K., Tajima, A., Iga, J.-I., Kinoshita, M., Watanabe, S., Umehara, H., Fuchikami, M., Okada, S., Boku, S., et al. (2015) · Epigenetics · doi:10.1080/15592294.2014.1003743 · Cited by 79
“There is growing evidence for the lasting influence of a modified DNA methylation status that is established early in life.(6,7) Aberrant DNA methylation in the blood of patients with MDD and the associations of different DNA methylation patterns with the phenotypic discordance of MDD between twins have been reported.”
BackgroundInvolvement of Genetic an d Environmental Factors in the Onset of Depression
Nabeshima, T., & Kim, H. (2013) · Experimental Neurobiology · doi:10.5607/en.2013.22.4.235 · Cited by 88
“Adolescents are susceptible to mental disorders such as affective disorders and schizophrenia [1].”
BackgroundEnvironmental Stressors and Epigenetic Control of the Hypothalamic-Pituitary-Adrenal Axis
Lee, R. S., & Sawa, A. (2014) · Neuroendocrinology · doi:10.1159/000369585 · Cited by 84
Sensitive Periods in Epigenetics: Bringing us Closer to Complex Behavioral Phenotypes
Nagy, C., & Turecki, G. (2012) · Epigenomics · doi:10.2217/epi.12.37 · Cited by 81
Epigenetic Effects of Early Developmental Experiences
Gudsnuk, K. M., & Champagne, F. A. (2011) · Clinics in Perinatology · doi:10.1016/j.clp.2011.08.005 · Cited by 85
Epigenetics, Depression and Antidepressant Treatment
Menke, A., Klengel, T., & Binder, E. B. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212803523590 · Cited by 80
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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