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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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“…despite some inconsistencies, point toward a decrease in BDNF levels in individuals exposed to CA and in animals exposed to ELA (Aas et al., 2014; Chen et al., 2006, 2008; Elzinga et al., 2011; Gatt et al., 2009; Kaufman et al., 2006; Perroud et al., 2013; Roth et al., 2009; Suri et al., 2013).”
BackgroundBDNF Promoter Methylation Associated with Suicidal Ideation in Patients with Breast Cancer
Kim, J., Kang, H., Kim, S.-Y., Kim, S., Shin, I., Kim, H. R., Park, M., Shin, M., Yoon, J.-H., & Yoon, J.-S. (2015) · The International Journal of Psychiatry in Medicine · doi:10.1177/0091217415574439 · Cited by 32
“As in other studies [23, 24], a CpG-rich region of the promoter between -694 and -577 relative to the transcriptional start, including nine CpG sites, was analyzed.”
BackgroundSingh, A. S., Chandra, R., Guhathakurta, S., Sinha, S., Chatterjee, A., Ahmed, S., Ghosh, S., & Rajamma, U. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.04.015 · Cited by 34
Lui, C., Hsu, M., Kuo, H., Chen, C.-C., Sheen, J., Yu, H., Tiao, M., Tain, Y., Chang, K., & Huang, L. (2015) · Developmental Neuroscience · doi:10.1159/000368768 · Cited by 32
The Epigenetic Code in Depression: Implications for Treatment
Schroeder, M., Hillemacher, T., Bleich, S., & Frieling, H. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.282 · Cited by 32
Childhood Adversity and Adult Physical Health
Ehrlich, K. B., Miller, G. E., & Chen, E. (2016) · Wiley eBooks · doi:10.1002/9781119125556.devpsy401 · Cited by 32
Links between trauma and psychosis (Review)
Giannopoulou, I., Georgiades, S., Stefanou, M., Spandidos, D. A., & Rizos, E. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.12085 · Cited by 38
Salberg, S., Noel, M. E., Burke, N. N., Vinall, J., & Mychasiuk, R. (2019) · Developmental Psychobiology · doi:10.1002/dev.21922 · Cited by 31
Lopez, M., Gilbert, J., Contreras, J., Halby, L., & Arimondo, P. B. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-11454-0_17 · Cited by 32
Viola, T. W., Wearick‐Silva, L. E., de Azeredo, L. A., Centeno‐Silva, A., Murphy, C. P., Marshall, P. R., Li, X., Singewald, N., Garcia, F. D., Bredy, T. W., et al. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4373-z · Cited by 32
“Evidence suggests a long-lasting epigenetic influence of early life stress, through permanently increased 5-methylcytosine occupancy at multiple Bdnf promoter regions in the PFC, which results in reduced Bdnf gene expression (Roth et al. 2009).”
BackgroundEffect of Maternal Stress Prior to Conception on Hippocampal BDNF Signaling in Rat Offspring
Niknazar, S., Nahavandi, A., Peyvandi, A. A., Peyvandi, H., Mehrjerdi, F. Z., & Karimi, M. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0143-5 · Cited by 31
Impact of early adverse experience on complexity of adult-generated neurons
Leslie, A. T., Akers, K. G., Krakowski, A. D., Stone, S. S. D., Sakaguchi, M., Arruda-Carvalho, M., & Frankland, P. W. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.38 · Cited by 30
Chao, Y.-C., Xie, F., Li, X., Guo, R., Yang, N., Zhang, C., Shi, R., Guan, Y., Yue, Y., & Wang, Y. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.03.007 · Cited by 30
Gene–Environment Interplay and Individual Differences in Behavior
Anreiter, I., Sokolowski, H. M., & Sokolowski, M. B. (2017) · Mind Brain and Education · doi:10.1111/mbe.12158 · Cited by 34
“Low maternal care in rats also negatively affects other HPA regulators and neuroplasticity (Chetty et al., 2014; Murgatroyd et al., 2009; Roth, Lubin, Funk, & Sweatt, 2009) through epigenetic mechanisms.”
BackgroundChang, L., Kigar, S. L., Ho, J. H., Cuarenta, A., Gunderson, H. C., Baldo, B. A., Bakshi, V. P., & Auger, A. P. (2018) · Brain Research · doi:10.1016/j.brainres.2018.12.040 · Cited by 33
“Animal models of ELS have indicated that the neonatal environment has long-term effects on behavior and neurobiological systems (Bale et al., 2010; Eiland and McEwen, 2010; Roth et al., 2009).”
BackgroundLee, Y., & Han, P. (2019) · Experimental Neurobiology · doi:10.5607/en.2019.28.3.337 · Cited by 30
Shepard, R. D., Langlois, L. D., Authement, M. E., & Nugent, F. S. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24613 · Cited by 29
Montirosso, R., Rosa, E., Giorda, R., Fazzi, E. M., Orcesi, S., Cavallini, A. R., & Provenzi, L. (2020) · BMJ Open · doi:10.1136/bmjopen-2019-035249 · Cited by 29
Shen, T., Li, X., Chen, L., Chen, Z., Tan, T., Hua, T., Chen, B., Yuan, Y., Zhang, Z., Kuney, L., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.07.111 · Cited by 29
Kosten, T. A., & Nielsen, D. A. (2014) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2014.03.010 · Cited by 33
“Methylation levels of the Bdnf gene promoter in prefrontal cortex are altered in offspring of dams exposed to the stress of limited nesting material (Roth et al., 2009) although levels in hypothalamus were not affected by prenatal stress (Mueller and Bale, 2008) and did not differ by LGC or sex in…”
Early life stress and the propensity to develop addictive behaviors
Walters, H. M., & Kosten, T. A. (2019) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2019.06.004 · Cited by 33
“There is a burgeoning literature in this field (Murgatroyd et al., 2009; Roth et al., 2009; Mueller and Bale, 2008; Weaver et al., 2004).”
BackgroundEpigenetic Mechanisms of Psychostimulant-Induced Addiction
Kalda, A., & Zharkovsky, A. (2015) · International review of neurobiology · doi:10.1016/bs.irn.2015.02.010 · Cited by 31
Predictable Chronic Mild Stress during Adolescence Promotes Fear Memory Extinction in Adulthood
Deng, J., Yan, W., Han, Y., Chen, C., Meng, S., Sun, C., Xu, L., Xue, Y.-X., Gao, X., Chen, N., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-08017-7 · Cited by 31
van de Ven, M. C. J., van den Heuvel, M. I., Bhogal, A., Lewis, T. L., & Thomason, M. E. (2019) · Developmental Psychobiology · doi:10.1002/dev.21900 · Cited by 30
Dong, B. E., Chen, H., & Sakata, K. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15017 · Cited by 29
“Our results suggest that this age-dependency should be considered when using drug treatments targeting the neurotransmitter systems; while pIV-BDNF deficiency occurs under chronic stress (Roth et al., 2009; Tsankova et al., 2006), the drug response likely differs across ages in pIV-BDNF deficiency.”
BackgroundEdyburn, K. L., & Meek, S. E. (2021) · Child Policy Nexus · doi:10.1002/sop2.12 · Cited by 29
Atashbahar, O., Sari, A. A., Takian, A., Olyaeemanesh, A., Mohamadi, E., & Barakati, S. H. (2022) · BMC Public Health · doi:10.1186/s12889-022-13571-5 · Cited by 29
“For example, based on the results of Roth’s study, early infant ill-treatment was associated with decreased expression of genes responsible for appropriate serotonin required to preserve mood balance [57].”
ResultEpigenetic mechanisms in learning and memory
Blaze, J., & Roth, T. L. (2012) · Wiley Interdisciplinary Reviews Cognitive Science · doi:10.1002/wcs.1205 · Cited by 32
Self-citationPerinatal stress and epigenetics.
(2021) · Handbook of Clinical Neurology · doi:10.1016/b978-0-12-820107-7.00008-2 · Cited by 28
Strzelewicz, A. R., Sanchez, E. O., Rondón-Ortiz, A. N., Raneri, A., Famularo, S. T., Bangasser, D. A., & Kentner, A. C. (2019) · Hormones and Behavior · doi:10.1016/j.yhbeh.2019.01.003 · Cited by 29
“In contrast to the negligible behavioral effects reported here, animals exposed to limited resource conditions typically display robust deficits in attachment learning and impaired social behaviors, depressive and anxiety-like behaviors and disrupted maternal care (Moriceau et al., 2009; Raineki et al., 2010; Raineki…”
BackgroundSales, A. J., Maciel, I. D. S., Suavinha, A. C. D. R., & Joca, S. R. L. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02145-4 · Cited by 28
“methylation levels in BDNF IV accompanied by reduced levels of this protein in the PFC [160].”
BackgroundMothering under the influence: how perinatal drugs of abuse alter the mother-infant interaction
Brancato, A., & Cannizzaro, C. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0052 · Cited by 28
“The recent observations support the existence of the transgenerational inheritance of the abusive maternal behaviour that is displayed later on by the exposure to contingent adverse environmental conditions (Roth et al., 2009).”
BackgroundNew approaches to manipulating the epigenome
Day, J. J. (2014) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2014.16.3/jday · Cited by 27
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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