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Differential Methylation of Genes in the Medial Prefrontal Cortex of Developing and Adult Rats Following Exposure to Maltreatment or Nurturing Care During Infancy
Open accessAbstract
Quality of maternal care in infancy is an important contributing factor in the development of behavior and psychopathology. One way maternal care could affect behavioral trajectories is through environmentally induced epigenetic alterations within brain regions known to play prominent roles in cognition, emotion regulation, and stress responsivity. Whereas such research has largely focused on the hippocampus or hypothalamus, the prefrontal cortex (PFC) has only just begun to receive attention. The current study was designed to determine whether exposure to maltreatment or nurturing care is associated with differential methylation of candidate gene loci (bdnf and reelin) within the medial PFC (mPFC) of developing and adult rats. Using a within-litter design, infant male and female rats were exposed to an adverse or nurturing caregiving environment outside their home cage for 30 min per day during the first postnatal week. Additional littermates remained with their biological caregiver within the home cage during the manipulations. We observed that infant rats subjected to caregiver maltreatment emitted more audible and ultrasonic vocalizations than littermates subjected to nurturing care either within or outside of the home cage. While we found no maltreatment-induced changes in bdnf DNA methylation present in infancy, sex-specific alterations were present in the mPFC of adolescents and adults that had been exposed to maltreatment. Furthermore, while maltreated females showed differences in reelin DNA methylation that were transient, males exposed to maltreatment and both males and females exposed to nurturing care outside the home cage showed differences in reelin methylation that emerged by adulthood. Our results demonstrate the ability of infant-caregiver interactions to epigenetically mark genes known to play a prominent role in cognition and psychiatric disorders within the mPFC. Furthermore, our data indicate the remarkable complexity of alterations that can occur, with both transient and later emerging DNA methylation differences that could shape developmental trajectories and underlie gender differences in outcomes.
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“one study found that in the PFC of female rats exposed to neonatal caregiver maltreatment, there was reduced Bdnf exon IV methylation at adolescence compared to normal care controls, but an increase at adulthood, and no differences at infancy [101].”
From Cell-type-specific epigenetic effects of early life stress on the brain (2022) · cites this paper as [101]
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“Epigenetic modifications detected in temporal proximity to environmental factors are not always the same as the ones detected later.”
From Cell-type-specific epigenetic effects of early life stress on the brain (2022) · cites this paper as [101]
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“…polymerase chain reaction (RT-PCR) To amplify immunoprecipitated DNA specific to our candidate genes, we used primers specific to the same or nearby region of the bdnf and reelin genes as we have previously used for DNA methylation studies (Blaze et al., 2013; Roth et al., 2009, 2014) (Figure 2).”
InfluentialSelf-citationThe Genetics of Epigenetic Inheritance: Modes, Molecules, and Mechanisms
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“Moreover, ELS has been shown to influence reelin expression in the hippocampus and mPFC in juvenile and adult rats (Gross et al., 2012; Zhang et al., 2013; Blaze et al., 2013).”
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“Finally, we have measured the expression of various epigenetic regulators occurring in response to this ELS model and found significant differences varying by sex and age in the mPFC of maltreated animals, with the strongest differences present in adulthood (Blaze & Roth, 2013).”
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“Methylation of Reelin was altered 24 hours following the final bout of maltreatment, however, methylation normalized by adolescence (Blaze et al., 2013).”
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“Exposure to adversity during this time has lifelong implications for the brain and, consequently, behavior (Fride et al., 1985; Heim et al., 1997; Brunson et al., 2001; McEwen, 2003; Lupien et al., 2009; Roth et al., 2009; Blaze and Roth, 2013, 2017; Blaze et al., 2013; Doherty et al., 2017).”
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“…in the regulatory region of the brainderived neurotrophic factor (BDNF) and reelin genes, such as enhanced DNA methylation and reduced H3 and H4 acetylation (Roth et al. 2009; Blaze et al. 2013) that results in reduced expression of BDNF and reelin in the medial prefrontal cortex (Sui et al. 2012).”
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“Both acute and chronic stress were shown to affect global methylation patterns (Blaze et al., 2018, 2013; Doherty et al., 2016; Mychasiuk et al., 2016; Rodrigues et al., 2015), as well as methylation of stress-associated gene promoters in brain, blood and germline cells (Barrès et al., 2012; Day &…”
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Childhood adverse events and BDNF promoter methylation in later-life
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“Methylation alterations are complex and not fully understood (41).”
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Self-citationEpigenetic Landscapes of the Adversity-Exposed Brain
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Environmental influences on the female epigenome and behavior
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“decreased methylation of Bdnf exon I but increased methylation of Bdnf exon IV in adulthood [117].”
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Watamura, S. E., & Roth, T. L. (2018) · Developmental Psychobiology · doi:10.1002/dev.21796 · Cited by 11
“…neglecting) Seminal Epigenetic Study/Studies Weaver et al., 2004; Champagne, et al., 2006 Daniels et al.,2009; Murgatroyd et al., 2009 Roth et al., 2009; Blaze et al., 2013 Additional Seminal Studies of Model Liu et al., 1997; Caldji et al., 1998; Champagne, Diorio, Sharma, & Meaney, 2001 Plotsky…”
BackgroundMethodSelf-citationThe Impact of Stress Within and Across Generations: Neuroscientific and Epigenetic Considerations
Miller, C. W. T. (2021) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000300 · Cited by 13
“multiple time points).(135)Maltreatment by caregivers in the first”
BackgroundDevelopmental administration of valproic acid alters DNA methylation and maternal behavior
Collins, N. J., Zimmerman, C. W., Phillips, N. L. H., Fern, S., Doherty, T. S., & Roth, T. L. (2022) · Developmental Psychobiology · doi:10.1002/dev.22231 · Cited by 9
Self-citationEfectos del estrés sobre los procesos de plasticidad y neurogénesis: una revisión
Zárate, S., Acevedo-Triana, C. A., Sarmiento-Bolaños, M. J., Cárdenas, F. P., & León, L. A. (2014) · Universitas Psychologica · doi:10.11144/javeriana.upsy13-3.eepp · Cited by 12
Mothers’ Attachment Representations and Children’s Brain Structure
Fitter, M., Stern, J. A., Straske, M. D., Allard, T. L., Cassidy, J. A., & Riggins, T. (2022) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2022.740195 · Cited by 19
Collins, N. J., Phillips, N. L. H., Reich, L. N., Milbocker, K. A., & Roth, T. L. (2020) · Adversity and Resilience Science · doi:10.1007/s42844-020-00015-5 · Cited by 10
Self-citationHow stress affects gene expression through epigenetic modifications
Bainomugisa, C. K., & Mehta, D. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-823039-8.00014-9 · Cited by 6
Provenzi, L., Villa, M., Mambretti, F., Citterio, A., Grumi, S., Bertazzoli, E., Biasucci, G., Decembrino, L., Gardella, B., Giacchero, R., et al. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.950455 · Cited by 6
“Increased BDNF methylation has been documented in response to adverse life conditions in central and peripheral tissues of both animal models and humans (48, 49) and similar trends in BDNF methylation have been reported between peripheral and central assessments (37).”
BackgroundThe lifetime impact of stress on fear regulation and cortical function
Trask, S., Kuczajda, M. T., & Ferrara, N. C. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109367 · Cited by 6
DNA methylation and behavioral changes induced by neonatal spinal transection
Doherty, T. S., Bozeman, A. L., Roth, T. L., & Brumley, M. R. (2019) · Infant Behavior and Development · doi:10.1016/j.infbeh.2019.101381 · Cited by 6
Self-citationNeurobiology and programming capacity of attachment learning to nurturing and abusive caregivers
Roth, T. L., Barr, G. A., Lewis, M. J., & Sullivan, R. M. (2016) · Wiley eBooks · doi:10.1002/9781118931684.ch6 · Cited by 6
Self-citationTimmerman, B. M., Mooney‐Leber, S. M., & Brummelte, S. (2021) · Developmental Psychobiology · doi:10.1002/dev.22212 · Cited by 5
Rao, R., Ennis, K., Mitchell, E. P., Tran, P. V., & Gewirtz, J. C. (2016) · Developmental Neuroscience · doi:10.1159/000442878 · Cited by 5
Fries, G. R. (2020) · Progress in inflammation research · doi:10.1007/978-3-030-39335-9_4 · Cited by 5
Prenatal and Early Postnatal Influences on Neurodevelopment: The Role of Epigenetics
Mariotti, V., Palumbo, S., & Pellegrini, S. (2019) · Springer eBooks · doi:10.1007/978-3-030-25816-0_6 · Cited by 5
Silva-Hurtado, T. J., Giua, G., Lassalle, O., Makrini, L., Strauss, B., Wager‐Miller, J., Freyermuth, J., Mackie, K., Valjent, E., Manzoni, O. J., et al. (2024) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2024.100426 · Cited by 4
Schoenrock, S. A., & Tarantino, L. M. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-417114-5.00009-7 · Cited by 4
Epigenetics: Stress and disease
Perez-Polo, J. R. (2017) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2017.08.002 · Cited by 4
Walker, S. L., & Glasper, E. R. (2024) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2024.101162 · Cited by 3
Role of Epigenetics in the Brain
Matt, S. M., Roth, E. D., & Roth, T. L. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-417114-5.00005-x · Cited by 3
Self-citationEpigenetics: Integrating Genetic Programs, Brain Development and Emergent Phenotypes
Weaver, I. C. G. (2014) · Cell & Developmental Biology · doi:10.4172/2168-9296.1000132 · Cited by 3
“A recent study found evidence of sex-specific DNA methylation changes in BDNF and reelin in the medial prefrontal cortex of offspring subjected to an adverse maternal environment that emerge in the transition between adolescence and adulthood [119].”
BackgroundCampbell, T. S., & Roth, T. L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821785-6.00013-x · Cited by 3
Self-citationWakid, M., Almeida, D., Denniston, R., Chawla, A., Aouabed, Z., Davoli, M. A., Ellerbeck, K., Rahimian, R., Yerko, V., Leonova-Erko, E., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03285-6 · Cited by 4
“…component of a broader forebrain network that mediates stress-evoked changes in cardiovascular activity [12, 13], and there is ample evidence demonstrating sustained and pervasive molecular [14 – 18], cellular [19 – 22] and functional abnormalities [23 – 28] of the prefrontal cortex following ELA.”
Neurodevelopmental effects of early life stress: PFC and cognition
Rachmany, L., Abreu, F. F., Walker, V., O'Neill, O. S., Sargin, D., & Teixeira, C. M. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.106663 · Cited by 5
Immune system and epigenomics under the light of spirituality/religiosity
Caldeira, D. S. (2023) · MedNEXT Journal of Medical and Health Sciences · doi:10.54448/mdnt23s105 · Cited by 2
Neonatal maltreatment and brain development
Yurdakök, K. (2014) · Journal of pediatric and neonatal individualized medicine · doi:10.7363/030228 · Cited by 2
“) in the early days of life can dramatically affect brain development that would cause adverse consequences throughout the lifetime and even in the offspring [13].”
BackgroundEveryday Epigenetics: From Molecular Intervention to Public Health and Lifestyle Medicine
Herbert, M. R. (2013) · North American Journal of Medicine and Science · Cited by 2
Role of epigenetics in the brain
Matt, S. M., Roth, E. D., & Roth, T. L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-823577-5.00007-6 · Cited by 2
Self-citationWeber, R., Mortazavi, A., Baram, T. Z., & Floriou‐Servou, A. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1671495 · Cited by 1
Metadata
- Authors
- Blaze, J., Scheuing, L., & Roth, T. L.
- Affiliations
- University of Delaware (US)
- Venue
- Developmental Neuroscience
- Publisher
- S. Karger AG
- Published
- 2013
- Volume
- 35
- Issue
- 4
- Pages
- 306-316
- ISSN
- 0378-5866 (ISSN-L)
- 1421-9859
- PMC
- PMC3847900
- OpenAlex
- W2031067009
- Cited by
- 123
- References
- 66
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 12 · 2020: 6 · 2019: 14 · 2018: 10 · 2017: 13 · 2016: 15 · 2015: 11 · 2014: 13 · 2013: 6
- FWCI
- 16.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Developmental Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Brain and Behavior Research Foundation
- University of Delaware Research Foundation
- National Institute of General Medical Sciences (P20GM103653)
- 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
- DNA methylation, medial prefrontal cortex, infant maltreatment, nurturing care, maternal care, brain-derived neurotrophic factor, reelin, sex differences, ultrasonic vocalizations, caregiver-infant interaction, epigenetic programming, postnatal development, rats
- MeSH terms
- Reelin Protein, Animals, Animals, Newborn, Behavior, Animal, Child, Child Abuse, Female, Humans, Male, Maternal Behavior, Nerve Tissue Proteins, Neuronal Plasticity, Pregnancy, Serine Endopeptidases, Sex Characteristics, Cell Adhesion Molecules, Neuronal, Gene Expression, Extracellular Matrix Proteins, Prefrontal Cortex, DNA Methylation, Brain-Derived Neurotrophic Factor, Rats, Long-Evans, Epigenesis, Genetic, Rats
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