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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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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,951
Epigenetic programming by maternal behavior
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaney, M. J. (2004) · Nature Neuroscience · doi:10.1038/nn1276 · Cited by 6,177
DNA methylation and its basic function
Moore, L. D., Le, T., & Fan, G. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.112 · Cited by 4,906
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., Turecki, G., & Meaney, M. J. (2009) · Nature Neuroscience · doi:10.1038/nn.2270 · Cited by 3,531
Heim, C., & Nemeroff, C. B. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01157-x · Cited by 2,791
Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders
Autry, A. E., & Monteggia, L. M. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005108 · Cited by 1,390
Lasting epigenetic influence of early-life adversity on the BDNF gene
Roth, T. L., Lubin, F. D., Funk, A. J., & Sweatt, J. D. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.028 · Cited by 1,273
Self-citationDynamic DNA methylation programs persistent adverse effects of early-life stress
Murgatroyd, C., Patchev, A. V., Wu, Y., Micale, V., Bockmühl, Y., Fischer, D., Holsboer, F., Wotjak, C. T., Almeida, O. F. X., & Spengler, D. (2009) · Nature Neuroscience · doi:10.1038/nn.2436 · Cited by 1,162
Epigenetic transmission of the impact of early stress across generations
Franklin, T. B., Russig, H., Weiss, I. C., Gräff, J., Linder, N., Michalon, A., Vizi, S., & Mansuy, I. M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.05.036 · Cited by 1,125
Mouse and rat BDNF gene structure and expression revisited
Aid, T., Kazantseva, A., Piirsoo, M., Palm, K., & Timmusk, T. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21139 · Cited by 943
Cicchetti, D., & Toth, S. L. (2005) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.1.102803.144029 · Cited by 861
Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory
Lubin, F. D., Roth, T. L., & Sweatt, J. D. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1786-08.2008 · Cited by 793
Self-citationWeaver, I. C. G., Meaney, M. J., & Szyf, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507526103 · Cited by 771
Tissir, F., & Goffinet, A. M. (2003) · Nature reviews. Neuroscience · doi:10.1038/nrn1113 · Cited by 767
Sex Differences in the Brain: The Not So Inconvenient Truth
McCarthy, M. M., Arnold, A. P., Ball, G. F., Blaustein, J. D., & De Vries, G. J. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5372-11.2012 · Cited by 724
Champagne, F. A., Weaver, I. C. G., Diorio, J., Dymov, S., Szyf, M., & Meaney, M. J. (2006) · Endocrinology · doi:10.1210/en.2005-1119 · Cited by 675
De Bellis, M. D., Keshavan, M. S., Shifflett, H., Iyengar, S., Beers, S. R., Hall, J., & Moritz, G. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01459-2 · Cited by 632
(2007) · PubMed · Cited by 597
Bredy, T. W., Wu, H., Crego, C., Zellhoefer, J., Sun, Y. E., & Barad, M. (2007) · Learning & Memory · doi:10.1101/lm.500907 · Cited by 548
The social environment and the epigenome
Szyf, M., McGowan, P. O., & Meaney, M. J. (2007) · Environmental and Molecular Mutagenesis · doi:10.1002/em.20357 · Cited by 547
Cortical DNA methylation maintains remote memory
Miller, C. A., Gavin, C. F., White, J. A., Parrish, R. R., Honasoge, A., Yancey, C. R., Rivera, I. M., Rubio, M. D., Rumbaugh, G., & Sweatt, J. D. (2010) · Nature Neuroscience · doi:10.1038/nn.2560 · Cited by 533
The Epigenetics of Sex Differences in the Brain: Figure 1.
McCarthy, M. M., Auger, A. P., Bale, T. L., Vries, G. J. D., Dunn, G. A., Forger, N. G., Murray, E. K., Nugent, B. M., Schwarz, J. M., & Wilson, M. E. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3331-09.2009 · Cited by 495
Hanson, J. L., Chung, M. K., Avants, B. B., Shirtcliff, E. A., Gee, J. C., Davidson, R. J., & Pollak, S. D. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0859-10.2010 · Cited by 455
Bluhm, R. L., Williamson, P. C., Osuch, E. A., Frewen, P. A., Stevens, T. K., Boksman, K., Neufeld, R. W. J., Théberge, J., & Lanius, R. A. (2009) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0925 · Cited by 422
Ivy, A. S., Brunson, K. L., Sandman, C., & Baram, T. Z. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.04.019 · Cited by 407
Ivy, A. S., Rex, C. S., Chen, Y., Dubé, C., Maras, P. M., Grigoriadis, D. E., Gall, C. M., Lynch, G., & Baram, T. Z. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1784-10.2010 · Cited by 402
Structural and functional plasticity of the human brain in posttraumatic stress disorder
Bremner, J. D., Elzinga, B. M., Schmahl, C. G., & Vermetten, E. H. G. J. M. (2007) · Progress in brain research · doi:10.1016/s0079-6123(07)67012-5 · Cited by 379
Fuchikami, M., Morinobu, S., Segawa, M., Okamoto, Y., Yamawaki, S., Ozaki, N., Inoue, T., Kusumi, I., Koyama, T., Tsuchiyama, K., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023881 · Cited by 378
DNA methylation signatures in development and aging of the human prefrontal cortex
Numata, S., Ye, T., Hyde, T. M., Guitart-Navarro, X., Tao, R., Wininger, M., Colantuoni, C., Weinberger, D. R., Kleinman, J. E., & Lipska, B. K. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.12.020 · Cited by 364
Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder
Smith, A. K., Conneely, K. N., Kilaru, V., Mercer, K. B., Weiss, T. E., Bradley, B., Tang, Y., Gillespie, C. F., Cubells, J. F., & Ressler, K. J. (2011) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31212 · Cited by 355
Labonte, B., Yerko, V., Gross, J., Mechawar, N., Meaney, M. J., Szyf, M., & Turecki, G. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.01.034 · Cited by 345
Roth, T. L., Zoladz, P. R., Sweatt, J. D., & Diamond, D. M. (2011) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.01.013 · Cited by 333
Self-citationNeuronal 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
The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells
Provençal, N., Suderman, M. J., Guillemin, C., Massart, R., Ruggiero, A., Wang, D., Bennett, A. J., Pierre, P. J., Friedman, D. P., Côté, S. M., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1470-12.2012 · Cited by 312
Uchida, S., Hara, K., Kobayashi, A., Funato, H., Hobara, T., Otsuki, K., Yamagata, H., McEwen, B. S., & Watanabe, Y. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1436-10.2010 · Cited by 310
The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders
Grayson, D. R., & Guidotti, A. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.125 · Cited by 280
Matrisciano, F., Tueting, P., Dalal, I., Kadriu, B., Grayson, D. R., Davis, J. M., Nicoletti, F., & Guidotti, A. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.04.013 · Cited by 271
Maternal Care and DNA Methylation of a Glutamic Acid Decarboxylase 1 Promoter in Rat Hippocampus
Zhang, T., Hellstrom, I. C., Bagot, R. C., Wen, X., Diorio, J. C., & Meaney, M. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1039-10.2010 · Cited by 271
Multiple regulators of ultrasonic vocalization in the infant rat
Hofer, M. A. (1996) · Psychoneuroendocrinology · doi:10.1016/0306-4530(95)00042-9 · Cited by 266
The Neurobiological Toll of Child Abuse and Neglect
Neigh, G. N., Gillespie, C. F., & Nemeroff, C. B. (2009) · Trauma Violence & Abuse · doi:10.1177/1524838009339758 · Cited by 248
Epigenetics of Early Child Development
Murgatroyd, C., & Spengler, D. (2011) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2011.00016 · Cited by 212
Roth, T. L., & Sullivan, R. M. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.01.032 · Cited by 204
Self-citationThe Development and Neurobiology of Infant Attachment and Fear
Landers, M. S., & Sullivan, R. M. (2012) · Developmental Neuroscience · doi:10.1159/000336732 · Cited by 193
Developing a neurobehavioral animal model of infant attachment to an abusive caregiver
Raineki, C., Moriceau, S., & Sullivan, R. M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.12.019 · Cited by 190
Epigenetics and the Biological Basis of Gene × Environment Interactions
Bagot, R. C., & Meaney, M. J. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.06.001 · Cited by 177
Epigenetic mechanisms in schizophrenia
Roth, T. L., Lubin, F. D., Sodhi, M., & Kleinman, J. E. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.06.009 · Cited by 176
Self-citationWöhr, M., & Schwarting, R. K. W. (2008) · Behavioral Neuroscience · doi:10.1037/0735-7044.122.2.310 · Cited by 161
Epigenetic Underpinnings of Developmental Sex Differences in the Brain
Nugent, B. M., & McCarthy, M. M. (2011) · Neuroendocrinology · doi:10.1159/000325264 · Cited by 145
Bagot, R. C., Zhang, T.-Y., Wen, X., Nguyen, T. T. T., Nguyen, H.-B., Diorio, J., Wong, T. P., & Meaney, M. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1204599109 · Cited by 141
Intergenerational transmission of maternal behavior in rhesus macaques and its underlying mechanisms
Dario Maestripieri, A., Lindell, S. G., & Higley, J. D. (2007) · Developmental Psychobiology · doi:10.1002/dev.20200 · Cited by 110
Sui, L., Wang, Y., Ju, L.-H., & Chen, M. (2012) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2012.03.007 · Cited by 109
Philip, N. S., Sweet, L. H., Tyrka, A. R., Price, L. H., Bloom, R. F., & Carpenter, L. L. (2012) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.10.008 · Cited by 108
Long‐lasting regulation of hippocampal Bdnf gene transcription after contextual fear conditioning
Mizuno, K., Dempster, E. L., Mill, J. S., & Giese, K.-P. (2012) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2012.00805.x · Cited by 98
Mychasiuk, R., Gibb, R., & Kolb, B. (2011) · Developmental Neuroscience · doi:10.1159/000335524 · Cited by 83
Martínez, L., Jiménez-Suárez, V., García-Sepúlveda, C. A., Ceballos, F., Delgado, J. M., Niño-Moreno, P., Doniz, L., Saavedra-Alanis, V. M., Castillo, C. G., & Santoyo, M. E. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.01.020 · Cited by 76
On the significance of similarities between ultrasonic vocalizations of infant and adult rats
BLUMBERG, M. S., & Alberts, J. R. (1991) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(05)80031-4 · Cited by 70
Jessen, H. M., & Auger, A. P. (2011) · Epigenetics · doi:10.4161/epi.6.7.16517 · Cited by 66
Hao, Y., Huang, W., Nielsen, D. A., & Kosten, T. A. (2011) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2011.00021 · Cited by 66
Howell, B., & Sánchez, M. M. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000460 · Cited by 59
Prenatal Bystander Stress Alters Brain, Behavior, and the Epigenome of Developing Rat Offspring
Mychasiuk, R., Schmold, N., Ilnytskyy, S., Kovalchuk, O., Kolb, B. E., & Gibb, R. L. (2011) · Developmental Neuroscience · doi:10.1159/000330034 · Cited by 47
Gross, C. M., Flubacher, A., Tinnes, S., Heyer, A., Scheller, M., Herpfer, I., Berger, T., Frotscher, M., Lieb, K., & Haas, C. A. (2010) · Hippocampus · doi:10.1002/hipo.20907 · Cited by 47
Qin, L., Tu, W.-Q., Sun, X.-M., Zhang, J., Chen, Y., & Zhao, H. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.10.018 · Cited by 42
Ontogenetic differences in retention of spatial learning tested with Morris water maze
Brown, R. W., & Kraemer, P. J. (1997) · Developmental Psychobiology · doi:10.1002/(sici)1098-2302(199705)30:4 · Cited by 34
Cassidy, A. W., Mulvany, S. K., Pangalos, M. N., Murphy, K. J., & Regan, C. M. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.045 · Cited by 26
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“In adulthood, both males and females are observed to have increased DNA methylation in Bdnf promoter I in the prefrontal cortex, but at promoter IV only abuse-exposed females are observed to have increased DNA methylation (Blaze et al., 2013).”
Background
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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