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Caregiver maltreatment causes altered neuronal DNA methylation in female rodents

  • Jennifer Blaze (a1) and Tania L. Roth (a1)


Negative experiences with a caregiver during infancy can result in long-term changes in brain function and behavior, but underlying mechanisms are not well understood. It is our central hypothesis that brain and behavior changes are conferred by early childhood adversity through epigenetic changes involving DNA methylation. Using a rodent model of early-life caregiver maltreatment (involving exposure to an adverse caregiving environment for postnatal days 1–7), we have previously demonstrated abnormal methylation of DNA associated with the brain-derived neurotrophic factor (Bdnf) gene in the medial prefrontal cortex (mPFC) of adult rats. The aim of the current study was to characterize Bdnf DNA methylation in specific cell populations within the mPFC. In the prefrontal cortex, there is approximately twice as many neurons as glia, and studies have recently shown differential and distinctive DNA methylation patterns in neurons versus nonneurons. Here, we extracted nuclei from the mPFC of adult animals that had experienced maltreatment and used fluorescence-activated cell sorting to isolate cell types before performing bisulfite sequencing to estimate methylation of cytosine–guanine sites. Our data indicate that early-life stress induced methylation of DNA associated with Bdnf IV in a cell-type and sex-specific manner. Specifically, females that experienced early-life maltreatment exhibited greater neuronal cytosine–guanine methylation compared to controls, while no changes were detected in Bdnf methylation in males regardless of cell type. These changes localize the specificity of our previous findings to mPFC neurons and highlight the capacity of maltreatment to cause methylation changes that are likely to have functional consequences for neuronal function.

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Corresponding author

Address correspondence and reprint requests to: Tania L. Roth, Department of Psychological and Brain Sciences, University of Delaware, 108 Wolf Hall, Newark, DE 19716; E-mail:


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This research was supported by NIGMS (1P20GM103653) and a University of Delaware Graduate Fellowship. We thank Dr. Robert Akins (Nemours-Alfred I. DuPont Hospital for Children), Dr. Jaclyn Schwarz (University of Delaware), Dr. Lynn Opdenaker (Center for Translational Cancer Research and Christiana Care Hospital), and Dr. Danay Baker-Andresen (University of Queensland) for their help with troubleshooting the fluorescence-activated cell sorting technique. We thank the Delaware Biotechnology Institute for the use of their core facilities (supported by the Delaware INBRE program, with Grant P20 GM103446 from NIGMS and the state of Delaware). We also thank Angela Maggio and Kristyn Borrelli for their assistance with behavioral coding.



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