Long-term effects of early-life caregiving experiences on brain-derived neurotrophic factor histone acetylation in the adult rat mPFC

Stress. 2015;18(6):607-15. doi: 10.3109/10253890.2015.1071790. Epub 2015 Aug 18.


Infant-caregiver experiences are major contributing factors to neural and behavioral development. Research indicates that epigenetic mechanisms provide a way in which infant-caregiver experiences affect gene activity and other downstream processes in the brain that influence behavioral development. Our laboratory previously demonstrated in a rodent model that exposure to maltreatment alters methylation of DNA associated with the brain-derived neurotrophic factor (bdnf) and reelin genes as well as mRNA of key epigenetic regulatory genes in the medial prefrontal cortex (mPFC). In the current study, we characterized patterns of histone acetylation at bdnf and reelin gene loci after our caregiver manipulations. Using a within-litter design (n = 8-10/group from eight litters), pups were exposed to adverse (maltreatment condition: exposure to a stressed caregiver) or nurturing (cross-foster condition: exposure to a nurturing caregiver) caregiving environments outside the home cage for 30 min daily during the first postnatal week. Remaining pups in a litter were left with the biological mother during each session (providing normal care controls). We then used chromatin immunoprecipitation (ChIP) and quantitative RT-PCR to measure histone 3 lysine 9/14 acetylation associated with bdnf promoters I and IV and the reelin promoter in the adult mPFC. Maltreated females had decreased acetylation at bdnf IV, while neither males nor females exhibited histone acetylation alterations at bdnf I or reelin. These data demonstrate the ability of maltreatment to have long-term consequences on histone acetylation in the mPFC, and provide further evidence of the epigenetic susceptibility of bdnf IV to the quality of infant-caregiver experiences.

Keywords: Development; H3K9; epigenetic; maltreatment; maternal; reelin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Epigenesis, Genetic*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Histones / genetics
  • Histones / metabolism*
  • Male
  • Maternal Behavior
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Prefrontal Cortex / metabolism*
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Rats
  • Reelin Protein
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism


  • Brain-Derived Neurotrophic Factor
  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Histones
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Reelin Protein
  • Reln protein, rat
  • Serine Endopeptidases