Altered hypothalamic DNA methylation and stress-induced hyperactivity following early life stress

Eamon Fitzgerald, Matthew C Sinton, Sara Wernig-Zorc, Nicholas M Morton, Megan C Holmes, James P Boardman, Amanda J Drake

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Exposure to early life stress (ELS) during childhood or prenatally increases the risk of future psychiatric disorders. The effect of stress exposure during the neonatal period is less well understood. In preterm infants, exposure to invasive procedures is associated with altered brain development and future stress responses suggesting that the neonatal period could be a key time for the programming of mental health. Previous studies suggest that ELS affects the hypothalamic epigenome, making it a good candidate to mediate these effects. In this study, we used a mouse model of early life stress (modified maternal separation; MMS). We hypothesised MMS would affect the hypothalamic transcriptome and DNA methylome, and impact on adult behaviour.
MMS involved repeated stimulation of pups for 1.5 hours/day, whilst separated from their mother, from postnatal day (P) 4-6. 3’mRNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing were performed on hypothalamic tissue at P6. Behaviour was assessed with the elevated plus, open field mazes and in-cage monitoring at 3-4 months of age.
MMS was only associated with subtle changes in gene expression, but there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity.
ELS has marked effects on DNA methylation in the hypothalamus in early life and results in stress-specific hyperactivity in young adulthood. These results have implications for the understanding of ELS-mediated effects on brain development.
Original languageEnglish
JournalEpigenetics and Chromatin
Early online date30 Jun 2021
DOIs
Publication statusE-pub ahead of print - 30 Jun 2021

Keywords / Materials (for Non-textual outputs)

  • Early life stress
  • DNA methylation
  • behaviour
  • Hypothalamus
  • brain development
  • Preterm birth

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