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

Fitzgerald, E., Sinton, M. C. , Wernig-Zorc, S., Morton, N. M., Holmes, M. C., Boardman, J. P. and Drake, A. J. (2021) Altered hypothalamic DNA methylation and stress-induced hyperactivity following early life stress. Epigenetics and Chromatin, 14, 31. (doi: 10.1186/s13072-021-00405-8) (PMID:34193254) (PMCID:PMC8247254)

Abstract

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 h/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.

• Item Type: Articles
• Additional Information: This work was funded by a PhD studentship (to EF) from Medical Research Scotland (PhD-878–2015), in collaboration with Aquila BioMedical (Edinburgh, UK) and a grant from the RS Macdonald Seedcorn Fund (to AJD and JPB), administered by Edinburgh Neuroscience. MCS was supported by a British Heart Foundation PhD studentship (FS/16/54/32730) and by the British Heart Foundation Centre of Research Excellence. SW-Z was funded by the Deutsche Forschungsgemeinschaft (SFB960). NMM was supported by a Wellcome Trust New Investigator Award (100981/Z/13/Z). MCH was supported by the Wellcome Trust (WT079009). JPB was supported by the MRC Centre for Reproductive Health Centre Grant (MRC G1002033). AJD was supported by the British Heart Foundation Centre of Research Excellence, University of Edinburgh.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sinton, Dr Matthew
• Authors: Fitzgerald, E., Sinton, M. C., Wernig-Zorc, S., Morton, N. M., Holmes, M. C., Boardman, J. P., and Drake, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Epigenetics and Chromatin
• Publisher: BioMed Central
• ISSN: 1756-8935
• ISSN (Online): 1756-8935
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Epigenetics and Chromatin 14: 31
• Publisher Policy: Reproduced under a Creative Commons License