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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 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.
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 language | English |
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Journal | Epigenetics and Chromatin |
Early online date | 30 Jun 2021 |
DOIs | |
Publication status | E-pub ahead of print - 30 Jun 2021 |
Keywords
- Early life stress
- DNA methylation
- behaviour
- Hypothalamus
- brain development
- Preterm birth
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Dive into the research topics of 'Altered hypothalamic DNA methylation and stress-induced hyperactivity following early life stress'. Together they form a unique fingerprint.Projects
- 5 Finished
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Exploiting the population isolate GWAS "jack-pot effect": Transgene modelling of a novel human visceral fat and blood pressure lowering gene.
Morton, N.
22/09/16 → 21/07/18
Project: Research
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Understanding epigenetic mechanisms linking preterm birth and neurodevelopmental disorders
Drake, A.
1/09/16 → 31/08/20
Project: Research