Related Experiment Video
Updated: Nov 17, 2025
Instrumentation of Near-term Fetal Sheep for Multivariate Chronic Non-anesthetized Recordings
Published on: October 25, 2015
Hippocampal epigenetic and insulin-like growth factor alterations in noninvasive versus invasive mechanical
Xingrao Ke1, Bohan Xing1, Mar Janna Dahl1
1Department of Pediatrics, Division of Neonatology, School of Medicine, University of Utah, Salt Lake City, UT, 84132-2202, USA.
Insights
Noninvasive respiratory support (NRS) in preterm lambs promotes higher insulin-like growth factor 1 (IGF1) mRNA levels and distinct epigenetic changes in the hippocampus compared to invasive mechanical ventilation (IMV). This suggests NRS may protect the developing brain via epigenetic mechanisms.
Area of Science:
- Neonatal neuroscience
- Molecular epigenetics
- Respiratory physiology
Background:
- Premature infants undergoing invasive mechanical ventilation (IMV) face risks of hippocampal damage, impacting learning and memory.
- Insulin-like growth factor 1 (IGF1) is crucial for hippocampal development.
- Noninvasive respiratory support (NRS) offers a gentler ventilation alternative.
Purpose of the Study:
- To investigate if NRS influences IGF1 mRNA variants and epigenetic profiles in the hippocampus compared to IMV.
- To determine the molecular impact of different ventilation strategies on the developing hippocampus.
Main Methods:
- Preterm lambs were exposed to NRS or IMV for 3 or 21 days.
- Hippocampal tissues were analyzed for IGF1 mRNA levels, splice variants (P1, P2, IGF1A, 1B), DNA methylation, and histone modifications (H3K4me3, H3K27me3, H3K36me3).
Main Results:
- NRS demonstrated significantly higher levels of IGF1 P1, 1A, and 1B mRNA variants compared to IMV.
- NRS also resulted in increased DNA methylation and greater occupancy of activating (H3K4me3), repressive (H3K27me3), and elongation (H3K36me3) histone marks.
Conclusions:
- NRS induces distinct IGF1 mRNA variant levels and epigenetic profiles in the hippocampus compared to IMV.
- These findings suggest NRS may mitigate hippocampal damage in preterm neonates through epigenetic regulation.
Background:
The brain of chronically ventilated preterm human infants is vulnerable to collateral damage during invasive mechanical ventilation (IMV). Damage is manifest, in part, by learning and memory impairments, which are hippocampal functions. A molecular regulator of hippocampal development is insulin-like growth factor 1 (IGF1). A gentler ventilation strategy is noninvasive respiratory support (NRS). We tested the hypotheses that NRS leads to greater levels of IGF1 messenger RNA (mRNA) variants and distinct epigenetic profile along the IGF1 gene locus in the hippocampus compared to IMV.
Methods:
Preterm lambs were managed by NRS or IMV for 3 or 21 days. Isolated hippocampi were analyzed for IGF1 mRNA levels and splice variants for promoter 1 (P1), P2, and IGF1A and 1B, DNA methylation in P1 region, and histone covalent modifications along the gene locus.
Results:
NRS had significantly greater levels of IGF1 P1 (predominant transcript), and 1A and 1B mRNA variants compared to IMV at 3 or 21 days. NRS also led to more DNA methylation and greater occupancy of activating mark H3K4 trimethylation (H3K4me3), repressive mark H3K27me3, and elongation mark H3K36me3 compared to IMV.
Conclusions:
NRS leads to distinct IGF1 mRNA variant levels and epigenetic profile in the hippocampus compared to IMV.
Impact:
Our study shows that 3 or 21 days of NRS of preterm lambs leads to distinct IGF1 mRNA variant levels and epigenetic profile in the hippocampus compared to IMV. Preterm infant studies suggest that NRS leads to better neurodevelopmental outcomes later in life versus IMV. Also, duration of IMV is directly related to hippocampal damage; however, molecular players remain unknown. NRS, as a gentler mode of respiratory management of preterm neonates, may reduce damage to the immature hippocampus through an epigenetic mechanism.
