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Early life stress and LPS interact to modify the mouse cortical transcriptome in the neonatal period
Eamon Fitzgerald1, James P Boardman2,3, Amanda J Drake1
1University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
Insights
Early life stress and inflammation interact to alter neonatal brain gene expression. This study reveals shared mechanisms in preterm infants, crucial for understanding cognitive impairment and developing interventions.
Area of Science:
- Neuroscience
- Developmental Biology
- Genomics
Background:
- Preterm birth (PTB) is linked to impaired brain development and cognitive deficits.
- Early life stress (ELS) and systemic inflammation are common in preterm infants, impacting neurodevelopment.
- Understanding their combined effects on the neonatal cortex is vital for therapeutic development.
Purpose of the Study:
- To investigate the interactive effects of infection (lipopolysaccharide; LPS) and ELS (modified maternal separation; MMS) on the neonatal mouse cortex transcriptome.
- To identify shared and distinct molecular mechanisms influenced by these early-life challenges.
- To provide insights into the neural basis of atypical cortical development in preterm infants.
Main Methods:
- A murine model was used, involving LPS administration and MMS during the early postnatal period.
- Four experimental groups were established: control, LPS only, MMS only, and LPS + MMS.
- Cortical tissue was collected at postnatal day 6 for 3'RNA sequencing.
Main Results:
- LPS exposure led to reduced weight gain and increased brain inflammation gene expression.
- More genes were differentially expressed in LPS and MMS groups individually compared to the combined LPS + MMS group.
- Significant overlap in gene expression patterns between LPS and MMS conditions suggests shared underlying mechanisms, particularly for upregulated genes.
Conclusions:
- LPS and MMS interact to modify the neonatal cortical transcriptome.
- These findings highlight the complex interplay of early-life insults on brain development.
- Understanding these interactions is crucial for addressing cognitive impairments associated with preterm birth.
Introduction:
Preterm birth (PTB) is closely associated with atypical cerebral cortical development and cognitive impairment. Early exposure to extrauterine life often results in atypical environmental and biological experiences that co-occur, including early life stress (ELS) and systemic inflammation. Understanding how these experiences interact to shape cortical development is an essential prerequisite to developing therapeutic interventions that will work in the complex postnatal environment of the preterm infant. Here, we studied the effects of a murine model of infection and ELS on the neonatal cortex transcriptome.
Methods:
We used a mouse model of infection (1 mg/kg LPS at postnatal day (P)3) +/- ELS (modified maternal separation; MMS on days P4-P6) at timepoints with neurodevelopmental relevance to PTB. We used 4 groups: control, LPS, MMS and LPS + MMS. Cortices were dissected at P6 for 3'RNA sequencing.
Results:
LPS exposure resulted in reduced weight gain and increased expression of inflammation-associated genes in the brain. More genes were differentially expressed following LPS (15) and MMS (29) than with LPS + MMS (8). There was significant overlap between the LPS and MMS datasets, particularly amongst upregulated genes, and when comparing LPS and MMS datasets with LPS + MMS. Gene Ontology terms related to the extracellular matrix and cytokine response were enriched following MMS, but not following LPS or LPS + MMS. 26 Reactome pathways were enriched in the LPS group, none of which were enriched in the LPS + MMS group. Finally, a rank-rank hypergeometric overlap test showed similarities, particularly in upregulated genes, in the LPS and MMS conditions, indicating shared mechanisms.
Conclusion:
LPS and MMS interact to modify the cortical transcriptome in the neonatal period. This has important implications for understanding the neural basis of atypical cortical development associated with early exposure to extrauterine life.
