A meta-analysis of the effects of early life stress on the prefrontal cortex transcriptome suggests long-term effects on myelin
Authors: Duan Toni Q. , Hagenauer Megan H. , Flandreau Elizabeth I. , Bader Anne , Nguyen Duy Manh , Maras Pamela M. , Merscher S. De Lima Randriely , Gyles Trevonn , Mclain Christabel , Meaney Michael. J. , Nestler Eric J. , Watson Stanley J. , Akil Huda 
Published: November 2024

Background

Early life stress (ELS) refers to exposure to negative childhood experiences, such as neglect, disaster, and physical, mental, or emotional abuse. ELS can permanently alter the brain, leading to cognitive impairment, increased sensitivity to future stressors, and mental health risks. The prefrontal cortex (PFC) is a key brain region implicated in the effects of ELS.

Methods

To better understand the effects of ELS on the PFC, we ran a meta-analysis of publicly available transcriptional profiling datasets. We identified five datasets (GSE89692, GSE116416, GSE14720, GSE153043, GSE124387) that characterized the long-term effects of multi-day postnatal ELS paradigms (maternal separation, limited nesting/bedding) in male and female laboratory rodents (rats, mice). The outcome variable was gene expression in the PFC later in adulthood as measured by microarray or RNA-Seq. To conduct the meta-analysis, preprocessed gene expression data were extracted from the Gemma database. Following quality control, the final sample size was n=89: n=42 controls & n=47 ELS: GSE116416 n=23 (no outliers); GSE116416 n=44 (2 outliers); GSE14720 n=7 (no outliers); GSE153043 n=9 (1 outlier), and GSE124387 n=6 (no outliers). Differential expression was calculated using thelimmapipeline followed by an empirical Bayes correction. For each gene, a random effects meta-analysis model was then fit to the ELS vs. Control effect sizes (Log2 Fold Changes) from each study.

Results

Our meta-analysis yielded stable estimates for 11,885 genes, identifying five genes with differential expression following ELS (false discovery rate< 0.05):transforming growth factor alpha(Tgfa),IQ motif containing GTPase activating protein 3(Iqgap3),collagen, type XI, alpha 1(Col11a1),claudin 11(Cldn11) andmyelin associated glycoprotein(Mag), all of which were downregulated.

Broadly, gene sets associated with oligodendrocyte differentiation, myelination, and brain development were downregulated following ELS. In contrast, genes previously shown to be upregulated in Major Depressive Disorder patients were upregulated following ELS.

Conclusion

These findings suggest that ELS during critical periods of development may produce long-term effects on the efficiency of transmission in the PFC and drive changes in gene expression similar to those underlying depression.

Graphical Abstract

Key Points

Early life stress (ELS) can have long-term effects on the prefrontal cortex (PFC) and its related cognitive and emotional functions.

To elucidate these long-term effects, we conducted a meta-analysis of five publicly available PFC transcriptional profiling datasets from adult rodents that had previously experienced ELS.

This meta-analysis revealed a consistent downregulation of myelin-related genes in the PFC following ELS, and an upregulation of genes related to Major Depressive Disorder.

Plain Language Summary

Early life stress refers to exposure to negative childhood experiences, such as neglect, disaster, and physical, mental, or emotional abuse. Early life stress can permanently alter the brain, including the prefrontal cortex, which can lead to cognitive and emotional dysfunction that lasts into adulthood. We performed a meta-analysis using five public datasets to identify consistent long-term effects of early life stress on gene expression (mRNA) in the prefrontal cortex of adult rodents. In these studies, rodents that had experienced early life stress consistently showed a decreased amount of mRNA for genes related to myelin. Myelin is the fatty layer that insulates the axons of neurons, allowing them to transmit electrical signals more efficiently. These gene expression changes may suggest long-term effects of early life stress on the efficiency of prefrontal neurotransmission, disrupting cognitive and emotional processing.