Abstract

A meta-analysis of the effects of early life stress on the prefrontal cortex transcriptome suggests long-term effects on myelin

Duan TQ, Hagenauer MH, Nguyen DM, Bader A, Flandreau EI, Maras PM, de Lima RMS, Meaney MJ, Watson SJ, Akil H
53rd Annual Meeting of the Society for Neuroscience. 2024.

Abstract

Early life stress (ELS) refers to exposure to negative childhood experiences, such as neglect, disaster, physical, mental, or emotional abuse. ELS can permanently alter an individual's brain, leading to cognitive impairment, sensitivity to future stressors, and mental health risks.

The prefrontal cortex (PFC) is a key brain region implicated in the effects of ELS. To better understand the effects of ELS on the PFC, we ran a meta-analysis of publicly available transcriptional profiling datasets. We identified four datasets (GSE89692, GSE116416, GSE14720, GSE153043) that characterized the long-term effects of multi-day ELS paradigms (maternal separation for >3hrs/day or limited nesting) in male and female laboratory rodents (rats, mice) during the postnatal period (between postnatal days 2-20). The outcome variable was gene expression in the PFC later in life (late juveniles or adults) as measured by microarray or RNA-Seq.

To conduct the meta-analysis, we extracted log2 transformed gene expression data and sample metadata from the Gemma database of curated and re-analyzed gene expression studies. After subsetting to the relevant samples (PFC, no intervention beyond ELS) and removing outliers, the final sample size was n=60 (GSE116416 n=23 (no outliers); GSE116416 n=21 (2 outliers); GSE14720 n=7 (no outliers); GSE153043 n=9 (1 outlier)). We excluded data from genes (defined by Entrez ID) that lacked variability in expression. We calculated ELS vs. Control differential expression using the limma pipeline (for microarray datasets) or the limma-trend pipeline (for RNA-Seq datasets), followed by an empirical Bayes correction. Meta-analysis was conducted by fitting a random effects model to the ELS vs. Control effect sizes (Log2 Fold Changes or Log2FC) and their respective sampling variances from each study.

We reached stable meta-analysis estimates for 12,152 genes. Two results survived false discovery rate correction (FDR<0.05): 1) the down-regulation of Claudin 11 (Cldn11: Log2FC=-0.31, FDR=0.00047), a myelin component and regulator of oligodendrocyte proliferation and migration, and 2) the upregulation of Solute Carrier Family 30 Member 3 (Slc30a3: Log2FC=0.18, FDR=0.0047), a zinc transporter found in synaptic vesicles. Amongst the top twenty results, there was also a downregulation of other myelin-related genes (Myelin Associated Glycoprotein (Mag): Log2FC=-0.25, FDR=0.093; Mal, T Cell Differentiation Protein (Mal) - a.k.a. Myelin And Lymphocyte Protein: Log2FC=-0.29, FDR=0.109). These findings suggest that ELS during critical periods of development may produce long-term effects on the efficiency of transmission in the PFC.