A meta-analysis of the effects of early life stress on the prefrontal cortex transcriptome suggests long-term effects on myelin
Bibliographic record
Abstract
Abstract 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 the limma pipeline 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 ) and myelin 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.007 | 0.014 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.021 |
| Bibliometrics | 0.002 | 0.004 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".