A meta-analysis of the effects of early life stress on the prefrontal cortex transcriptome suggests long-term effects on myelin
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,007 | 0,014 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,004 | 0,021 |
| Bibliométrie | 0,002 | 0,004 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».