Consistent changes in global gene expression patterns despite strong variation in individual gene expression in the male mouse hippocampus following early life stress.

Overview

1. Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
2. Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, the Netherlands
3. Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil
4. Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neurosciences-King's College London, UK
5. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
6. Oncode Institute, Utrecht, the Netherlands
7. Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
8. Institute for Genome Stability in Ageing and Disease, Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
9. University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Abstract

Exposure to excessive and/or chronic stressors during early life is a well-established risk factor for later life stress-related mood disorders. Glucocorticoids are often implied as mediators of the long-term effects of early life stress (ELS), given their powerful transcriptional effects via the glucocorticoid receptor (GR). Previous work in rodents showed that the GR-antagonist RU486 administered during early puberty can reverse some of the behavioral and cellular effects of ELS. Here, we investigated the long-term transcriptional effects of ELS, using the limited bedding and nesting model, on the hippocampus of adult or adolescent male mice. The effects on the adult dorsal hippocampal transcriptome, established in two separate cohorts (of two labs), were found to be inconsistent. The same inconsistency was observed when investigating the transcriptome in adolescent mice – thus examining the tissue with a shorter interval after ELS – in tissue from two cohorts where virtually all sources of variation were controlled for, involving the same ELS protocol, laboratory, and experimenter. Interestingly, despite the limited overlap of individual differentially expressed genes between cohorts, we did observe a consistent pattern at a more global transcriptional level: a preferential upregulation of shorter genes and progressive downregulation with increasing gene length (as a continuous variable) after ELS, consistent with a gene-length-dependent transcription decline (GLTD) pattern. This GLTD pattern was accompanied by an enrichment of aging-associated transcriptomic changes in glial and vascular brain cell types during adolescence, a signature that was attenuated in adulthood. Together, these findings indicate that while individual gene-level responses to ELS are highly variable, robust and reproducible transcriptional patterns emerge at the level of global gene architecture (based on length) and cellular aging signatures.

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Sanguino-Gómez, J., Buurstede, J. C., Umeoka, E. H., da Silva Umeoka, M. S., Gentenaar, M., Garcia-Cairasco, N., Juruena, M. F., Vermeij, W. P., Hoeijmakers, J. H., Krugers, H. J., Joëls, M., & Meijer, O. C. (2026). Consistent changes in global gene expression patterns despite strong variation in individual gene expression in the male mouse hippocampus following early life stress. Neurobiology of stress, 42, 100808. https://doi.org/10.1016/j.ynstr.2026.100808

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