2025/10/24 by Jinglin Xiong, Megan Hastings Hagenauer, C. P. Rhoads +8 · 1 voice
Neuroscience · #Tryptophan and brain disorders #Stress Responses and Cortisol #Neurotransmitter Receptor Influence on Behavior
paper · doi:10.1101/2025.10.23.683091
openalex created_date 2025/10/24 · openalex publication_date 2025/10/24 · openalex updated_date 2026/07/14
Abstract Background Chronic stress is a major risk factor for psychiatric disorders, including anxiety, depression, and post-traumatic stress disorder. Chronic stress can cause structural alterations like grey matter atrophy in key emotion-related areas such as the prefrontal cortex (PFC). To identify biological pathways affected by chronic stress in the PFC, researchers have performed transcriptional profiling (RNA-sequencing, microarray) to measure gene expression in rodent models. However, transcriptional signatures in the PFC that are shared across different chronic stress paradigms and laboratories remain relatively unexplored. Methods We performed a meta-analysis of publicly available transcriptional profiling datasets within the Gemma database. We identified six datasets that characterized the effects of either chronic social defeat stress (CSDS) or chronic unpredictable mild stress (CUMS) on gene expression in the PFC in mice ( n =117). We fit a random effects meta-analysis model to the chronic stress effect sizes (log(2) fold changes) for each transcript ( n =21,379) measured in most datasets. We then compared our results with two other published chronic stress meta-analyses, as well as transcriptional signatures associated with psychiatric disorders. Results We identified 133 genes that were consistently differentially expressed across chronic stress studies and paradigms (false discovery rate (FDR)<0.05). Fast Gene Set Enrichment Analysis (fGSEA) revealed 53 gene sets enriched with differential expression (FDR<0.05), dominated by glial and neurovascular markers ( e.g., oligodendrocyte, astrocyte, endothelial/vascular) and stress-related signatures ( e.g., major depressive disorder, hormonal responses). Immediate-early gene markers of neuronal activity ( Fos, Junb, Arc, Dusp1 ) were consistently suppressed. Many of the identified effects resembled those seen in previous meta-analyses characterizing stress effects (CSDS, early life stress), despite minimal overlap in included samples. Moreover, some effects resembled previous observations from psychiatric disorders, including alcohol abuse disorder, major depressive disorder, bipolar disorder, and schizophrenia. Conclusion Our study demonstrates that chronic stress induces a robust, cross-paradigm PFC signature characterized by down-regulation of glia/myelin and vascular pathways and suppression of immediate-early gene activity, highlighting cellular processes linking chronic stress exposure, PFC dysfunction, and psychiatric disorders. Graphical Abstract Key Points Chronic stress is linked to many human psychiatric disorders involving the prefrontal cortex (PFC). Meta-analysis showed that stressed mice had less gene expression for glia and neural activity in the PFC. PFC gene expression in chronically stressed mice mirrors patterns seen in psychiatric patients. Plain Language Summary Chronic stress has been shown to have lasting effects on the brain, contributing to cognitive impairments and the risk of psychiatric disorders such as anxiety, depression, and post-traumatic stress disorder. The prefrontal cortex, a brain region that is important for behavioral and attentional control, is sensitive to chronic stress. We combined information from six public mouse datasets to identify consistent effects of chronic stress on gene expression (mRNA) in the prefrontal cortex. In these studies, mice that had experienced chronic stress showed a decreased amount of mRNA related to a variety of non-neuronal support cells (glia) and blood vessels, and general neural activity. The mouse chronic stress signature overlapped with gene-activity patterns reported in human psychiatric conditions, suggesting a biological bridge between chronic stress and the onset of psychopathology.