Alternative splicing in mouse brains affected by psychological stress is enriched in the signaling, neural transmission and blood-brain barrier pathways

Abstract

Psychological stress increases the risk of major psychiatric disorders. Psychological stress on mice was reported to induce differential gene expression (DEG) in mice brain regions. Alternative splicing is a fundamental aspect of gene expression and has been associated with psychiatric disorders but has not been investigated in the stressed brain yet. This study investigated changes in gene expression and splicing under psychological stress, the related pathways, and possible relationship with psychiatric disorders. RNA-seq raw data of 164 mouse brain samples from 3 independent datasets with stressors including chronic social defeat stress (CSDS), early life stress (ELS), and two-hit stress of combined CSDS and ELS were collected. There were more changes in splicing than in gene expression in the ventral hippocampus and medial prefrontal cortex, but stress-induced changes of individual genes by differential splicing and differential expression could not be replicated. In contrast, pathway analyses produced robust findings: stress-induced differentially spliced genes (DSGs) were reproducibly enriched in neural transmission and blood-brain barrier systems, and DEGs were reproducibly enriched in stress response-related functions. The hub genes of DSG-related PPI networks were enriched in synaptic functions. The corresponding human homologs of stress-induced DSGs were robustly enriched in AD-related DSGs as well as BD and SCZ in GWAS. These results suggested that stress-induced DSGs from different datasets belong to the same biological system throughout the stress response process, resulting in consistent stress response effects.