Modulation of behavioral and hippocampal transcriptomic responses in rat prolonged chronic unpredictable stress model by fluoxetine, eicosapentaenoic acid and lipopolysaccharide

Abstract

AbstractAnimal models are widely used to study common stress-induced affective disorders, such as anxiety and depression. Here, we examine behavioral and brain transcriptomic (RNA-seq) responses in rat prolonged chronic unpredictable stress (PCUS) model, and their modulation by 4-week treatment with fluoxetine, eicosapentaenoic acid (EPA), lipopolysaccharide (LPS) and their combinations. Overall, chronic stress produced anxiety-like phenotype, corrected by fluoxetine alone or in combination with EPA or LPS. EPA was anxiolytic in several tests, whereas LPS alone increased anxiety. PCUS evoked pronounced transcriptomic changes in rat hippocampi, differentially expressing >200 genes, while all pharmacological manipulations (except fluoxetine+EPA) affected only few genes. Gpr6, Drd2 and Adora2a were downregulated by chronic stress in a treatment-resistant manner, suggesting highly conserved nature of these pathogenetic genomic responses to chronic stress. Overall, these findings support the validity of rat PCUS paradigm as an effective tool to study stress-related pathologies, and calls for further research to probe how various conventional and novel drugs modulate behavioral and brain transcriptomic biomarkers of chronic stress in rodent models.