Prefrontal-cortex transcriptome profiles in mice with social defeat stress of varying duration

The project is directed to investigation of the gene activity dynamics during the development of a depression-like state. Chronic defeat stress induces a depression-like state in mice, which is similar to depressive states in humans according to similarities in symptoms, etiology, and sensitivity to antidepressants and anxiolytics as well as cerebral neurochemical changes. We analyzed the effects of social defeat stress of varying duration (10 and 30 days) on the behavioral patterns and prefrontal-cortex transcriptome (RNA-seq) in C57BL/6 mice. Commonly used 10-day exposure to social defeat stress resulted in a high level of social avoidance with no sign of depression-associated behavior. Contrariwise, most animals exposed to 30-day stress demonstrated clear hallmarks of depression, including higher level of social avoidance, increased immobility in the forced swim test, and anhedonic behavior. The monitoring of transcriptome changes revealed massive alterations in gene expression on the 10th day. Surprisingly, expression of a few genes was only affected on the 30th day of stress, apparently, due to a reversal of the majority of the early stress-induced changes to the original basal state. Moreover, we have found that glucocorticoid-sensitive genes are clearly enriched targets on the 10th day of stress, but these genes stop responding to the elevated corticosterone level after the 30th day of stress. The majority of genes altered by 30-day stress were downregulated, with the most relevant ones participating in chromatin-modifications and neuroplasticity (e,g, guanine nucleotide exchange factors (GEFs) of Rho-family GTPases). Very different molecular responses occur in both short-term and long-term social stress. Early-stress response associates with social avoidance and with up- and down- regulation of many genes, including signal transduction and cell adhesion pathways. Downregulation of a few genes, in particular, histone -modifying methyltransferases, is a signature of response to prolonged stress that induces depression. Altogether, our data show that the development of depression under social stress conditions is correlated with suppression of the overactivity of molecular response to induced stress, involving gene regulation resistance to corticoid molecules, potentially via chromatin remodeling mechanism.