Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure

To understand the mechanisms underlying resilience to chronic stress exposure observed in mice with disinhibited SST neurons (SSTCre:γ2f/f mice), we analyzed and compared the transcriptome profiles of the medial prefrontal cortex (mPFC) from male and female control (SSTCre) and mutant (SSTCre:γ2f/f) mice, with and without exposure to 21 days of chronic variable stress (CVS). We found that SSTCre:g2f/f male, but not female, mice are resilient to CVS-induced changes in the mPFC transcriptome. The CVS-induced transcriptome of stress-resilient male mice was characterized by fewer and distinct CVS-induced gene expression changes compared to the CVS-induced transcriptome of stress-vulnerable SSTCre controls. The transcriptome of non-stressed stress-resilient male mice showed stress-like transcriptome changes along with defects in signal transduction similar to stress exposed SSTCre stress-vulnerable controls. These features of non-stressed stress-resilient mice were normalized by chronic stress exposure, along with enhancement of mRNA translation. Stress-induced differentially expressed genes of stress-vulnerable, but not stress-resilient mice were prominently associated with risk genes of human stress-related psychiatric disorders.