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

Abstract Analyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons or brain region-specific chemogenetic activation of SST neurons in mice results in stress resilience. Here, we used RNA sequencing of mice with disinhibited SST neurons to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female mice with disinhibited SST neurons is characterized by resilience to chronic stress-induced transcriptome changes in the medial prefrontal cortex. Interestingly, the transcriptome of non-stressed stress-resilient male mice resembled the transcriptome of chronic stress-exposed stress-vulnerable mice. However, the behavior and the serum corticosterone levels of non-stressed stress-resilient mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of stress-resilient mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes indicating stress-induced enhancement of mRNA translation. Behaviorally, the mice with disinhibited SST neurons were not only resilient to chronic stress-induced anhedonia — they also showed an inversed anxiolytic-like response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in expression of putative stress resilience genes, through a sex-specific brain substrate.