Transcriptome changes of disinhibited somatostatin neurons in the medial prefrontal cortex mediating male-specific stress resilience

Somatostatin (SST)-expressing interneurons are critical modulators of vulnerability to chronic stress and are strongly implicated in the pathophysiology of stress-related affective disorders. Consistent with this role, we have recently demonstrated that selective enhancement of SST neuron activity—achieved via cell type–specific Cre-mediated inactivation of GABA _A receptors (SSTCre:γ2 ^f/f mice)—robustly promotes resilience to chronic variable stress (CVS) at the behavioral and tissue transcriptomic levels. Notably, the neural substrate underlying this resilience is sex-specific: in males, it localizes to the medial prefrontal cortex (mPFC), whereas in females it maps to the ventral hippocampus. Building on these findings, we sought to define the SST neuron–specific transcriptomic and biological properties associated with stress resilience in male mice. We compared purified SST neurons from the mPFC of stress-vulnerable (SSTCre) and stress-resilient (SSTCre:γ2 ^f/f ) male mice, using corresponding female mice as negative controls. Our analyses reveal a striking, sex-specific transcriptomic resilience phenotype. Specifically, we found that the transcriptome of mPFC SST neurons from male—but not female—SSTCre:γ2 ^f/f mice exhibits marked resistance to CVS-induced perturbations. In male SSTCre:γ2 ^f/f mice, SST neurons displayed a substantially reduced number of differentially expressed genes (DEGs) following CVS exposure, along with a loss of correlation of stress-induced transcriptional changes relative to SSTCre littermates. In contrast to males, SST neurons from the mPFC of female SSTCre:γ2 ^f/f mice exhibited an increased number of CVS-responsive DEGs and a transcriptomic profile that was inversely correlated with that of SSTCre controls. In agreement with these transcriptomic changes, gene set enrichment analyses identified markedly fewer CVS-responsive biological functions in the resilient male mice compared to their vulnerable littermates. Normalized enrichment scores for gene ontology summary terms indicated that SST neurons from male SSTCre:γ2 ^f/f mice are protected from CVS-induced downregulation of gene sets governing neural cell fate, apoptosis, and cell adhesion, and exhibit partial resilience to CVS-induced disruptions in mitogen-activated protein kinase signaling and cytoskeletal organization. By contrast, SST neurons from the female SSTCre mice showed no measurable CVS-induced alterations in these same gene programs. Collectively, these findings provide compelling evidence that the male-specific, SST neuron–intrinsic resilience mechanisms within the mPFC are key determinants of the previously described tissue-level and behavioral stress resilience phenotypes in SSTCre:γ2 ^f/f mice.