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

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.