SOMATOSTATIN INTERNEURONS TUNE PREFRONTAL NETWORKS FOR ADAPTIVE STRESS COPING

Passive coping represents a core behavioral feature of affective disorders, including major depression. Accumulating evidence implicates altered neurotrophic (BDNF) signaling and dysfunction of somatostatin (SST) interneurons within cortical circuits; however, the causal links between these changes and depression-related behaviors remain unclear. In this study, we investigated the role of BDNF signaling in SST interneurons by selectively deleting the BDNF receptor tyrosine kinase B (TrkB) from SST neurons in mice (SST-TrkB KO). SST-TrkB KO mice of both sexes displayed reduced passive coping behavior, while anxiety-like behavior and cognitive performance remained unaffected. Whole-brain mapping of coping-related neuronal activity during the tail suspension test using c-Fos/SST immunolabeling identified the medial prefrontal cortex (mPFC) as a key candidate hub. To directly assess its causal involvement, TrkB expression was selectively knocked down in SST interneurons using shRNA-mediated silencing. This intervention reproduced the reduction in passive coping observed in the knockout model. Importantly, knocked down of prefrontal TrkB receptors in parvalbumin or vasoactive polypeptide positive interneurons did not affect coping behavior. Furthermore, brain-wide activity mapping following prefrontal TrkB knockdown revealed altered activation patterns and connectivity across multiple stress-related network nodes. Together, these findings indicate that SST interneurons play a critical role in shaping prefrontal regulatory functions, thereby influencing stress coping strategies and potentially broader depression-related phenotypes.