People with two mutated copies of Wolfram syndrome gene 1 (WFS1) develop a disorder characterized by a wide range of symptoms, whereas people with only one mutant version of this gene are more likely to develop depression. To explore whether this gene controls depressive behaviors through the medial prefrontal cortical (mPFC) circuit – a region previously implicated in stress, depression, and behavioral resilience – Shrestha et al. studied the Wfs1 gene in mice. First they found that the expression of Wfs1 was enriched in layer 2/3 pyramidal neurons of the mPFC. Next they deleted Wfs1 in the cortex and the mPFC to generate Wfs1 cortex CKO mice, which exhibit stress-induced depressive behaviors and elevated stress hormone release. Shrestha et al. also investigated how the mPFC neurons connect to other brain regions (such as the nucleus accumbens (NAc), amygdala (Amg), thalamus (Thal) and cortex (Ctx)), and the effects of Wfs1 on endoplasmic reticulum (ER) function. Taken together, these results reveal details about the molecular pathways of Wfs1-expressing mPFC neurons that regulate depressive behaviors. This also provides a starting point for future studies to narrow down pathogenic mechanisms and identify potential novel therapeutic targets.