Given the central role that striatal circuits play in both stress and depression, the simplest interpretation of our results is that loss of Wfs1 in mPFC impairs signaling to the striatum, and that failure to stimulate GABAergic output from the NAc to the PVN (Russo et al., 2012) is responsible for hyperactivation of the HPA axis in this model of stress-induced depression. This evidence concerns the gene WFS1 and major depressive disorder.