In sum, our findings support for the hypothesis that depression is linked to disruption of homeostatic control of cortical micronetwork and unveil dynorphin/KOR signaling and CLAGlu-PLPV circuit as a signal and circuit-based mechanism by which chronic stress evokes depression through dysfunction of PL micronetwork via impairing excitatory inputs from the CLA to PL PV neurons. This evidence concerns the gene OPRK1 and major depressive disorder.