mGluR5 in EC^CCK to BLA Circuit Modulates Depressive-Like Phenotypes through CCK Signaling

Dysregulation of metabotropic glutamate receptor 5 (mGluR5) and cholecystokinin (CCK) signaling has been implicated in major depressive disorder (MDD), but the underlying circuit mechanisms remain unclear. Here, we define how mGluR5 regulates depressive-like behaviors through CCK signaling in the entorhinal cortex (EC) to basolateral amygdala (BLA) pathway. Anatomical tracing and optogenetics show that CCK-expressing neurons in the EC project to the BLA and that their activation increases glutamatergic activity in this region. Bidirectional circuit manipulation establishes causality: optogenetic stimulation induces, whereas inhibition alleviates, depressive-like phenotypes. Expansion microscopy reveals postsynaptic mGluR5 enrichment along this pathway. Chronic social defeat stress (CSDS) downregulates mGluR5 in the BLA. Pharmacologically, mGluR5 antagonism phenocopies CCK-driven pro-depressive effects, whereas CCK knockout mice resist behavioral consequences of mGluR5 inhibition. Mechanistically, mGluR5 agonism suppresses CCK release, disrupts BLA long-term potentiation, and mitigates CSDS-induced behaviors. Circuit-specific mGluR5 knockdown in the EC^CCK→BLA pathway increases stress susceptibility. These findings identify an mGluR5-CCK axis within an EC^CCK→BLA circuit that governs stress-induced affective states.