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

ABSTRACT 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.