Projection-targeted photopharmacology reveals distinct anxiolytic roles for presynaptic mGluR2 in prefrontal- and insula-amygdala synapses.

Dissecting how membrane receptors regulate neural circuits is critical for deciphering principles of neuromodulation and mechanisms of drug action. Here, we use a battery of optical approaches to determine how presynaptic metabotropic glutamate receptor 2 (mGluR2) in the basolateral amygdala (BLA) controls anxiety-related behavior in mice. Using projection-specific photopharmacological activation, we find that mGluR2-mediated presynaptic inhibition of ventromedial prefrontal cortex (vmPFC)-BLA, but not posterior insular cortex (pIC)-BLA, connections produces a long-lasting decrease in spatial avoidance. In contrast, presynaptic inhibition of pIC-BLA connections decreases social avoidance and novelty-induced hypophagia without impairing working memory, establishing this projection as a novel target for the treatment of anxiety disorders. Fiber photometry and viral mapping reveal distinct activity patterns and anatomical organization of vmPFC-BLA and pIC-BLA circuits. Together, this work reveals new aspects of BLA neuromodulation with therapeutic implications while establishing a powerful approach for optical mapping of drug action.