Projection-targeted photopharmacology reveals distinct anxiolytic roles for presynaptic mGluR2 in prefrontal- and insula-amygdala synapses.
| Publication Type | Academic Article |
| Authors | Munguba H, Srivastava I, Gutzeit V, Singh A, Vijay A, Kristt M, Arefin A, Thukral S, Broichhagen J, Stujenske J, Liston C, Levitz J |
| Journal | Neuron |
| Volume | 113 |
| Issue | 6 |
| Pagination | 912-930.e6 |
| Date Published | 01/28/2025 |
| ISSN | 1097-4199 |
| Keywords | Prefrontal Cortex, Receptors, Metabotropic Glutamate, Synapses |
| Abstract | 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. |
| DOI | 10.1016/j.neuron.2025.01.002 |
| PubMed ID | 39879977 |
| PubMed Central ID | PMC11925682 |