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
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