A Cortico-amygdala Neural Substrate for Endocannabinoid Modulation of Fear Extinction

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2023 Jul 22

PMID 37480845

Authors

Ozge Gunduz-Cinar

Laura I Castillo

Maya Xia

Elise Van Leer

Emma T Brockway

Gabrielle A Pollack

Farhana Yasmin

Olena Bukalo

Aaron Limoges

Sarvar Oreizi-Esfahani

Veronika Kondev

Rita Baldi

Ao Dong

Judy Harvey-White

Resat Cinar

George Kunos

Yulong Li

Larry S Zweifel

Sachin Patel

Andrew Holmes

Affiliations

Soon will be listed here.

Abstract

Preclinical and clinical studies implicate endocannabinoids (eCBs) in fear extinction, but the underlying neural circuit basis of these actions is unclear. Here, we employed in vivo optogenetics, eCB biosensor imaging, ex vivo electrophysiology, and CRISPR-Cas9 gene editing in mice to examine whether basolateral amygdala (BLA)-projecting medial prefrontal cortex (mPFC) neurons represent a neural substrate for the effects of eCBs on extinction. We found that photoexcitation of mPFC axons in BLA during extinction mobilizes BLA eCBs. eCB biosensor imaging showed that eCBs exhibit a dynamic stimulus-specific pattern of activity at mPFCBLA neurons that tracks extinction learning. Furthermore, using CRISPR-Cas9-mediated gene editing, we demonstrated that extinction memory formation involves eCB activity at cannabinoid CB1 receptors expressed at vmPFCBLA synapses. Our findings reveal the temporal characteristics and a neural circuit basis of eCBs' effects on fear extinction and inform efforts to target the eCB system as a therapeutic approach in extinction-deficient neuropsychiatric disorders.

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