Neuron
Volume 105, Issue 6, 18 March 2020, Pages 1062-1076.e6
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Article
Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

https://doi.org/10.1016/j.neuron.2019.12.024Get rights and content
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Highlights

  • The BLA-plPFC circuit is engaged by stress exposure and its activation is anxiogenic

  • Stress enhances glutamate release in a reciprocal BLA-plPFC-BLA subcircuit

  • BLA-plPFC glutamatergic drive is constrained by multimodal 2-AG signaling

  • 2-AG signaling collapse mediates stress-induced circuit strengthening and anxiety

Summary

Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.

Keywords

2-arachidonoylglycerol
glutamate
prefrontal cortex
anxiety
cannabinoid
amygdala
stress
optogenetics
cannabis
posttraumatic stress disorder

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