Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

David J. Marcus, Gaurav Bedse, Andrew D. Gaulden, James D. Ryan, Veronika Kondev, Nathan D. Winters, Luis E. Rosas-Vidal, Megan Altemus, Ken Mackie, Francis S. Lee, Eric Delpire, Sachin Patel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1062-1076.e6
Issue number6
StatePublished - Mar 18 2020


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

ASJC Scopus subject areas

  • General Neuroscience


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