Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

Neuron. 2020 Mar 18;105(6):1062-1076.e6. doi: 10.1016/j.neuron.2019.12.024. Epub 2020 Jan 13.


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; amygdala; anxiety; cannabinoid; cannabis; glutamate; optogenetics; posttraumatic stress disorder; prefrontal cortex; stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / complications
  • Anxiety / physiopathology
  • Arachidonic Acids / metabolism
  • Basolateral Nuclear Complex / metabolism
  • Basolateral Nuclear Complex / physiology*
  • Endocannabinoids / metabolism*
  • Glutamic Acid / metabolism
  • Glycerides / metabolism
  • Male
  • Mice
  • Neural Pathways / metabolism
  • Neural Pathways / physiology
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiology*
  • Restraint, Physical
  • Stress, Psychological / complications
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology*
  • Synaptic Transmission / physiology


  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • Glutamic Acid
  • glyceryl 2-arachidonate