Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening
Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPRC) has been implicated in the generation of negative affective states under stressful conditions in both humans and rodents; however, the synaptic and molecular 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 (pIPFC) circuit is functionally engaged by acute stress exposure and that activation of this pathway can recapitulate the anxiogenic effects of stress. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synapse strength within reciprocal BLA-pIPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2- AQ)-mediated endocannabinoid signaling as key mechanism limiting glutamate release at BLA-pIPFC 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 circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and pIPFC and the translation of environmental stress to affective pathology.