Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions

Background Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF₁) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Methods Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF₁ (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Results Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF₁ signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. Conclusions The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF₁ represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes.