Specific behaviors during auditory fear conditioning and postsynaptic expression of AMPA receptors in the basolateral amygdala predict interindividual differences in fear generalization in male rats

Auditory fear conditioning in rats is a widely used method to study learning, memory, and emotional responding. Despite procedural standardizations and optimizations, there is substantial interindividual variability in fear expression during test, notably in terms of fear expressed toward the testing context alone. To better understand which factors could explain this variation between subjects, we here explored whether behavior during training and expression of AMPA receptors (AMPARs) after long-term memory formation in the amygdala could predict freezing during test. We studied outbred male rats and found strong variation in fear generalization to a different context. Hierarchical clustering of these data identified two distinct groups of subjects that independently correlated with a specific pattern of behaviors expressed during initial training (i.e., rearing and freezing). The extent of fear generalization correlated positively with postsynaptic expression of GluA1-containing AMPA receptors in the basolateral nucleus of the amygdala. Our data thus identify candidate behavioral and molecular predictors of fear generalization that may inform our understanding of some anxiety-related disorders, such as posttraumatic stress disorder (PTSD), that are characterized by overgeneralized fear.