Neural signature of delayed fear generalization under stress

Although the generalization of fear to stimuli resembling a threatening stimulus is an adaptive mechanism, fear overgeneralization is maladaptive and thought to play a key role in anxiety-related disorders. Since there is typically a delay between an initial fear experience and a situation in which fear (over)generalization may occur, we assessed delayed fear generalization and its neural signature. Moreover, as stress is known to affect fear learning, we further tested whether acute stress modulates fear generalization. Therefore, we conducted a two-day fear generalization study, with initial fear acquisition on Day 1 and a fear generalization test after a 24-hr delay in the MRI scanner. Prior to fear generalization testing, participants were exposed to a stressor or a control manipulation. Our behavioral data showed the expected generalization of fear. At a neural level, fear generalization was accompanied by increased fear-signaling for stimuli that resembled the conditioned stimulus in the bilateral insula and frontal operculum, whereas activity declined in frontal, hippocampal, and temporal regions, including the ventromedial prefrontal cortex, as stimuli became more similar to the conditioned stimulus. Importantly, stress did not modulate fear generalization, neither on a behavioral nor on a neural level. Interestingly, in an explorative comparison to two other studies that used the same paradigm but tested generalization immediately after acquisition, we observed increased fear generalization in the delayed relative to the immediate generalization test. In sum, our results suggest that stress leaves fear generalization and its neural signature unaffected but that a temporal delay might increase the extent to which fear responses are generalized to stimuli resembling the threatening stimulus.