Generalization and extinction of learned fear alter primary sensory input to the brain

Neuroplasticity in sensory systems permits the brain to refine sensory discrimination between threat-predictive and neutral stimuli, but dysfunctional sensory plasticity might underlie maladaptive fear generalization. Using an odor-cued fear conditioning paradigm designed to induce broad fear generalization in a mouse model, we found that odor-evoked synaptic output from olfactory nerve into the brain's olfactory bulb was greatly increased not only for the original threat-predictive odor but also for novel odors that evoked generalized fear, even under anesthesia. Extinction training in which the threat-predictive odor was presented repeatedly without aversive stimulation reversed the behavioral fear and the increased olfactory nerve output evoked by the threat predictive odor. Extinction training also reversed the generalization of fear and enhanced neurophysiological response to new odors, as did alternative extinction paradigms using novel odorants, thus showing that the output of the olfactory nerve also parallels the generalization of extinction learning. Taken together the increased primary olfactory signaling evoked by fear-evoking odors and the reversal of this increase when the mouse is no longer afraid of an odor suggests that the olfactory nerve plasticity matches the mouse's perception of threat, even for olfactory stimuli and neuronal populations that have never actually been paired with shock. It is surprising that such beliefs about odor-shock contingencies would manifest as early as the synaptic input from the nose to the brain. This sensory plasticity might contribute to maladaptive generalization of fear such as in post-traumatic syndrome and generalized anxiety disorder.