Fear extinction reverses dendritic spine formation induced by fear conditioning in the mouse auditory cortex

Significance Whether learning-induced changes in neuronal circuits are inhibited or erased during the process of unlearning remains unclear. In this study, we examined the impact of auditory-cued fear conditioning and extinction on the remodeling of synaptic connections in the living mouse auditory cortex. We found that fear conditioning leads to cue-specific formation of new postsynaptic dendritic spines, whereas fear extinction preferentially eliminates these new spines in a cue-specific manner. Our findings suggest that learning-related changes of synaptic connections in the cortex are at least partially reversed after unlearning. Fear conditioning-induced behavioral responses can be extinguished after fear extinction. While fear extinction is generally thought to be a form of new learning, several lines of evidence suggest that neuronal changes associated with fear conditioning could be reversed after fear extinction. To better understand how fear conditioning and extinction modify synaptic circuits, we examined changes of postsynaptic dendritic spines of layer V pyramidal neurons in the mouse auditory cortex over time using transcranial two-photon microscopy. We found that auditory-cued fear conditioning induced the formation of new dendritic spines within 2 days. The survived new spines induced by fear conditioning with one auditory cue were clustered within dendritic branch segments and spatially segregated from new spines induced by fear conditioning with a different auditory cue. Importantly, fear extinction preferentially caused the elimination of newly formed spines induced by fear conditioning in an auditory cue-specific manner. Furthermore, after fear extinction, fear reconditioning induced reformation of new dendritic spines in close proximity to the sites of new spine formation induced by previous fear conditioning. These results show that fear conditioning, extinction, and reconditioning induce cue- and location-specific dendritic spine remodeling in the auditory cortex. They also suggest that changes of synaptic connections induced by fear conditioning are reversed after fear extinction.

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