Resilience and susceptibility to fear extinction are associated with alterations in neurogenesis and brain-wide activity

Fear-related disorders, characterized by inappropriate learned fear and resistance to extinction, are among the most prevalent psychiatric conditions. Potential modifications in neurogenesis and brain activity were studied as possible individual factors associated with the development of these pathologies. By using Pavlovian fear conditioning and extinction paradigm, male and female mice were categorized in resilient and susceptible phenotypes based on their individual fear extinction behavior. Increased neurogenesis, as revealed by higher expression of the early neuronal marker doublecortin in the subgranular zone of the dentate gyrus, was observed in susceptible male and female mice. This result suggests the existence of a compensatory mechanism given that the DNA-alkylating agent temozolomide induced an impairment of fear extinction and a reduction of neurogenesis in male mice. The use of c-Fos immunofluorescence revealed several brain regions that were differently activated in susceptible Animals, although these differences were less evident in female mice. Categorization by k-means clustering based on c-Fos labelling was significantly associated with phenotype of extinction in male, but not female, Animals. Pairwise Pearson correlations between brain regions showed that resilience and susceptibility to fear extinction are related to divergent circuit-level reorganizations. These findings reveal new individual factors involved in the variability of fear extinction response which could be of interest for the development of future therapeutic strategies.

Brain-wide activity; Fear; Mice; Neurogenesis; Resilience; Susceptibility.