Fear circuit–based neurobehavioral signatures mirror resilience to chronic social stress in mouse

Consistent evidence from human data points to successful threat–safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat–safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat–safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat–safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.