Reconceptualising resilience within a translational framework is supported by unique and brain-region specific transcriptional signatures in mice

Chronic social defeat (CSD) in mice has been increasingly employed in experimental resilience research. Particularly, the degree of CSD-induced social avoidance is used to classify animals into resilient (socially non-avoidant) versus susceptible (avoidant). Inspired by human data pointing to threat-safety discrimination and responsiveness to extinction training of aversive memories as characteristics of resilient individuals, we here describe a translationally informed stratification which identified three phenotypic subgroups of mice following CSD: the Discriminating-avoiders, characterised by successful social threat-safety discrimination and successful extinction of social avoidance; the Indiscriminate-avoiders, showing fear generalisation, and the Non-avoiders (absence of social avoidance) displaying impaired conditioned learning. Furthermore, and supporting the biological validity of our approach, we uncovered subgroup-specific transcriptional signatures in classical fear conditioning and anxiety-related brain regions. Our reconceptualisation of resilience in mice refines the currently used dichotomous classification and contributes to advancing future translational approaches. Chronic social defeat (CSD) took place for 10 days on 165 mice (Defeated) while 55 animals served as a control group. Following the last session by 24h, the Modified Social Interaction test (MSIT) was performed. Following the test, Defeated mice were divided into three subgroups in addition to the Control group. Cue discrimination test followed the MSIT 48h later on the first subset of animals; n=10 Non-avoiders, n=17 Indiscriminate-avoiders, and n=11 Discriminating-avoiders. Active avoidance task followed the MSIT 48h later on another subset of animals; n=18 Non-avoiders, n=10 Indiscriminate-avoiders, and n=9 Discriminating-avoiders. Social avoidance extinction treatment followed the MSIT 24h later and lasted for 16 consecutive days on yet another subset of animals; n=21 Indiscriminate-avoiders and n=25 Discriminating-avoiders. Following the last session by 24h, the second MSIT took place. Finally, remaining animals were sacrificed following the (first) MSIT and used for transcriptome analysis.