Distinct patterns of neural activity during initial defeat encounter are predictive of future susceptibility or resilience to chronic defeat

Social stress is a significant factor in triggering psychiatric disorders, including depression. The effects of chronic stress accumulate, and the way in which an individual responds to those initial stress exposures can shape subsequent stress reactivity. The chronic social defeat stress (CSDS) model in mice has been used to examine neurobiological mechanisms underlying individual variability in stress outcomes. After 10 days of social defeat, mice diverge into distinct groups based on their social behavior: “resilient” mice maintain high social exploration whereas “susceptible” mice avoid social stimuli. Here, we used Fos-TRAP 2 technology to permanently label neural activity on day 1 of defeat while allowing mice to undergo the full CSDS protocol and subsequent social interaction testing. Using a customized, high-throughput method for counting FosTRAP-positive cells across a total of 66 brain regions, we showed that social defeat provoked a brain-wide synchronization of neural activity. Moreover, the specific response patterns captured during that first defeat were dramatically different depending on whether mice would go on to develop a resilient vs. susceptible phenotype, suggesting that largely distinct networks of brain regions recruited during the initial experience shape the eventual behavioral outcome. Finally, within defeated mice, higher activation within paraventricular zone of the hypothalamus on day 1 correlated with more resilient social interaction ratios that emerged after several days of stress. This work represents a comprehensive description of the brain-wide neural network encoding social defeat, revealing how distinct neural responses to the initial defeat encounter precede the emergence of different coping behaviors after chronic defeat.