Adaptive reorganization of local sleep and prelimbic cortical circuits predict behavioral resilience to social defeat stress

Understanding the biological mechanisms responsible for resilience to stress—the ability to overcome adverse conditions—remains a major challenge. While sleep is a known regulator of resilience, the localized cortical dynamics that facilitate this process remain unclear. We hypothesized that resilience to social stress is determined by local sleep changes within the prelimbic cortex (PrL), a region critical for top-down control of stress-responsive circuits. To test this, we conducted longitudinal single-unit and local field potential (LFP) recordings in the prelimbic (PrL) cortex of male mice before and after a five-day social defeat stress paradigm. Our results demonstrate that population-wide neuronal silences, or "OFF-periods," primarily occur during NREM sleep and strongly correlate with the local slow-waves. Notably, resilient mice exhibit significantly higher baseline coupling between OFF-period density and the number of slow-waves compared to susceptible animals. Following stress, resilient mice showed a unique reorganization of cortical silence patterns, characterized by an increase in shorter OFF-periods and a more uniform temporal distribution across NREM sleep. Furthermore, social stress was associated with a widespread, stochastic-like redistribution of cortical firing rates that was most pronounced in the resilient phenotype. These findings suggest that behavioral resilience is predicted by the capacity for flexible network redistribution and heightened synchronization during local NREM sleep. Furthermore, this study identifies pre-existing, localized sleep-dependent signatures— specifically a stronger coupling between OFF-period density and slow-wave activity —that serve as potential predictors of resilience prior to stress. Significance Statement The biological mechanisms driving resilience—the ability to overcome stressful conditions—remain poorly understood. While non-rapid eye movement sleep promotes resilience, the cortical mechanisms underlying sleep’s actions are unclear. Here, we demonstrate that local sleep within the prelimbic cortex—specifically neuronal silence—predicts stress resilience. Using single-unit recordings, we show that neuronal silence is coupled with slow-waves, the hallmark of non-rapid eye movement sleep, and this relationship is strengthened in resilient mice. Furthermore, resilience is associated with a post-stress reorganization of neuronal silence and a redistribution of cortical firing rates. These findings suggest that behavioral resilience is predicted by the prefrontal cortex’s capacity for reorganization during sleep and provide a framework for understanding how sleep-dependent circuit plasticity protects against stress.