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  1. Evaluation Summary:

    This well-written report provides new insights for neuroscientists studying sleep architecture and stress sensitivity. A particularly important conclusion is that differences in sleep architecture before chronic social defeat stress may serve as a predictive biomarker of stress resilience. Overall the work is very strong, but there are some conceptual and methodological issues that need to be addressed.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

  2. Reviewer #1 (Public Review):

    The goal of the current study is to determine the impact of sleep on resilience to social stress. The research team accomplished their goals using male mice that underwent social defeat stress by a larger conspecific. The team found that sleep is necessary and sufficient for promoting stress resilience to social defeat stress. They also identified the prefrontal cortex as a major player in the link between sleep and stress resilience.

    Overall, this is a well-written manuscript that is strengthened by the translational relevance and significance, the well-executed study design, and the robustness of the data.

  3. Reviewer #2 (Public Review):

    This study examined whether and how sleep has a determinative role in behavioral responses to chronic social defeat stress (CSDS), and to what degree individual variability in sleep can predict those same behavioral responses. The manuscript reports that while sleep restriction increased susceptibility to CSDS, increased sleep from excitatory DREADDs in the preoptic area promoted resilience. After CSDS, resilient mice exhibited increased NREM and REM sleep. Prior to CSDS, mice later identified as resilient and susceptible had different patterns of recovery from sleep restriction. Mice later identified as resilient also exhibited higher baseline local field potential power density in the ventromedial prefrontal cortex.

    Behavior, chemogenetics, electrophysiology, and sleep telemetry all complement each other well in this study, and each is used to answer a different facet of the central question. Including baseline recordings and measurements provides great insight into factors that may predict resilience or susceptibility. The electrophysiology analyses indicate one mechanism involved in this relationship between sleep and stress. The local field potential recordings in the PFC also provide extensive and novel information on the power across different frequency bands, both before and after sleep restriction, in both resilient and susceptible samples. The same data compares infralimbic vs. prelimbic cortex for finer granularity and further detail. The sophisticated phase coherence analysis is particularly intriguing and deserves follow-up. Overall, the data analysis is rigorous, thorough, and thoughtful; however, these experiments alone do not sufficiently support the claims made in the results and discussions sections.

    Several deviations from the standardized chronic social defeat stress protocol should be considered when interpreting the results. The method used here employs 3 daily 10-minute defeats, instead of a single daily 5- to 10-minute defeat. To better answer whether sleep deprivation is sufficient to induce susceptibility, sleep deprivation could be combined with a sub-threshold defeat entailing three 5-minute defeats in a single day, a paradigm to which most sleep-replete animals should be resilient. Control animals were briefly introduced to empty CD1 cages, rather than housed with other C57s in the same divided cages as those defeated. The social interaction ratio for determining susceptibility and resilience excluded animals falling between 0.9 and 1.1, instead of using 1.0 as the threshold. Small sample sizes further limit the conclusions that can be drawn.

    The chemogenetic experiments are lacking an optimal control group. It has been demonstrated that CNO when administered systemically is metabolized into clozapine, a powerful psychotropic drug that could have behavioral and physiological effects even in DREADD- animals. Because the CNO was not administered directly into the preoptic area via cannula, an additional experimental group of CNO-only without social defeat stress would be useful for interpreting the results.

    Throughout the report, the initiation of the CSDS regimen is considered the "time-marker" for pre- and post-stress. This does not seem accurate; before sleep study measurements can be conducted, the mice have been subject to significant surgical procedures. It seems possible that factors including the application of, and recovery from, these procedures could be playing a role in subsequent individual differences in stress susceptibility. This possibility should be made more clear in the report, and (at minimum) ensure that the distinction between "before stress" and "before social defeat stress" is always made.

  4. Reviewer #3 (Public Review):

    The authors demonstrate in mice that the amount of sleep is related to stress resilience, and specifically that increased sleep after stress exposure supports resilient behavior. The aims are achieved through an array of methodologies, which highly strengthens the conclusions of the work. The question of whether sleep is related to stress resilience is highly significant and in the current research, the authors tackle the questions by evaluating differences in sleep homeostasis in stress-resilient compared to stress-susceptible mice. To induce more stress-susceptibility, the authors challenge the mice with sleep restriction, and to induce more stress-resilience, the authors chemogenetically induce increased NREM sleep. Mechanistically the authors demonstrate that cortically mediated NREM sleep is sufficient to promote resilience. Despite the challenging nature of the technological approaches at hand, particularly in mice, the experiments are well-designed and the authors are commended for the execution of these studies.

    It is very difficult to separate sleep loss and stress responses, as losing sleep is inevitably a stressful experience. The authors attempt to quell the notion that sleep restriction was also stressful to the animals by measuring fecal corticosterone, however, the measurements were from fecal pellets collected during an entire 24 hr period raises concerns that acute changes in HPA response may not be evident through this measurement. This is a challenging notion to tackle and deserves a bit more consideration.

    Chemogenetic experiments induce a beautiful increase in NREM sleep at the expense of REM loss, yet all the animals treated with chemogenetic agents are resilient to social defeat stress. The authors conclude that because sleep restriction also reduced REM, yet opposite effects occur on social interaction, REM sleep is unlikely to be related to resilience. In this context, it would be beneficial to discuss the theories of sleeping to forget and sleeping to remember, and supporting literature that REM sleep is critical to the consolidation of memories, particularly upon stressful experiences.