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.

Social Threat-Safety Test Uncovers Psychosocial Stress-Related Phenotypes.

Social stress is a major cause of the development of mental disorders. To enhance the translational value of preclinical studies, social stress experience and its behavioral impact on mice should be comparable to humans. Chronic social defeat (CSD) utilizes a type of social stress involving physical attacks and sensory threats to induce mental dysfunctions resembling human affective disorders. To strengthen the psychosocial component of CSD, a 10-day CSD protocol was applied in which daily physical attacks are standardized to three 10 s episodes followed by a 24 h sensory phase. After the 10th sensory phase, the CSD protocol is followed by a refined behavioral assay called the social threat-safety test (STST). Post-stress behavioral assays need to determine how and to what extent the social stressor has influenced behavior. The STST allows chronically socially defeated male mice to interact with 2 novel male individuals (social targets): one social target from the attacking strain encountered during the CSD days and the other from a novel strain. Both are presented simultaneously in different compartments of a three-chambered test arena. The test enables a simultaneous assessment of social avoidance development to measure successful aversive conditioned learning and social threat-safety discrimination ability. The development of social avoidance towards both strains reflects a generalized aversive response and thus, a measurement of stress susceptibility. Meanwhile, the development of social avoidance towards only the attacking strain reflects threat-safety discrimination and thus, a measurement of stress resilience. Finally, the absence of social avoidance towards the attacking strain reflects impaired aversive conditioned learning. The protocol aims to refine the currently used mouse models of stress susceptibility/resilience by including translational criteria, specifically threat-safety discrimination and aversive response generalization, to categorize a single group of chronically socially defeated animals into resilient and susceptible subgroups, eventually advancing future translational approaches.

Ecological validity of social defeat stressors in mouse models of vulnerability and resilience.

Laboratory mouse models offer opportunities to bridge the gap between basic neuroscience and applied stress research. Here we consider the ecological validity of social defeat stressors in mouse models of emotional vulnerability and resilience. Reports identified in PubMed from 1980 to 2020 are reviewed for the ecological validity of social defeat stressors, sex of subjects, and whether results are discussed in terms of vulnerability alone, resilience alone, or both vulnerability and resilience. Most of the 318 reviewed reports (95%) focus on males, and many reports (71%) discuss vulnerability and resilience. Limited ecological validity is associated with increased vulnerability and decreased resilience. Elements of limited ecological validity include frequent and repeated exposure to defeat stressors without opportunities to avoid or escape from unfamiliar conspecifics that are pre-screened and selected for aggressive behavior. These elements ensure defeat and may be required to induce vulnerability, but they are not representative of naturalistic conditions. Research aimed at establishing causality is needed to determine whether ecologically valid stressors build resilience in both sexes of mice.

A Resilience Related Glial-Neurovascular Network Is Transcriptionally Activated after Chronic Social Defeat in Male Mice.

Upon chronic stress, a fraction of individuals shows stress resilience, which can prevent long-term mental dysfunction. The underlying molecular mechanisms are complex and have not yet been fully understood. In this study, we performed a data-driven behavioural stratification together with single-cell transcriptomics of the hippocampus in a mouse model of chronic social defeat stress. Our work revealed that in a sub-group exhibiting molecular responses upon chronic stress, the dorsal hippocampus is particularly involved in neuroimmune responses, angiogenesis, myelination, and neurogenesis, thereby enabling brain restoration and homeostasis after chronic stress. Based on these molecular insights, we applied rapamycin after the stress as a proof-of-concept pharmacological intervention and were able to substantially increase stress resilience. Our findings serve as a data resource and can open new avenues for further understanding of molecular processes underlying stress response and for targeted interventions supporting resilience.

Long-term effects of intermittent early life stress on primate prefrontal-subcortical functional connectivity.

Correlational studies of humans suggest that exposure to early life stress has long-term effects on neural circuits involved in vulnerability and resilience to mental health disorders. Stress-related mental health disorders are more prevalent in women than in men. Here, female squirrel monkeys are randomized to intermittently stressful (IS) social separations or a non-separated (NS) control condition conducted from 17 to 27 weeks of age. Nine years later in mid-life adulthood, resting-state functional magnetic resonance imaging was employed to parcellate prefrontal cortex (PFC). Resulting subdivisions were then used to characterize functional connectivity within PFC, and between PFC subdivisions and subcortical regions that are known to be altered by stress. Extensive hyper-connectivity of medial and orbitofrontal PFC with amygdala, hippocampus, and striatum was observed in IS compared to NS monkeys. Functional hyper-connectivity in IS monkeys was associated with previously reported indications of diminished anxiety-like behavior induced by prepubertal stress. Hyper-connectivity of PFC with amygdala and with hippocampus was also associated with increased ventral striatal dopamine D2 and/or D3 receptor (DRD2/3) availability assessed with positron emission tomography (PET) of [11C]raclopride binding in adulthood. Ventral striatal DRD2/3 availability has been linked to cognitive control, which plays a key role in stress coping as an aspect of emotion regulation. These findings provide causal support for enduring neurobiological effects of early life stress and suggest novel targets for new treatments of stress-related mental health disorders.

Psycho-social factors associated with mental resilience in the Corona lockdown.

The SARS-CoV-2 pandemic is not only a threat to physical health but is also having severe impacts on mental health. Although increases in stress-related symptomatology and other adverse psycho-social outcomes, as well as their most important risk factors have been described, hardly anything is known about potential protective factors. Resilience refers to the maintenance of mental health despite adversity. To gain mechanistic insights about the relationship between described psycho-social resilience factors and resilience specifically in the current crisis, we assessed resilience factors, exposure to Corona crisis-specific and general stressors, as well as internalizing symptoms in a cross-sectional online survey conducted in 24 languages during the most intense phase of the lockdown in Europe (22 March to 19 April) in a convenience sample of N = 15,970 adults. Resilience, as an outcome, was conceptualized as good mental health despite stressor exposure and measured as the inverse residual between actual and predicted symptom total score. Preregistered hypotheses (osf.io/r6btn) were tested with multiple regression models and mediation analyses. Results confirmed our primary hypothesis that positive appraisal style (PAS) is positively associated with resilience (p < 0.0001). The resilience factor PAS also partly mediated the positive association between perceived social support and resilience, and its association with resilience was in turn partly mediated by the ability to easily recover from stress (both p < 0.0001). In comparison with other resilience factors, good stress response recovery and positive appraisal specifically of the consequences of the Corona crisis were the strongest factors. Preregistered exploratory subgroup analyses (osf.io/thka9) showed that all tested resilience factors generalize across major socio-demographic categories. This research identifies modifiable protective factors that can be targeted by public mental health efforts in this and in future pandemics.

Chronic social defeat-induced social avoidance as a proxy of stress resilience in mice involves conditioned learning.

Chronic social defeat (CSD)-induced social avoidance is considered to model a feature of stress-related mental dysfunction, while its absence has been used as a proxy of resilience in rodents. However, knowledge on the mechanisms shaping CSD-induced individual outcomes remains fragmentary. Fear conditioning has been described as a suitable model in humans for better understanding the pathophysiology of stress related mental disorders. We sought to explore the extent to which conditioned learning is involved in CSD-induced social avoidance. In experiment 1 (social avoidance specificity), C57BL/6 J male mice underwent CSD followed by a modified social interaction test offering the simultaneous choice between an unknown mouse from the aggressor's strain or a mouse from a different strain and phenotypic characteristics. In experiment 2 (social avoidance extinction), CSD-extinction sessions involving only the sensory phase of CSD were conducted on one group of defeated mice whereas a second group only received handling, followed by social interaction test with a novel mouse from the aggressor's strain. Our results provide evidence that CSD-induced social avoidance does not generalize to other phenotypic characteristics than those of the aggressors and can be successfully reversed during extinction training. Taken together, our findings strongly point to the involvement of conditioned learning in shaping CSD-induced social avoidance, a finding that is of interest to future studies into the neurobiology of resilience.

Stress inoculation in mice induces global resilience.

Each year, more than half a billion people in the world are affected by stress-related health disorders. Consequently, there is an urgent need for new insights to guide interventions designed to increase stress resilience. Studies of humans and various animals have uncovered the process of stress inoculation, in which exposure to mild stressors enhances subsequent stress resilience. Here, we investigate whether stress inoculation-induced resilience in mice consistently occurs across a multiplicity of different stress contexts (tests). C57BL/6 J adult male mice were randomised either to stress inoculation training (n = 36) or to a non-inoculated, but handled control condition (n = 36). Thereafter, indications of coping and resilience were assessed during (i) acute social defeat in a context similar to that used for stress inoculation training, and (ii) fear conditioning and learned extinction in a novel context. Stress inoculation effects were also assessed during (iii) tail-suspension and (iv) open-field tests that each represent milder stressors. Stress-inoculated mice showed more active defence behaviour during acute social defeat, higher sociability before and after defeat, and greater indications of learned extinction of conditioned fear compared to non-inoculated control mice. Stress-inoculated mice also responded with diminished tail-suspension immobility and open-field defecation. Results suggest that stress inoculation protects against various stressors that differ in quality and relative intensity. Stress inoculation research in mice may serve as the basis for mechanistic studies of global resilience in humans.