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      Individual baseline behavioral traits predict the resilience phenotype after chronic social defeat

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          Abstract

          Chronic social defeat (CSD) has been widely used as a psychosocial stress model in mice, with the magnitude of CSD-induced social avoidance as the major behavioral hallmark of the resilient and susceptible groups. Despite significant progress in the study of the neurobiology of resilient and susceptible mice, the nature and ethological relevance of CSD-induced social avoidance and social approach, particularly measured using a CD1 mouse, needs conceptual clarification. Based on the findings of a recent study revealing substantial individuality in genetically homogeneous inbred mice, we investigated whether certain baseline individual characteristics of male C57BL/6J mice predict the resilient outcome after CSD. We focused on two well-studied individual traits that seem to have heritable underpinnings—approach to novelty and avoidance of harm, which are essential for the expression of the exploratory drive. Our results showed that the exploration levels and the approach to novelty and harm were different before and after CSD in resilient and susceptible mice. Before the stress, resilient mice had higher horizontal activity in a novel environment, shorter approach latencies, and higher exploration times for social and non-social targets than susceptible mice. However, susceptible mice performed better in the passive avoidance task than resilient mice as they were more successful in learning to avoid potential adversity by suppressing the spontaneous exploratory drive. Our findings challenge the validity of the current selection criteria for the susceptible and resilient groups and encourage comprehensive assessment of both baseline and stress-induced individual behavioral signatures of mice.

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          Most cited references44

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          Animal models of neuropsychiatric disorders.

          Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.
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            Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.

            While stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying such resilience are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations that differ along several behavioral and physiological domains. By a combination of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability or insusceptibility. We show that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain's reward circuits in actively maintaining an emotional homeostasis.
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              A standardized protocol for repeated social defeat stress in mice.

              A major impediment to novel drug development has been the paucity of animal models that accurately reflect symptoms of affective disorders. In animal models, prolonged social stress has proven to be useful in understanding the molecular mechanisms underlying affective-like disorders. When considering experimental approaches for studying depression, social defeat stress, in particular, has been shown to have excellent etiological, predictive, discriminative and face validity. Described here is a protocol whereby C57BL/6J mice that are repeatedly subjected to bouts of social defeat by a larger and aggressive CD-1 mouse results in the development of a clear depressive-like syndrome, characterized by enduring deficits in social interactions. Specifically, the protocol consists of three important stages, beginning with the selection of aggressive CD-1 mice, followed by agonistic social confrontations between the CD-1 and C57BL/6J mice, and concluding with the confirmation of social avoidance in subordinate C57BL/6J mice. The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3-4 weeks for completion.
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                Author and article information

                Contributors
                Journal
                Neurobiol Stress
                Neurobiol Stress
                Neurobiology of Stress
                Elsevier
                2352-2895
                29 December 2020
                May 2021
                29 December 2020
                : 14
                : 100290
                Affiliations
                [a ]Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center, Mainz, Germany
                [b ]Leibniz Institute for Resilience Research, Mainz, Germany
                [c ]Institute of Physiological Chemistry, University Medical Center, Mainz, Germany
                Author notes
                []Corresponding author. marmilic@ 123456uni-mainz.de
                Article
                S2352-2895(20)30080-1 100290
                10.1016/j.ynstr.2020.100290
                7797906
                33457472
                539d1c09-6e19-4a1a-acee-8c15b3b53f9c
                © 2021 The Authors. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 September 2020
                : 22 December 2020
                : 22 December 2020
                Categories
                Original Research Article

                chronic social defeat,social avoidance,individual trait,exploration,novelty seeking,avoidance of harm

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