Research reportDifferent susceptibility to social defeat stress of BalbC and C57BL6/J mice
Research highlights
▶ The manuscript illustrates how different mouse strains respond to the social defeat stress highlighting strain-specific coping strategies in physiology and behavior to the social stressor. ▶ We believe this approach may provide a valid experimental tool to study different susceptibility levels to stress and vulnerability to its deleterious consequences, aiming at establishing a translational model with relevance for human pathology.
Introduction
It is well-established that individuals differ in the perception and in the psychological consequences of adverse life events [1]. In particular, environmental variables, such as stressful experiences, and predisposing genetic factors are thought to interact and to influence resistance/vulnerability to risk for psychiatric disorders, by mediating the adaptive/mal-adaptive stress-coping strategies [1].
The underlying mechanisms of individual variability in stress resilience can be made accessible using animal models of individual differences in response to social stress procedures such as the one represented by social defeat [2]. Social defeat is a meaningful experience particularly in species relying on interactions with conspecifics like the house mice, whose social life organization is mainly determined by aggressive interactions [3]. Social defeat can be accomplished by forcing the experimental subject to intrude into the space occupied by an aggressive and unfamiliar mouse (i.e., the resident animal) leading to subordination of the test mouse [4]. Social defeat stress can have persistent behavioral and neurobiological effects even after a single experience [5], [6], [7], [8], [9], [10], [11]. Complementarily, when encountered on an intermittent, unpredictable basis, and experienced over protracted periods, the cost of the biological efforts to adapt may become excessive, thus increasing vulnerability to stress-related pathologies [12].
Multiple approaches can be performed to examine individual differences in response to stress. For example it has been established that, when a considerably large number of C57BL6/J inbred mice is subjected to chronic social defeat, defeated mice can be segregated into susceptible and unsusceptible populations [13]. Considering other experimental stressors, the relationship between stressor experience and stress resiliency/susceptibility has been assessed by studying the stress response of different inbred mouse strains [14], [15]. Several behavioral inter-strain differences and the relative contribution of genetic factors to stress/anxiety reactions have been repeatedly demonstrated [14]. However, it must be noted that these differences may depend on the specific behavioral test selected [16], [17] and may differ depending on the adopted stressor (i.e. psychogenic/neurogenic versus naturalistic) [18], [19], [20]. Therefore the experimental approach based on the comparison of different strains subjected to social defeat, which to our knowledge has not been previously applied, has the potential to identify the variables contributing to depressive-like changes.
We subjected C57BL6/J and BALB/c mice to social defeat and evaluated the expression of different coping strategies on the basis of several behavioral and physiological measures related to stress. We selected these strains because of their frequent use in scientific research and because they diverge in measures of behavior [14], [21], [22], [23], [24] and physiology [25], [26], [27], [28], [29]. Specifically, several prior studies have demonstrated that C57BL6/J mice are stress-resilient, exhibit a lower level of anxiety, and have less emotionality than BalbC mice that, in turn, are considered more stress-sensitive, anxious, and emotional [14], [20], [30]. In the BalbC strain, stressors can provoke marked hypothalamic–pituitary–adrenal (HPA) responses and central monoamine variations at hypothalamic and mesolimbic brain regions that could explain the heightened stress reactivity of this strain [20], [30], [31], [32], [33]. Importantly, the excessive utilization of norepinephrine and serotonin in response to chronic stressors is moderated in C57BL6/J mice (i.e., the initial excessive utilization is tempered), whereas the already high levels of amine utilization becomes further pronounced in BalbC mice [34], [35], [36]. These strain-specific neurobiological adaptations may underlie the high responsivity to both acute and chronic stress in BalbC mice, as well as the reduced responsivity to acute stress and a capability to acclimate more readily to chronic stress in C57BL6/J mice.
In the present studies, mice of both strains were subjected, in separate experiments, to acute or chronic social defeat with the aim to highlight strain-dependent coping strategies with this social stress. The immediate consequences of a single social defeat were evaluated on different behavioral parameters, such as home-cage activity, social avoidance, sucrose preference, and body weight that can reflect some of the diagnostic criteria for mood disorders (i.e., psychomotor retardation, social withdrawal, anhedonia and body weight loss/gain) (DSM-IV-TR™, 2000). Furthermore, the long-term consequences of repeated social defeats were evaluated in a longitudinal study that was primarily focused on behavioral measures relevant for anxiety- and depressive-like states (i.e., social avoidance, forced swim test); secondarily, the existence of persistent alterations due to repeated social defeats was evaluated on parameters related to metabolism (i.e., body weight, food intake, leptin, insulin, abdominal fat stores), stress (i.e., ACTH, adrenal glands, gonadal organs), and immune system (i.e., cytokines, thymus, spleen), as a whole associated with psychiatric disturbances.
Section snippets
Animals
C57BL6/J (n = 55) and BalbC (n = 56) mice (Charles River Labs, Calco, Italy) weighing 18–20 g at the beginning of the experiments served as experimental subjects. Subjects were group housed in 59.5 cm × 38.0 cm × 20.0 cm polycarbonate cages upon arrival under constant temperature (21 ± 2 °C) and a 12/12 h light/dark cycle (dark phase: 1800–0600 h). Food and water were available ad libitum.
All experimental procedures were carried out in accordance with Italian law (Legislative Decree no. 116, 27 January 1992),
Statistics
Statistical analyses were conducted using Statistica V8 (Statsoft, Inc., Tulsa, OK). Data distribution was checked for satisfying ANOVA's assumptions and, if appropriate, data were log transformed, which resulted to be needed only for internal organ weight data.
Home-cage activity data were analyzed as total values during the 24 h observation time by means of one-way ANOVA with social defeat stress (defeated versus controls) as between-subject variable.
Body weight gain data were analyzed as
Body weight
Defeated mice body weight gain did not differ from control values (F(1,33) = 1.83; ns) [control: −0.53 ± 0.11 g; defeated: −0.38 ± 0.12 g].
Home-cage activity
The total duration of locomotion was significantly decreased in defeated mice compared to controls (C57BL6/J: F(1,14) = 5.26; p < 0.05) (Fig. 2).
Social avoidance test
In general the time in the ‘interaction zone’ was significantly increased in the ‘aggressor phase’ in C57BL6/J (F(1,18) = 14.19; p < 0.01) compared to the ‘non-social phase’ of the test (data not shown). On the other hand, the time
Experiments 1 and 2—effects of single social defeat on C57BL6/J and BalbC mice
In the present experimental conditions, a single social defeat triggered strain- and parameter-dependent consequences.
Acute social defeat triggers a prompt stress response based upon increases in markers of HPA axis activation, suggestive of a fast activation of the sympatho-adrenal system [41]. Home-cage activity was reliably decreased in both strains of defeated subjects, in accordance with data of stress-induced immobility obtained across different acute stress procedures and mouse strains
General conclusions
Individual variability is of pivotal importance when assessing the negative consequences of stress experiences. In the present studies, the use of the ethologically relevant social defeat stress in two mouse lines demonstrated strain-specific coping strategies, following either its single or repeated experience. One social defeat episode decreased the home-cage activity in both strains, and it elicited body weight loss in BalbC but not in C57BL6/J defeated mice. As for the repeated exposure to
Acknowledgements
The authors wish to thank Claudia Granato, Alessia Guidi, Valentina Pavoni, Alessandro Poffe and Claudio Righetti for their excellent technical assistance in the conducting of experiments and Dr. Francesca Michielin for her valuable discussion with respect to the statistical analyses.
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