Social Buffering is Dependent on Mutual Experience in Adolescent Male Mice Exposed to Social Defeat Stress

Abstract

Background: Individuals who experience emotional, physical, or sexual abuse as children suffer from higher rates of major depressive disorder, drug abuse, and suicide. Early life interventions such as peer support groups can be beneficial to adolescents who experience trauma, suggesting that social support is important in facilitating rehabilitation and promoting resiliency to stress. Although there are some animal paradigms that can model how peer-peer interactions influence stress-reactivity, less is known about how individual stress experiences influence the effectiveness of social buffering.

Methods: The vicarious social defeat stress (VSDS) paradigm allows for the assessment of two different stress modalities, physical (PS) and emotional (ES) stress, which confer different levels of stress with similar biological and behavioral outcomes. Using a modified VSDS paradigm in which pairs of mice experience ES and PS together we can begin to evaluate how stress exposure influences the buffering efficacy of social relationships. Adolescent mice (postnatal day 35) were randomly combined into dyads and were allocated into either mutual experience or cohabitation pairs. Within each dyad, one mouse was assigned to the physically stressed (PS) condition and was repeatedly exposed to an aggressive CD1 mouse while the other mouse was designated as the partner. In the mutual experience dyads the partner mice witnessed the defeat bout (ES) while in the cohabitation dyads the partner was separated from the PS mouse and returned after the 10 min defeat bout was terminated (non-stressed). After 10 days of defeat, mice were tested in the social interaction test (SIT), the elevated plus maze (EPM), and the forced swim test (FST).

Results: PS-exposed mice in the cohabitation dyads, but not those in the mutual experience dyads, showed significantly more avoidance of a novel CD1 aggressor or c57BL/6 mouse, in the SIT. Surprisingly, both partner conditions showed avoidance to a CD1. Interestingly, non-stressed partner mice spent less time in the open arms of the EPM, suggesting increased anxiety; only PS-exposed mice in cohabitation dyads showed more time spent immobile in the FST, indicative of increased learned helplessness.

Conclusions: These data suggest that the efficacy of social buffering can be mediated by individual stress experience.

Keywords: adolescence; chronic social defeat stress; social buffering; stress; stress transmission; vicarious social defeat stress.

Figure 1.

Experimental design. The vicarious social defeat stress paradigm was performed as previously described, with minor modifications. Mice were paired with a weight-matched conspecific and randomly assigned to either mutual experience or cohabitation dyads. Within each mutual experience dyad, one mouse was assigned to experience emotional (ES) and the other physical (PS) stress for 10 consecutive days. Pre-defeat, dyads were placed into the empty compartment of a divided hamster cage containing a CD1 aggressor. During the defeat bout the PS- mice were placed into the CD1 compartment, while the ES-exposed mice only observed the defeat bout. After ten minutes, the mice in the PS condition were returned to the adjacent compartment and the pair was housed overnight next to the recently encountered aggressor (post-defeat). The cohabitation dyads differed only in that the partner mouse was removed and placed into a holding cage during the defeat bouts. Given that the partners in the cohabitation dyads do not directly or indirectly experience stress, they are also considered non-stressed partners. Mice in the control (CON) condition were single housed next to a CD1 but separated by a Plexiglas divider such that each mouse was housed in its own compartment. Image Created with BioRender.com.

Figure 2.

Having a stress-exposed partner buffers stress-induced avoidance in mice exposed to physical stress. Following ten days of stress exposure, adolescent mice were tested in the social interaction test with a CD1 (a) or a c57BL6/J (b) as the social target. Both partner mice spent significantly less time with the novel CD1 regardless of whether they experienced stress (p < .05). Interestingly, the PS-exposed mice with a partner that did not witness the defeat spent less time interacting with the novel CD1, which was attenuated in PS-exposed mice that had a mutually experiencing partner. The mice in the CON condition showed equal levels of exploration in the interaction zone with or without a CD1 present (p > .05). Only the non-stressed partner mice (co-habituating partners) showed avoidance to a novel conspecific. Stress-induced CORT modulation was significantly increased in adolescent mice exposed to SDS (c) compared to their respective controls (p < .05). Similarly, PS mice in the co-habitation dyads showed significantly higher CORT expression compared to their control counterparts (p < .05) *p < .05, **p < .01, ***p < .001.

Figure 3.

Interaction correlations within the dyads. A correlation analysis revealed that mutual experience dyads showed a stronger concurrence in SI score when interacting with a novel CD1 (p < .05), compared to cohabitation dyads (a). There was no significant relationship within the mutual experience or cohabitation dyads when interacting with a novel c57BL6/J (b).

Figure 4.

Non-stressed partners show increased anxiety-like behavior. Mice were tested in the elevated plus maze (EPM) 48 h after the last defeat. Raw time spent in the open arms of the EPM was not significantly different between the groups (a); however, time spent as a percent of time in each arm ([open arm time/(open arm + closed arm time)]*100), revealed that non-stressed partners spent less time in the open arms of the EPM (b). The non-stressed partner also had significantly more time spent in the closed arms compared to stressed partner mice and CON mice (p < .05, respectively; c). **p < .01, ***p < .001. To assess depression-like behavior, mice were tested in the forced swim test 48 h after the last defeat bout (d). Physically stressed mice with a non-stressed partner spent significantly more time immobile compared to the mice in the CON condition (p < .05). **p < .01.