Neurobiological Sequelae of Witnessing Stressful Events in Adult Mice

Abstract

Background It is well known that exposure to severe stress increases the risk for developing mood disorders. However, most chronic stress models in rodents involve at least some form of physically experiencing traumatic events. Methods This study assessed the effects of a novel social stress paradigm that is insulated from the effects of physical stress. Specifically, adult male C57BL/6J mice were exposed to either emotional (ES) or physical stress (PS) for ten minutes per day for ten days. ES mice were exposed to the social defeat of a PS mouse by a larger more aggressive CD-1 mouse from the safety of an adjacent compartment. Results Like PS mice, ES mice exhibited a range of depression- and anxiety-like behaviors both 24 hr and 1 month after the stress. Increased levels of serum corticosterone, part of the stress response, accompanied these behavioral deficits. Based on prior work which implicated gene expression changes in the ventral tegmental area (a key brain reward region) in the PS phenotype, we compared genome-wide mRNA expression patterns in this brain region of ES and PS mice using RNA-seq. We found significant overlap between these conditions, which suggests several potential gene targets for mediating the behavioral abnormalities observed. Conclusions Together, these findings demonstrate that witnessing traumatic events is a potent stress in adult male mice capable of inducing long-lasting neurobiological perturbations.

Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

“…Witness defeat was performed as previously described (15). Subthreshold witness defeat used a 14-d incubation period.…”

“…Mice witnessed a conspecific undergoing RSDS, but had no physical contact with the aggressor. Circulating levels of IL-6 were elevated in witness mice compared with controls 30 d after the last stressor, when the phenotype of social avoidance emerges (15) (Fig. 1F and Fig.…”

“…Neither constitutive IL-6 deletion nor hematopoietic progenitor cell-specific IL-6 deletion affected anxiety-associated exploratory behaviors in the elevated plus maze (Table S2). To determine whether IL-6 from leukocytes impacted the behavioral response to a purely emotional stressor (with no physical component), we exposed IL-6 −/− and WT BM chimeric mice to the witness model described previously (15). BM chimeras from high-IL-6 releasing controls displayed robust social avoidance behavior, whereas IL-6 −/− BM chimeras demonstrated resilient behavior (Fig.…”

“…Although systemic injection of proinflammatory cytokines induces "sickness behavior" reminiscent of depressive symptoms (12), a causal relationship between peripherally derived cytokines and stress-related disorders awaits confirmation. To directly address whether systemic inflammation functionally contributes to stress vulnerability, we used two social stress paradigms: repeated social defeat stress (RSDS) (13,14) and a purely emotional stressor (witness defeat) (15). As in humans (16,17), chronic social subordinations in mice lead to depression-like behavior, including social avoidance, in a subset of mice termed susceptible, whereas resilient mice resist the development of such behavior (18)(19)(20).…”

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Such exposures interrupt ongoing activities (Church, 1959), increase depression and anxiety-like behaviors (Warren et al, 2013), and elicit fear learning (Chen et al, 2009;Jeon et al, 2010;Yusufishaq and Rosenkranz, 2013). Emotionally salient stimuli generally recruit the dorsomedial prefrontal cortex (dmPFC) and the basolateral amygdala (BLA), which have strong reciprocal projections (Hubner et al, 2014;McDonald, 1998) and are involved in fear learning (Gilmartin et al, 2014;Marek et al, 2013;Senn et al, 2014), including contextual learning during observational fear (Amano et al, 2010;Jeon et al, 2010).…”