Hierarchical Status Predicts Behavioral Vulnerability and Nucleus Accumbens Metabolic Profile Following Chronic Social Defeat Stress

Abstract

Extensive data highlight the existence of major differences in individuals' susceptibility to stress [1-4]. While genetic factors [5, 6] and exposure to early life stress [7, 8] are key components for such neurobehavioral diversity, intriguing observations revealed individual differences in response to stress in inbred mice [9-12]. This raised the possibility that other factors might be critical in stress vulnerability. A key challenge in the field is to identify non-invasively risk factors for vulnerability to stress. Here, we investigated whether behavioral factors, emerging from preexisting dominance hierarchies, could predict vulnerability to chronic stress [9, 13-16]. We applied a chronic social defeat stress (CSDS) model of depression in C57BL/6J mice to investigate the predictive power of hierarchical status to pinpoint which individuals will exhibit susceptibility to CSDS. Given that the high social status of dominant mice would be the one particularly challenged by CSDS, we predicted and found that dominant individuals were the ones showing a strong susceptibility profile as indicated by strong social avoidance following CSDS, while subordinate mice were not affected. Data from H-NMR spectroscopy revealed that the metabolic profile in the nucleus accumbens (NAc) relates to social status and vulnerability to stress. Under basal conditions, subordinates show lower levels of energy-related metabolites compared to dominants. In subordinates, but not dominants, levels of these metabolites were increased after exposure to CSDS. To the best of our knowledge, this is the first study that identifies non-invasively the origin of behavioral risk factors predictive of stress-induced depression-like behaviors associated with metabolic changes.

Stress‐Induced Depression: Is Social Rank a Predictive Risk Factor?

“…Importantly, the recognition of social status as a potentially key determinant of susceptibility and resilience to stress is in agreement with earlier work proposing strong links between social status, stress responsiveness, and depression . However, underscoring dominant individuals as the vulnerable ones is at odds with substantial literature establishing a link between social subordination and depression . Therefore, in this review, after discussing the rationale for identifying non‐invasively risk factors of stress susceptibility, we will re‐open the debate as to whether a specific social status (i.e., dominance or subordination) predicts vulnerability to develop stress‐induced depression or whether additional factors should be accounted for …”

“…This somehow puzzling discovery has posed the question as to whether the observed differences in stress effects represent random variability or, instead, emerge from non‐genetic pre‐existing factors? In a recent study in C57BL/6J inbred mice, we have identified rank attained within a homecage social hierarchy as a strong predictor of the development of depression‐like behaviors following exposure to chronic social defeat stress (CSDS), with dominant mice being the ones that showed susceptibility . These data imply that social rank in pre‐established hierarchies could emerge as a predictive risk factor, that can be identified non‐invasively, of stress‐induced depression‐like behaviors.…”

An energetic view of stress: Focus on mitochondria

“…Data from 1 H NMR spectroscopy indicated that subordinates show lower levels of energy-related metabolites than dominant mice (Larrieu et al, 2017). When exposed to chronic social defeat, dominant males were the ones that specifically showed vulnerability to display depression-like behaviors.…”

“…When exposed to chronic social defeat, dominant males were the ones that specifically showed vulnerability to display depression-like behaviors. While levels of brain energy metabolites increased in ‘resilient’, subordinate mice, metabolites in dominant, ‘vulnerable’ animals tended to be reduced following exposure to chronic social defeat (Larrieu et al, 2017). …”

Differential mitochondrial morphology in ventral striatal projection neuron subtypes

“…These properties are altered in MSN subtypes in diseased states including neurodegeneration, addiction, stress-induced affective behavior, pain, and repetitive behaviors (Chen et al, 2017;Fieblinger et al, 2014;Francis et al, 2015Francis et al, , 2017Galvan, Andre, Wang, Cepeda, & Levine, 2012;Graziane et al, 2016;Hearing et al, 2016;Heinsbroek et al, 2017;Kim, Park, Lee, Park, & Kim, 2011;LeGates et al, 2018;Lim, Huang, Grueter, Rothwell, & Malenka, 2012;Massaly et al, 2019;Ren et al, 2016;Rothwell et al, 2014;Schwartz et al, 2014;Terrier, Luscher, & Pascoli, 2016). Additionally, in some of these pathological states, mitochondrial properties are disrupted in MSNs Hollis et al, 2015;Larrieu et al, 2017). Additionally, in some of these pathological states, mitochondrial properties are disrupted in MSNs Hollis et al, 2015;Larrieu et al, 2017).…”