Exposure to Vicarious Social Defeat Stress and Western-Style Diets During Adolescence Leads to Physiological Dysregulation, Decreases in Reward Sensitivity, and Reduced Antidepressant Efficacy in Adulthood

Abstract

A dramatic increase in the prevalence of major depression and diet-related disorders in adolescents has been observed over several decades, yet the mechanisms underlying this comorbidity have only recently begun to be elucidated. Exposure to western-style diet (WSD), high in both fats (45% kcal) and carbohydrates (35% kcal): e.g., high fat diet (HFD), has been linked to the development of metabolic syndrome-like symptoms and behavioral dysregulation in rodents, as similarly observed in the human condition. Because adolescence is a developmental period highlighted by vulnerability to both stress and poor diet, understanding the mechanism(s) underlying the combined negative effects of WSDs and stress on mood and reward regulation is critical. To this end, adolescent male C57 mice were exposed to vicarious social defeat stress (VSDS), a stress paradigm capable of separating physical (PS) versus psychological/emotional (ES) stress, followed by normal chow (NC), HFD, or a separate control diet high in carbohydrates (same sucrose content as HFD) and low in fat (LFD), while measuring body weight and food intake. Non-stressed control mice exposed to 5 weeks of NC or HFD showed no significant differences in body weight or social interaction. Mice exposed to VSDS (both ES and PS) gain weight rapidly 1 week after initiation of HFD, with the ES-exposed mice showing significantly higher weight gain as compared to the HFD-exposed control mice. These mice also exhibited a reduction in saccharin preference, indicative of anhedonic-like behavior. To further delineate whether high fat was the major contributing factor to these deficits, LFD was introduced. The mice in the VSDS + HFD gained weight more rapidly than the VSDS + LFD group, and though the LFD-exposed mice did not gain weight as rapidly as the HFD-exposed mice, both the VSDS + LFD- and VSDS + HFD-exposed mice exhibited attenuated response to the antidepressant fluoxetine. These data show that diets high in both fats and carbohydrates are responsible for rapid weight gain and reduced reward sensitivity; and that while consumption of diet high in carbohydrate and low in fat does not lead to rapid weight gain, both HFD and LFD exposure after stress leads to reduced responsiveness to antidepressant treatment.

Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models

“…Studies using this approach have yielded findings that are generally consistent with the human literature with repeated social defeat producing increased “depressive-like” symptoms in both mice and rats ( Iñiguez et al, 2016 ; Burke et al, 2017 ; Alves-Dos-Santos et al, 2020 ; Shimizu et al, 2020 ; Mancha-Gutiérrez et al, 2021 ). These behavioral effects also emerge under circumstances where adolescent mice witness, but are not directly involved in, social defeat, a paradigm called vicarious social defeat (VSD) ( Finnell et al, 2018 ; Garcia-Carachure et al, 2020 ; Warren et al, 2020 ) and can be further exacerbated by additional environmental adversities, such as eating an unhealthy diet ( Sial et al, 2021 ). Although the majority of studies using chronic social defeat in adolescence have examined males, due to the ease with which aggressive mice and rats will attack smaller males, studies using the VSD procedure in adolescent male and female rodents have shown roughly similar effects across sexes ( Finnell et al, 2018 ; Warren et al, 2020 ), Social defeat studies have identified changes in the same brain regions shown to be altered after the LBN approach, including the hippocampus, prefrontal cortex, ventral tegmental area and nucleus accumbens ( Rodríguez-Arias et al, 2018 ; Blanco-Gandia et al, 2019 ).…”

Synergistic consequences of early-life social isolation and chronic stress impact coping and neural mechanisms underlying male prairie vole susceptibility and resilience

“…The majority of work investigating CSDS has shown that repeated exposures to social defeat stress in mice causes a robust depression-like phenotype marked by increased social withdrawal, increased immobility in the forced swim test, reduced sucrose preference (a measure of anhedonia), physiological dysregulation, and decreases in reward sensitivity (Golden et al, 2011 ; Iñiguez et al, 2014 ; Sial et al, 2021 ). Much of this work has been extremely beneficial to understanding how early experiences can predispose animals to cope with stressful events experienced in later life.…”

Neurobiological Mechanisms Modulating Emotionality, Cognition and Reward-Related Behaviour in High-Fat Diet-Fed Rodents

“…[152]. In another study, HFD-fed mice subjected to a vicarious social defeat stress, wherein one mouse witnesses the physical defeat of a conspecific from the safety of an adjacent compartment (i.e., uncoupling of emotional and physical stress), showed increased social avoidance and reduced hedonic response [153].…”

“…For example, exposure to predator odour threat increased anxiety-related behaviours in HFD-fed rats and reduced brain volume, especially the hippocampal volume, compared to HFD-fed unstressed rats [ 152 ]. In another study, HFD-fed mice subjected to a vicarious social defeat stress, wherein one mouse witnesses the physical defeat of a conspecific from the safety of an adjacent compartment (i.e., uncoupling of emotional and physical stress), showed increased social avoidance and reduced hedonic response [ 153 ].…”

“…Taken together, these studies highlight that the chronic activation of the stress response in rodents interfered with HFD treatment to produce behavioural and metabolic impairments that depended on the type and the duration of stress exposure. Interestingly, HFD treatment could reduce the antidepressant efficacy of fluoxetine, a selective serotonin reuptake inhibitor, on stress-induced depression-like behaviour [ 153 , 158 ]. These data suggest that diet plays a role in antidepressant efficacy and parallel some clinical findings showing poor responsiveness to antidepressant therapy in patients suffering from obesity and related metabolic disorders [ 159 , 160 ].…”