Background Animal models capable of differentiating the neurobiological intricacies between physical and emotional stress are scarce. Current models rely primarily on physical stressors (e.g. chronic unpredictable or mild stress, social defeat, learned helplessness), and neglect the impact of psychological stress alone. This is surprising given extensive evidence that a traumatic event needs not be directly experienced to produce enduring perturbations on an individual’s health and psychological well-being. Post-traumatic stress disorder (PTSD), a highly debilitating neuropsychiatric disorder characterized by intense fear of trauma-related stimuli, often occurs in individuals that have only witnessed a traumatic event. New method By modifying the chronic social defeat stress (CSDS) paradigm to include a witness component (witnessing the social defeat of another mouse), we demonstrate a novel behavioral paradigm capable of inducing a robust behavioral syndrome reminiscent of PTSD in emotionally stressed adult mice. Results We describe the vicarious social defeat stress (VSDS) model that is capable of inducing a host of behavioral deficits that include social avoidance and other depressive-and anxiety-like phenotypes in adult male mice. VSDS exposure induces weight loss and spike in serum corticosterone (CORT) levels. A month after stress, these mice retain the social avoidant phenotype and have an increased CORT response when exposed to subsequent stress. Comparison with existing method(s) The VSDS is a novel paradigm capable of inducing emotional stress by isolating physical stress/confrontation in mice. Conclusions The VSDS model can be used to study the short- and long-term neurobiological consequences of exposure to emotional stress in mice.

Background Major Depressive Disorder (MDD) afflicts up to 10% of adolescents. However, nearly 50% of those afflicted are considered non-responsive to available treatments. Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist has shown potential as a rapid-acting and long-lasting treatment for MDD in adults. Thus, the effectiveness and functional consequences of ketamine exposure during adolescence were explored. Methods Adolescent male rats (postnatal day [PD] 35) received two ketamine (0, 5, 10 or 20 mg/kg) injections, 4 hours apart, after exposure to day 1 of the forced swim test (FST). The next day, rats were re-exposed to the FST to assess ketamine-induced antidepressant-like responses. Separate groups were exposed to chronic unpredictable stress (CUS) to confirm findings from the FST. After these initial experiments, adolescent naïve rats were exposed to either 1 or 15 consecutive days (PD35–49) of ketamine (20 mg/kg) twice/daily. Ketamine's influence on behavioral reactivity to rewarding (i.e., sucrose preference) and aversive (i.e., elevated plus-maze, FST) circumstances was then assessed 2 months after treatment. To control for age-dependent effects, adult rats (PD75–89) were exposed to identical experimental conditions. Results Ketamine (20 mg/kg) reversed the CUS-induced depression-like behaviors in the FST. Repeated ketamine exposure resulted in anxiolytic- and antidepressant-like responses 2 months after drug exposure. None of the ketamine doses used were capable of inducing drug-seeking behaviors as measured by place preference conditioning. Conclusions Repeated ketamine exposure induces enduring resilient-like responses regardless of age of exposure. These findings point to ketamine, and its repeated exposure, as a potentially useful antidepressant during adolescence.

Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional stress (ES) or physical stress (PS) on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day 35) or adult (8-week-old) mice were exposed to ES or PS using a witness social defeat paradigm. Then, 24 h after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted extracellular signal-related kinase 2 (ERK2), reduced transcription of ΔFosB and had no effect on cAMP response element-binding protein (CREB) mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc.

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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.

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