Acute and Chronic Plasma Metabolomic and Liver Transcriptomic Stress Effects in a Mouse Model with Features of Post-Traumatic Stress Disorder

Abstract

Acute responses to intense stressors can give rise to post-traumatic stress disorder (PTSD). PTSD diagnostic criteria include trauma exposure history and self-reported symptoms. Individuals who meet PTSD diagnostic criteria often meet criteria for additional psychiatric diagnoses. Biomarkers promise to contribute to reliable phenotypes of PTSD and comorbidities by linking biological system alterations to behavioral symptoms. Here we have analyzed unbiased plasma metabolomics and other stress effects in a mouse model with behavioral features of PTSD. In this model, C57BL/6 mice are repeatedly exposed to a trained aggressor mouse (albino SJL) using a modified, resident-intruder, social defeat paradigm. Our recent studies using this model found that aggressor-exposed mice exhibited acute stress effects including changed behaviors, body weight gain, increased body temperature, as well as inflammatory and fibrotic histopathologies and transcriptomic changes of heart tissue. Some of these acute stress effects persisted, reminiscent of PTSD. Here we report elevated proteins in plasma that function in inflammation and responses to oxidative stress and damaged tissue at 24 hrs post-stressor. Additionally at this acute time point, transcriptomic analysis indicated liver inflammation. The unbiased metabolomics analysis showed altered metabolites in plasma at 24 hrs that only partially normalized toward control levels after stress-withdrawal for 1.5 or 4 wks. In particular, gut-derived metabolites were altered at 24 hrs post-stressor and remained altered up to 4 wks after stress-withdrawal. Also at the 4 wk time point, hyperlipidemia and suppressed metabolites of amino acids and carbohydrates in plasma coincided with transcriptomic indicators of altered liver metabolism (activated xenobiotic and lipid metabolism). Collectively, these system-wide sequelae to repeated intense stress suggest that the simultaneous perturbed functioning of multiple organ systems (e.g., brain, heart, intestine and liver) can interact to produce injuries that lead to chronic metabolic changes and disorders that have been associated with PTSD.

Gene and stress history interplay in emergence of PTSD-like features

“…Supporting our claim we demonstrated many traumatic features emerging after a delay following the withdrawal of stress (20)(21)(22)(23). Concluding, the present data display many PTSD-simulating phenotypic and molecular signatures immediately after the trauma-withdrawal; and many of these traits were sustained through, or even emerged after the interval of delay.…”

“…Our model concurred with the etiological and face validators mandated for a PTSD rodent model (12). Using C57BL/6j mice as Agg-E cohort, this model characterized the genomics (21,22) and metabolomics (23) signatures of PTSD. The present model utilizes SJL male mice trained to be aggressive towards the intruders; hence unlike the typical social stress models (24,25), the present A c c e p t e d M a n u s c r i p t 4 model limited the direct intruder-resident interactions to not more than one minute; longer direct interaction could cause serious and undesired injury in Agg-E mice.…”

“…Concluding, the present data display many PTSD-simulating phenotypic and molecular signatures immediately after the trauma-withdrawal; and many of these traits were sustained through, or even emerged after the interval of delay. As a 'construct validity' of the PTSD rodent model many of the reported putative genomic (21), transcriptomic (22), metabolomic (23) and Accordingly, this rodent model meaningfully simulates the combat related PTSD paradigm and validated some of the essential criteria of PTSD rodent models.…”

“…The concern(12,26) that repeated social stress may elicit habituation rather than triggering the PTSD-like features was mitigated by carefully implementing the 'randomness' in the occurrence of the life-threatening events.Thereby the 'ethological validity' of the model namely the unpredictable and uncontrollable nature of the PTSD simulating trauma was established. Moreover, the 'dose-response'-type feature was presented as 10-day long stress in comparison to 5-day long stress emerged more proficient in eliciting PTSD-like features(20)(21)(22)(23). In addition, the 'face validity' of PTSD-like features(12,26) was manifested by introducing the stressed mice to the contextual cues immediately after withdrawing the trauma and at a delayed interval, wherein 4 weeks is arguably equivalent to nearly three years of human life.…”

Longitudinal associations between post-traumatic stress disorder and metabolic syndrome severity

“…For example, PTSD may lead to both cardiovascular and HPA axis system dysregulation (Kibler et al, 2014; Brudey et al, 2015), which would be expected to increase blood pressure, circulating lipids, blood sugars, and inflammation (Epel, 2009); together, these alterations can increase central fat deposits (Epel, 2009). At the same time, PTSD-related increases in reactive oxygen species (Miller et al, 2014; Gautam et al, 2015; Atli et al, in press) may alter the expression of genes important for regulating metabolic processes, ultimately compounding metabolic dysregulation (Grattagliano et al, 2008). In addition, PTSD-related poor sleep (Gavrieli et al, 2015; Talbot et al, 2015), unhealthy diet (Hall et al, 2015), insufficient exercise (Georgiades et al, 2000; Hall et al, 2015), cigarette and alcohol use (Dennis et al, 2014), and psychotropic medication use (Vancampfort et al, 2015) may exert effects on metabolic health that additively and/or synergistically further contribute to the cascade of broad metabolic dysfunction.…”