title: 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.
authors: US Army Center for Environmental Health Research, Fort Detrick, MD, United States of America; The Geneva Foundation, Tacoma, WA 98402, United States of America.
authors: Aarti
authors: A
authors: Gautam
authors: US Army Center for Environmental Health Research, Fort Detrick, MD, United States of America; The Geneva Foundation, Tacoma, WA 98402, United States of America.
authors: Peter
authors: P
authors: D'Arpa
authors: US Army Center for Environmental Health Research, Fort Detrick, MD, United States of America; The Geneva Foundation, Tacoma, WA 98402, United States of America.
authors: Duncan E
authors: DE
authors: Donohue
authors: Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Frederick, MD, United States of America.
authors: Seid
authors: S
authors: Muhie
authors: US Army Center for Environmental Health Research, Fort Detrick, MD, United States of America; The Geneva Foundation, Tacoma, WA 98402, United States of America.
authors: Nabarun
authors: N
authors: Chakraborty
authors: Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Frederick, MD, United States of America.
authors: Brian T
authors: BT
authors: Luke
authors: NIH West Coast Metabolomics Center, University of California Davis, Davis, CA, United States of America.
authors: Dmitry
authors: D
authors: Grapov
authors: Army Institute for Public Health, Aberdeen Proving Ground, Aberdeen, MD 21010-5403, United States of America.
authors: Erica E
authors: EE
authors: Carroll
authors: US Army Center for Environmental Health Research, Fort Detrick, MD, United States of America; The Geneva Foundation, Tacoma, WA 98402, United States of America.
authors: James L
authors: JL
authors: Meyerhoff
authors: US Army Center for Environmental Health Research, Fort Detrick, MD, United States of America.
authors: Rasha
authors: R
authors: Hammamieh
authors: US Army Center for Environmental Health Research, Fort Detrick, MD, United States of America.
authors: Marti
authors: M
authors: Jett
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D009195:Peroxidase
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