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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.

SUBMITTER: Gautam A

PROVIDER: S-EPMC4309402 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Acute and chronic plasma metabolomic and liver transcriptomic stress effects in a mouse model with features of post-traumatic stress disorder.

Gautam Aarti A D'Arpa Peter P Donohue Duncan E DE Muhie Seid S Chakraborty Nabarun N Luke Brian T BT Grapov Dmitry D Carroll Erica E EE Meyerhoff James L JL Hammamieh Rasha R Jett Marti M

PloS one 20150128 1

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 eff ...[more]

PMID: 25629821

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Project description:BackgroundSocial-stress mouse model, based on the resident-intruder paradigm was used to simulate features of human post-traumatic stress disorder (PTSD). The model involved exposure of an intruder (subject) mouse to a resident aggressor mouse followed by exposure to trauma reminders with rest periods. C57BL/6 mice exposed to SJL aggressor mice exhibited behaviors suggested as PTSD-in-mouse phenotypes: intermittent freezing, reduced locomotion, avoidance of the aggressor-associated cue and apparent startled jumping. Brain tissues (amygdala, hippocampus, medial prefrontal cortex, septal region, corpus striatum and ventral striatum) from subject (aggressor exposed: Agg-E) and control C57BL/6 mice were collected at one, 10 and 42 days post aggressor exposure sessions. Transcripts in these brain regions were assayed using Agilent's mouse genome-wide arrays.ResultsPathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling. Expression-based assessments of activation patterns showed increased activations of pathways related to anxiety disorders (hyperactivity and fear responses), impaired cognition, mood disorders, circadian rhythm disruption, and impaired territorial and aggressive behaviors. In amygdala, activations of these pathways were more pronounced at earlier time-points, with some attenuation after longer rest periods. In hippocampus and medial prefrontal cortex, activation patterns were observed at later time points. Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched. In contrast, signaling processes related to neurogenesis and synaptic plasticity were inhibited.ConclusionsOur data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory. These pathways along with comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic conditions of PTSD patients.

Project description:BackgroundPuerarin is a root extract of Pueraria lobate that can alleviate the behavioral disorders and could be therapy for post-traumatic stress disorder (PTSD). However, the underlying mechanism of puerarin in PTSD is unclear, so, we hypothesized that integration of its metabolomic and transcriptomic profiles in rat serum could help to identify the mechanisms of the protective action of puerarin.MethodsWe used the single prolonged stress procedure to establish a model of PTSD in rats and then subjected them to treatment with or without puerarin. Serum metabolomics and transcriptomics were analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry and mRNA sequencing. The differential metabolites were evaluated by multivariate analysis, and Bayes discriminant analysis and receiver operator characteristic (ROC) analysis were used to discover potential diagnostic or therapeutic biomarkers. Transcriptomic data were obtained from mRNA sequencing, and we identified the key target genes of puerarin in the treatment of PTSD by integrated analysis of bioinformatics, real-time reverse transcription-polymerase chain reaction (RT-PCR) and data mining. Finally, an integrative analysis of the different metabolites and differentially expressed genes was performed using MetaboAnalysis to investigate the possible molecular mechanisms.ResultsThe metabolomics analysis showed that 17 dysregulated metabolites in PTSD were reversed by puerarin treatment, and daidzein, 3-succinoylpyridine, 5-(2,5-dihydroxyhexyl) oxolan-2-one and elaidic acid were identified as potential biomarkers for the treatment and diagnosis of PTSD. Transcriptomics analysis showed that dysregulation of 99 genes in PTSD was reversed by puerarin treatment, and further revealed that CD36 molecule (CD36), HBS1-like translational GTPase (HBS1L), CD59 molecule (CD59) and dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) were not only key targets for puerarin's action in the treatment of PTSD but also potential biomarkers for the diagnosis and treatment of PTSD. Finally, integrated analysis of the metabolomic and transcriptomic data revealed that puerarin treatment for PTSD was mainly regulated by the metabolic pathways of one carbon pool by folate, synthesis and degradation of ketone bodies, and antigen processing and presentation.ConclusionsOur results are a new genetic insight into the mechanism of action of puerarin in PTSD treatment. We identified four metabolites and four genes that might be considered as novel biomarkers for the diagnosis and treatment of patients with PTSD.

Dataset Information

Acute and chronic plasma metabolomic and liver transcriptomic stress effects in a mouse model with features of post-traumatic stress disorder.

Publications

Acute and chronic plasma metabolomic and liver transcriptomic stress effects in a mouse model with features of post-traumatic stress disorder.

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