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Cerebellar and multi-system metabolic reprogramming associated with trauma exposure and post-traumatic stress disorder (PTSD)-like behavior in mice.

ABSTRACT: Mitochondrial metabolism is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We recently reported that mice exposed to a novel paradigm for the induction of PTSD-like behavior displayed reduced mitochondrial electron transport chain (mtETC) complex activity as well as decreased multi-system fatty acid oxidation (FAO) flux. Based on these results, we hypothesized that stressed and PTSD-like animals would display evidence of metabolic reprogramming in both cerebellum and plasma consistent with increased energetic demand, mitochondrial metabolic reprogramming, and increased oxidative stress. We performed targeted metabolomics in both cerebellar tissue and plasma, as well as untargeted nuclear magnetic resonance (NMR) spectroscopy in the cerebellum of 6 PTSD-like and 7 resilient male mice as well as 7 trauma-naïve controls. We identified numerous differences in amino acids and tricarboxylic acid (TCA) cycle metabolite concentrations in the cerebellum and plasma consistent with altered mitochondrial energy metabolism in trauma exposed and PTSD-like animals. Pathway analysis identified metabolic pathways with significant metabolic pathway shifts associated with trauma exposure, including the tricarboxylic acid cycle, pyruvate, and branched-chain amino acid metabolism in both cerebellar tissue and plasma. Altered glutamine and glutamate metabolism, and arginine biosynthesis was evident uniquely in cerebellar tissue, while ketone body levels were modified in plasma. Importantly, we also identified several cerebellar metabolites (e.g. choline, adenosine diphosphate, beta-alanine, taurine, and myo-inositol) that were sufficient to discriminate PTSD-like from resilient animals. This multilevel analysis provides a comprehensive understanding of local and systemic metabolite fingerprints associated with PTSD-like behavior, and subsequently altered brain bioenergetics. Notably, several transformed metabolic pathways observed in the cerebellum were also reflected in plasma, connecting central and peripheral biosignatures of PTSD-like behavior. These preliminary findings could direct further mechanistic studies and offer insights into potential metabolic interventions, either pharmacological or dietary, to improve PTSD resilience.

SUBMITTER: Preston G

PROVIDER: S-EPMC7872981 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Cerebellar and multi-system metabolic reprogramming associated with trauma exposure and post-traumatic stress disorder (PTSD)-like behavior in mice.

Preston Graeme G Emmerzaal Tim T Radenkovic Silvia S Lanza Ian R IR Oglesbee Devin D Morava Eva E Kozicz Tamas T

Neurobiology of stress 20210123

Mitochondrial metabolism is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We recently reported that mice exposed to a novel paradigm for the induction of PTSD-like behavior displayed reduced mitochondrial electron transport chain (mtETC) complex activity as well as decreased multi-system fatty acid oxidation (FAO) flux. Based on these results, we hypothesized that stressed and PTSD-like animals would display evidence of metaboli ...[more]

PMID: 33604421

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Project description:Contemporary symptom-based diagnosis of post-traumatic stress disorder (PTSD) largely overlooks related neurobehavioral mechanisms and relies entirely on subjective interpersonal reporting. Previous studies associating biomarkers with PTSD have mostly used symptom-based diagnosis as the main outcome measure, disregarding the wide variability and richness of PTSD phenotypical features. Here, we aimed to computationally derive potential biomarkers that could efficiently differentiate PTSD subtypes among recent trauma survivors. A three-staged semi-unsupervised method ("3C") was used to firstly categorize individuals by current PTSD symptom severity, then derive clusters based on clinical features related to PTSD (e.g. anxiety and depression), and finally to classify participants' cluster membership using objective multi-domain features. A total of 256 features were extracted from psychometrics, cognitive functioning, and both structural and functional MRI data, obtained from 101 adult civilians (age = 34.80 ± 11.95; 51 females) evaluated within 1 month of trauma exposure. The features that best differentiated cluster membership were assessed by importance analysis, classification tree, and ANOVA. Results revealed that entorhinal and rostral anterior cingulate cortices volumes (structural MRI domain), in-task amygdala's functional connectivity with the insula and thalamus (functional MRI domain), executive function and cognitive flexibility (cognitive testing domain) best differentiated between two clusters associated with PTSD severity. Cross-validation established the results' robustness and consistency within this sample. The neural and cognitive potential biomarkers revealed by the 3C analytics offer objective classifiers of post-traumatic morbidity shortly following trauma. They also map onto previously documented neurobehavioral mechanisms associated with PTSD and demonstrate the usefulness of standardized and objective measurements as differentiating clinical sub-classes shortly after trauma.

Project description:BackgroundSelf-stigma refers to the internalisation of negative societal views and stereotypes. Self-stigma has been well-characterised in the context of mental disorders such as schizophrenia but has received little attention in relation to post-traumatic stress disorder (PTSD).ObjectiveThis work aimed to determine the prevalence of self-stigma in a sample of adults with PTSD and to establish factors associated with the internalisation of stigma in this population.MethodParticipants were 194 adults (mean age 46.07 (SD = 12.39); 64.4% female; 96.6% white Caucasian; residing in the UK), who self-reported a diagnosis of PTSD and currently screened positive for the disorder according to the PTSD Checklist for DSM-5 (PCL-5). Structured interviews and validated self-report questionnaires were used to ascertain clinical and sociodemographic information for analysis.ResultsThe prevalence of self-stigma measured by the Internalized Stigma of Mental Illness Scale (ISMIS) was 41.2% (95% CI 34.24-48.22). There was no evidence of an association between self-stigma and gender (β = -2.975 (95% CI -7.046-1.097) p = .151), age (β = 0.007 (95% CI -0.152-0.165) p = .953), sexual trauma (β = 0.904 (95% CI -3.668-5.476) p = .697), military trauma (β = -0.571 (95% CI -4.027-7.287) p = .571). Self-stigma was associated with lower income and higher levels of anxiety (β = 5.722 (95% CI 2.922-8.522) p = <.001), depression (β = 6.937 (95% CI 4.287-9.588) p = <.000), and traumatic stress symptoms (β = 3.880 (95% CI 1.401-6.359) p = .002).ConclusionsThe results indicate that self-stigma may be a significant issue among people with a diagnosis of PTSD. Further work is needed to understand the long-term impact and to develop interventions to address the internalisation of stigma in this population.HighlightsThe prevalence of self-stigma among a sample of participants with PTSD was 41.2%.There was no evidence of an association between self-stigma and gender, age or sexual / military trauma.Self-stigma was associated with lower income and higher levels of anxiety, depression, and traumatic stress symptoms.

Dataset Information

Cerebellar and multi-system metabolic reprogramming associated with trauma exposure and post-traumatic stress disorder (PTSD)-like behavior in mice.

Publications

Cerebellar and multi-system metabolic reprogramming associated with trauma exposure and post-traumatic stress disorder (PTSD)-like behavior in mice.

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