A network analysis investigating the associations between posttraumatic stress symptoms, markers of inflammation and metabolic syndrome.

Chronic systemic inflammation has been implicated in trauma exposure, independent of a psychiatric diagnosis, and in posttraumatic stress disorder (PTSD) and its highly comorbid conditions, such as metabolic syndrome (MetS). The present study used network analysis to examine the interacting associations between pro-inflammatory cytokines, posttraumatic stress (PTS) symptoms and symptom clusters, and individual components of MetS, in a cohort of 312 participants (n = 139 PTSD cases, n = 173 trauma-exposed controls). Pro-inflammatory cytokines were measured in serum samples using immunoturbidimetric and multiplex assays. Three network models were assessed, and the decision on which model to use was guided by network stability estimates and denseness. Weak negative associations were observed between interleukin one beta (IL-1ß) and detachment (D6) and irritability (E1); tumour necrosis factor alpha (TNFα) and hypervigilance (E3); and C-reactive protein (CRP) and emotional cue reactivity (B4), which could be due to high cortisol levels present in a female-majority cohort. Network models also identified positive associations between CRP and waist circumference, blood pressure, and high-density lipoprotein cholesterol (HDL-C). The strongest association was observed between CRP and waist circumference, providing evidence that central obesity is an important inflammatory component of MetS. Some networks displayed high instability, which could be due to the small pool of participants with viable cytokine data. Overall, this study provides evidence for associations between inflammation, PTS symptoms and components of MetS. Future longitudinal studies measuring pro-inflammatory cytokines in the immediate aftermath of trauma are required to gain better insight into the role of inflammation in trauma-exposure and PTSD.

Identifying genetic loci that are associated with changes in gene expression in PTSD in a South African cohort.

The molecular mechanisms underlying posttraumatic stress disorder (PTSD) are yet to be fully elucidated, especially in underrepresented population groups. Expression quantitative trait loci (eQTLs) are DNA sequence variants that influence gene expression, in a local (cis-) or distal (trans-) manner, and subsequently impact cellular, tissue, and system physiology. This study aims to identify genetic loci associated with gene expression changes in a South African PTSD cohort. Genome-wide genotype and RNA-sequencing data were obtained from 32 trauma-exposed controls and 35 PTSD cases of mixed-ancestry, as part of the SHARED ROOTS project. The first approach utilised 108 937 single-nucleotide polymorphisms (SNPs) (MAF > 10%) and 11 312 genes with Matrix eQTL to map potential eQTLs, while controlling for covariates as appropriate. The second analysis was focused on 5638 SNPs related to a previously calculated PTSD polygenic risk score for this cohort. SNP-gene pairs were considered eQTLs if they surpassed Bonferroni correction and had a false discovery rate <0.05. We did not identify eQTLs that significantly influenced gene expression in a PTSD-dependent manner. However, several known cis-eQTLs, independent of PTSD diagnosis, were observed. rs8521 (C > T) was associated with TAGLN and SIDT2 expression, and rs11085906 (C > T) was associated with ZNF333 expression. This exploratory study provides insight into the molecular mechanisms associated with PTSD in a non-European, admixed sample population. This study was limited by the cross-sectional design and insufficient statistical power. Overall, this study should encourage further multi-omics approaches towards investigating PTSD in diverse populations.

A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population.

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants (n = 260) and controls (n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD (p < 5 × 10-6). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke's pseudo R 2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score (R 2 = 0.00856, p = 0.0367) and PCL-5 score (R 2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke's pseudo R 2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2, corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics.

Maternal separation stress reduced prenatal-ethanol-induced increase in exploratory behaviour and extracellular signal-regulated kinase activity.

In an attempt to better represent the aetiology of fetal alcohol spectrum disorder (FASD) and the associated psychological deficits, prenatal-ethanol exposure was followed by maternal separation in a rat model in order to account for the effects of early-life adversities in addition to in utero alcohol exposure. Extracellular signal-regulated kinase 1/2 (ERK1/2) and glycogen synthase kinase 3-ß (GSK3ß) are converging points for many signalling cascades and have been implicated in models of FASD and models of early-life stress. Therefore, these kinases may also contribute to the behavioural changes observed after the combination of both developmental insults. In this study, ethanol-dams voluntarily consumed a 0.066% saccharin-sweetened 10% ethanol (EtOH) solution for 10 days prior to pregnancy and throughout gestation while control-dams had ad libitumaccess to a 0.066% saccharin (sacc) solution. Whole litters were randomly assigned to undergo maternal separation (MS) for 3 h/day from P2 to P14 while the remaining litters were left undisturbed (nMS). This resulted in 4 experimental groups: control (sacc + nMS), MS (sacc + MS), EtOH (EtOH + nMS) and EtOH + MS. Throughout development, EtOH-rats weighed less than control rats. However, subsequent maternal separation stress caused EtOH + MS-rats to weigh more than EtOH-rats. In adulthood both MS- and EtOH-rats were hyperactive but the combination produced activity levels similar to that of control rats. All treated animals (MS-, EtOH- and EtOH + MS-rats) demonstrated a negative affective state shown by increased number and duration of 22 kHz ultrasonic vocalizations compared to control rats. Prenatal-ethanol exposure increased the P-GSK3ß/GSK3ß ratio in the prefrontal cortex (PFC) and maternal separation decreased the P-GSK3ß/GSK3ß ratio in the dorsal hippocampus (DH) of adult rats. However, maternal separation stress decreased the effect of prenatal-ethanol exposure on the P-ERK/ERK ratio in the PFC and DH and reduced prenatal-ethanol-induced hyperactivity. Therefore, indicating a significant interaction between prenatal-ethanol exposure and early-life stress on behaviour and the brain and may implicate P-ERK1/2 signalling in exploratory behaviour.

Early-Ethanol Exposure Induced Region-Specific Changes in Metabolic Proteins in the Rat Brain: A Proteomics Study.

In utero exposure to alcohol has been shown to cause a spectrum of cognitive and behavioral deficits. This study aimed to explore the long-term effects of early-ethanol exposure on proteins in the brain. Male Sprague-Dawley rat pups were exposed to 12% ethanol (4 g/kg/day i.p.) or volume-controlled saline during the third human trimester equivalent (P4-P9). At P31, prefrontal cortex (PFC) and dorsal hippocampus (DH) proteins were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) and liquid chromatography mass spectrometry (LC-MS). Early-ethanol exposure increased the capacity for metabolism of NADH and oxidative phosphorylation, as shown by an upregulation of NADH dehydrogenase (ubiquinone, 1 alpha subcomplex 9) while simultaneously decreasing the capacity to protect against oxidative stress in the PFC. Early-ethanol exposure decreased the capacity for ATP synthesis (> 2-fold down regulation of ATP synthase) and increased glycogen synthesis in the DH (> 2-fold decrease in glycogen synthase kinase-3ß). The effects of early-ethanol exposure on glucose metabolism and ATP production appeared to be region specific. In addition, early-ethanol exposure decreased structural proteins in both the PFC and DH. A greater number of proteins were altered in the DH than in the PFC, indicating that the DH may be more susceptible to the effects of early-ethanol exposure. These proteomic profiles provide valuable insight into the long-term molecular changes in the brain induced by early-ethanol exposure.

Early ethanol exposure and vinpocetine treatment alter learning- and memory-related proteins in the rat hippocampus and prefrontal cortex.

This study investigates the effects of early exposure to ethanol on cognitive function and neural plasticity-related proteins in the rat brain. Sprague-Dawley rats were administered 12% ethanol solution (4 g/kg/day i.p.) or saline from P4 to P9. Vinpocetine, a phosphodiesterase type 1 inhibitor, was tested to determine whether it could reverse any changes induced by early ethanol exposure. Hence, from P25 to P31, ethanol-exposed male rats were injected with vinpocetine (20 mg/kg/day i.p.) or vehicle (DMSO) prior to undergoing behavioral testing in the open field and Morris water maze (MWM) tests. Ethanol exposure did not adversely affect spatial memory in the MWM. A key finding in this study was a significant ethanol-induced change in the function of the phosphorylated extracellular signal-related kinase (P-ERK) signaling pathway in the prefrontal cortex (PFC) and dorsal hippocampus (DH) of rats that did not display overt behavioral deficits. The P-ERK/ERK ratio was decreased in the PFC and increased in the DH of ethanol-exposed rats compared with controls. Rats that received vinpocetine in addition to ethanol did not display any behavioral changes but did show alterations in neural plasticity-related proteins. Mitogen-activated protein kinase phosphatase was increased, whereas brain-derived neurotrophic factor was decreased, in the PFC of vinpocetine-treated ethanol-exposed rats, and phosphorylated-glycogen synthase kinase ß and synaptophysin were increased in the DH of these rats. This study provides insight into the long-term effects of early ethanol exposure and its interaction with vinpocetine in the rat brain. © 2016 Wiley Periodicals, Inc.