Unpacking constructs: a network approach for studying war exposure, daily stressors and post-traumatic stress disorder

Conflict affected populations are exposed to stressful events during and after war, and it is well established that both take a substantial toll on individuals' mental health. Exactly how exposure to events during and after war affect mental health is a topic of considerable debate. Various hypotheses have been put forward on the relation between stressful war exposure (SWE), daily stressors (DS) and the development of post-traumatic stress disorder (PTSD). This paper seeks to contribute to this debate by critically reflecting upon conventional modeling approaches and by advancing an alternative model to studying interrelationships between SWE, DS, and PTSD variables. The network model is proposed as an innovative and comprehensive modeling approach in the field of mental health in the context of war. It involves a conceptualization and representation of variables and relationships that better approach reality, hence improving methodological rigor. It also promises utility in programming and delivering mental health support for war-affected populations

ATTACHMENT STYLE MODERATES POLYGENIC RISK FOR PTSD IN U.S. MILITARY VETERANS: RESULTS FROM THE NATIONAL HEALTH AND RESILIENCE IN VETERANS STUDY

Polygenic risk scores (PRS) derived from genome-wide association studies (GWAS) of posttraumatic stress disorder (PTSD) may inform risk models of PTSD. To date, however, no known study has examined moderators such as attachment style that may impact the relation between PRS and PTSD. Main and interactive effects of PRS and attachment style on PTSD symptoms were evaluated in a nationally representative sample of trauma-exposed, European-American U.S. military veterans (N=2,030). PRS were derived from a GWAS of PTSD re-experiencing symptoms (N=146,660) in the Million Veteran Program. Higher re-experiencing PRS and secure attachment style were independently associated with more severe PTSD symptoms. A significant PRS-by-attachment style interaction was also observed, with a positive association between re-experiencing PRS and PTSD symptoms observed only in the context of insecure attachment style. PRS enrichment analyses conducted to identify biological pathways of PRS revealed a significant interaction between attachment style and a variant mapping to the IGSF11 gene. This gene is implicated in the regulation of excitatory synaptic transmission and plasticity. These findings suggest that attachment style may moderate polygenic risk for PTSD, with potential implications for preventative treatment for those at highest risk

microRNA -19b is a sex-dependent regulator of posttraumatic stress symptoms and widespread pain

Posttraumatic widespread pain (PTWP) and posttraumatic stress symptoms (PTSS) are frequent forms of trauma that occur at different rates in women and men. Genetic approaches to study pathways using model organisms and mutants have identified hundreds of genes correlated with PTWP/PTSS. Our lab sought to identify microRNAs (miRNAs) that contribute to sex-dependent differences in vulnerability to these outcomes. In the current study, we first identified miRNA that are predicted to regulate PTWP/PTSS genes using Monte Carlo simulations. We found that the most significant miRNA predicted to target PTWP/PTSS genes was miR-19b, a microRNA that has been shown previously to be regulated in response to estrogen and stress exposure. Next, we assessed whether miR-19b expression predicts PTWP/PTSS in a cohort of individuals experiencing motor vehicle collision, one of the most common forms of trauma currently experienced by Americans. Logistic regression demonstrated a sex dependent relationship between initial miR-19b levels following motor vehicle collision and later development of PTWP/ PTSS. The sex-dependent expression of miR-19b was also observed in a rat model of single prolonged stress, which is thought to be analogous to PTSS. We found miR-19b to be regulated by 17-β-estradiol in rat dorsal root ganglion neurons and amygdala, which are neural tissues commonly implicated in PTSS. The potential importance of miR-19b to PTWP/PTSS pathogenesis is highlighted by results showing that miR-19b can directly bind a number of pain and PTSS associated transcripts including circadian rhythm pathway genes. Together, our results suggest that miR-19b plays a regulatory role in PTWP and PTSS development following trauma/stress exposure. Thus, the level of miR-19b expression following motor vehicle collision may predict PTWP/PTSS and enable preventative treatment.Bachelor of Scienc

Why Killing in War is Traumatic: Emmanuel Levinas and a model of moral injury from actions we have normative permission to perform

This investigation will provide a model to make sense of why it is so inherently traumatic to kill another human – independent of normative circumstances. It will examine the construct of moral injury, a term that has entered the diagnostic and social lexicons under the guise of an explanation of why certain acts may be psychologically deleterious, and has rapidly become the ‘signature’ war-wound of contemporary engagements. Current research agendas identify existential dissonance caused by perpetrative agency, specifically killing, as the most potent causal factor. While research into why perpetration appears so etiologically significant is available under various guises, these accounts have been unable, or unwilling, to unravel the normative assignations that surround the suffering experienced. The paucity of such approaches in providing a basis for understanding why we would feel bad for certain actions which we have normative permission to perform, is the basis for an alternative, phenomenologically driven investigation, informed by the French philosopher, Emmanuel Levinas. Major topics such as death and suffering of ourselves and others, will be shown to play central roles in conceiving, and justifying, a compelling alternative to existing narratives. Through a disambiguation of the origins of one’s obligations, obligations that are inadvertently lain bare by agency, an ‘ethical model’ will be proposed that proffers a framework to accurately describe the previously unexplained distress pathway that arises from our agency (or lack there-of). In articulating a model which anchors both our ethical and moral sensibilities, a tool emerges with which to make philosophical and psychological sense of suffering that is buried deeper than normative determinations of moral expediency

The Effects of Traumatic Stress & Role of the Neuropeptide Y System as a Therapeutic in Females

The incidence of many stress-elicited disorders is markedly influenced by sex. Women are twice as likely as men to develop posttraumatic stress disorder (PTSD), depression, anxiety disorders, and social impairments following exposure to traumatic stress. However, most of the studies in animal models examining putative therapeutics for stress-triggered impairments, including single prolonged stress (SPS), were performed predominantly with males. Previous studies in males demonstrated that intranasal neuropeptide Y (NPY) can provide therapeutic relief of many SPS-triggered symptoms. Nevertheless, the overwhelming majority of studies found that NPY levels in females in many brain regions are lower than in male rodents. NPY processing by proteolytic enzymes, such as dipeptidyl peptidase IV (DPP4), may contribute to decreased full-length NPY levels. Here, we examined SPS as an appropriate model to elicit many PTSD-associated symptoms in females, whether intranasal NPY is able to alter the development of SPS-triggered behavioral impairments and factors that may contribute to NPY dosage requirement for females. Sprague Dawley, SPS-exposed female rats were compared to unstressed controls on forced swim test (FST) for depressive/despair behavior and for levels of expression of several genes in the locus coeruleus (LC) 12 days after SPS exposure. Using a separate cohort of animals, stressed females and unstressed controls were examined on the elevated plus maze (EPM) for anxiety behavior and LC gene expression 7 days after SPS stressors. Starting at 7 days after SPS, the third cohort of stressed females was tested on several behavioral tests, including the open field test (OFT) and EPM for anxiety and for social interaction. Immediately after the SPS stressors in experiment 1, 2 and 3, female rats were given intranasal NPY at 150 µg, 300µg and 600µg, respectively, or the vehicle. To further investigate a dose-response effect of NPY, SPS-exposed females were immediately infused intranasally with one of several doses, starting with 600µg/rat - 4 times the dose effective in males – and tested for depressive/despair behavior on the FST more than 14 days afterwards. In a fifth cohort of animals, females were infused intranasally with either 600μg NPY, omarigliptin (a DPP4 inhibitor), or both right after the SPS stressors. After 14 days they were tested on several behavioral tests. Lastly, CSF was collected from male and female rats 30 min after intranasal delivery of NPY and its levels were measured to assess potential differences in intranasal uptake of the peptide. SPS elicited significant depressive/despair like behavior on the FST, anxiety behavior on the OFT and EPM, as well as impaired social interaction. Following FST, the rats displayed elevated tyrosine hydroxylase (TH), CRHR1 and Y1R mRNA levels in the LC, consistent with increased activation of the noradrenergic system. The expression level of these mRNAs was unchanged following EPM, except Y1R. On the FST, there was a dose-response effect of intranasal NPY, with 1200µg, but not 600µg, preventing development of the SPS-elicited depressive-like behavior. The omarigliptin and 600µg NPY combined treatment, but neither alone, was also sufficient at preventing depressive-like behavior on the FST. This combined treatment did not significantly prevent the development of anxiety behavior on the OFT and EPM or impaired social interaction. The results demonstrate that: (1) SPS elicits several behavioral manifestations and molecular indicators of PTSD in females; (2) early intervention with a high dose of intranasal NPY has therapeutic potential also for females; (3) NPY cleavage by DPP4 may play a role in the higher dose requirement for females

Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia