Noncoding RNAs: Stress, Glucocorticoids, and Posttraumatic Stress Disorder

Abstract

Posttraumatic stress disorder (PTSD) is a pathologic response to trauma that impacts ∼8% of the population and is highly comorbid with other disorders, such as traumatic brain injury. PTSD affects multiple biological systems throughout the body, including the hypothalamic-pituitary-adrenal axis, cortical function, and the immune system, and while the study of the biological underpinnings of PTSD and related disorders are numerous, the roles of noncoding RNAs (ncRNAs) are just emerging. Moreover, deep sequencing has revealed that ncRNAs represent most of the transcribed mammalian genome. Here, we present developing evidence that ncRNAs are involved in critical aspects of PTSD pathophysiology. In that regard, we summarize the roles of three classes of ncRNAs in PTSD and related disorders: microRNAs, long-noncoding RNAs, and retrotransposons. This review evaluates findings from both animal and human studies with a special focus on the role of ncRNAs in hypothalamic-pituitary-adrenal axis abnormalities and glucocorticoid dysfunction in PTSD and traumatic brain injury. We conclude that ncRNAs may prove to be useful biomarkers to facilitate personalized medicines for trauma-related brain disorders.

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

“…Genetically regulated gene expression in brain and non-brain tissues is associated with PTSD 20 We imputed GReX across 32,898 individuals (9,087 cases and 23,811 controls; demographics in Table S1A; analytic plan in Figure S1) from the largest multi-cohort PTSD GWAS, collected by PGC-PTSD and tested for association with case-control status. Since PTSD development involves multi-systemic dysregulation (Daskalakis et al, 2018a;Sareen, 2014), we imputed GReX in 22 tissues, using GTEx-and CMC-derived predictor models (11 brain regions, five 25 cardiovascular tissues, three endocrine tissues, one peripheral nerve, subcutaneous adipose tissue and whole blood).…”

“…For the PGC-PTSD cohorts for which we had access to raw data, we imputed genetically regulated gene 5 expression (GReX) for each individual, across 11 brain regions, 5 cardiovascular tissues, 2 endocrine tissues, 1 peripheral nerve, 1 adipose tissue and whole blood, driven by prior hypotheses about the involvement of those tissues in PTSD (Averill et al, 2017;Daskalakis et al, 2018a;Nemeroff et al, 2006;Sareen, 2014) using PrediXcan (Gamazon et al, 2015). We then calculated associations between GReX and case-control status, correcting for ten genotype derived principal-components.…”

PTSD Biomarker Database: Deep Dive Meta-database for PTSD Biomarkers, Visualizations, and Analysis Tools

“…Post-traumatic stress disorder (PTSD) is a common psychiatric disorder that occurs in some individuals after a traumatic event (Pietrzak, et al, 2012) and is diagnosed by mental health professionals based on the presentation of four symptom clusters -intrusions, avoidance, negative cognitions/mood, and hyperarousal (American Psychiatric Association, 2013). PTSD pathophysiology is complex and affects multiple interconnected biological systems that regulate mental and physical health functions and are associated with PTSD's clinical heterogeneity and diverse comorbidity profiles (Pitman, et al, 2012;Kang, et al, 2015;Passos, et al ., 2015;Bina and Langevin, 2018;Daskalakis, et al, 2018;Speer, et al, 2018).…”

Bioinformatic analysis of long-lasting transcriptional and translational changes in the basolateral amygdala following acute stress

“…The short seed region of the miRNA allows for redundancy and binding of one miRNA to many putative target mRNA sequences that can be predicted with web-based algorithms [19; 20; 21]. The miRNA signature that results immediately after stress has been primarily studied in chronic stress paradigms [22], with some focus on immediate effects of acute stress. However, the potential for long-lasting changes in miRNA expression after acute stress is unknown.…”

“…The latter would be expected to yield highly relevant information, as miRNAs principally repress protein translation. Moreover, the existing datasets in the literature have focused almost exclusively on the effects of chronic stress [22], while the few that have employed acute stress focused on immediate effects and give no insight into the long-term consequences of a brief stress exposure [26; 34]. To address these limitations, we used sequencing and mass spectrometry technologies to identify long-lasting neuroadaptations in the BLC that are regulated by a single stressful event.…”