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      DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression

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          Abstract

          DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

          Abstract

          DICER1 is required for the maturation of miRNAs which regulate expression of thousands of genes. Here the authors show significantly reduced levels of DICER1 in individuals having post-traumatic stress disorder and comorbid depression suggestive of a role in the molecular mechanism of the condition.

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          Most cited references44

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          An overview of the immune system.

          We are continually exposed to organisms that are inhaled, swallowed, or inhabit our skin and mucous membranes. Whether these organisms penetrate and cause disease is a result of both the pathogenicity of the organism (the virulence factors at its disposal) and the integrity of host defence mechanisms. The immune system is an interactive network of lymphoid organs, cells, humoral factors, and cytokines. The essential function of the immune system in host defence is best illustrated when it goes wrong; underactivity resulting in the severe infections and tumours of immunodeficiency, overactivity in allergic and autoimmune disease. In this review we have covered the normal function of the immune system in recognising, repelling, and eradicating pathogens and other foreign molecules.
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            A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder.

            Previous functional neuroimaging studies have demonstrated exaggerated amygdala responses and diminished medial prefrontal cortex responses during the symptomatic state in posttraumatic stress disorder (PTSD). To determine whether these abnormalities also occur in response to overtly presented affective stimuli unrelated to trauma; to examine the functional relationship between the amygdala and medial prefrontal cortex and their relationship to PTSD symptom severity in response to these stimuli; and to determine whether responsivity of these regions habituates normally across repeated stimulus presentations in PTSD. Case-control study. Academic medical center. Volunteer sample of 13 men with PTSD (PTSD group) and 13 trauma-exposed men without PTSD (control group). We used functional magnetic resonance imaging (fMRI) to study blood oxygenation level-dependent signal during the presentation of emotional facial expressions. The PTSD group exhibited exaggerated amygdala responses and diminished medial prefrontal cortex responses to fearful vs happy facial expressions. In addition, in the PTSD group, blood oxygenation level-dependent signal changes in the amygdala were negatively correlated with signal changes in the medial prefrontal cortex, and symptom severity was negatively related to blood oxygenation level-dependent signal changes in the medial prefrontal cortex. Finally, relative to the control group, the PTSD group tended to exhibit diminished habituation of fearful vs happy responses in the right amygdala across functional runs, although this effect did not exceed our a priori statistical threshold. These results provide evidence for exaggerated amygdala responsivity, diminished medial prefrontal cortex responsivity, and a reciprocal relationship between these 2 regions during passive viewing of overtly presented affective stimuli unrelated to trauma in PTSD.
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              A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling.

              Chronic stressors are known to increase vulnerability to medical illness, but the mechanisms underlying this phenomenon are poorly understood. To identify transcriptional control pathways that are modified by chronic stress, we conducted genomewide expression microarrays on familial caregivers of brain-cancer patients (n = 11) and matched control subjects (n = 10). Analyses were conducted on peripheral blood monocytes, which are cells that have the ability to initiate and maintain many inflammatory responses. Salivary cortisol was collected over the course of 3 days as volunteers went about normal activities. Caregivers' patterns of cortisol secretion were similar to those of matched control subjects. However, their monocytes showed diminished expression of transcripts bearing response elements for glucocorticoids, and heightened expression of transcripts with response elements for NF-kappaB, a key pro-inflammatory transcription factor. Caregivers also showed relative elevations in the inflammatory markers C-reactive protein and interleukin-1 receptor antagonist. These findings suggest that even in the absence of excess adrenocortical output, stress brings about functional resistance to glucocorticoids in monocytes, which enables activation of pro-inflammatory transcription control pathways. This persistent activation of inflammatory mechanisms may contribute to stress-related morbidity and mortality.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                03 December 2015
                2015
                : 6
                : 10106
                Affiliations
                [1 ]Atlanta VA Medical Center , Atlanta, Georgia 30033, USA
                [2 ]Department of Psychiatry, School of Medicine, Emory University , Atlanta, Georgia 30322, USA
                [3 ]McLean Hospital, Harvard Medical School , Belmont, Massachusetts 02478, USA
                [4 ]Department of Psychology, University of Illinois at Urbana-Champaign , Illinois 61820, USA
                [5 ]Carl R. Woese Institute for Genomic Biology , Illinois 61820, USA
                [6 ]Department of Human Genetics, School of Medicine, Emory University , Atlanta, Georgia 30322, USA
                [7 ]Department of Psychiatry and MRC Unit on Anxiety and Stress Disorders, University of Cape Town , Cape Town, South Africa
                [8 ]School of Global Public Health, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, USA
                [9 ]Harvard T.H. Chan School of Public Health , Boston, Massachusetts 02115, USA
                [10 ]School of Public Health, Boston University , Boston, Massachusetts 02118, USA
                [11 ]Center for Integrative Genomics, School of Biology, Georgia Institute of Technology , Atlanta, Georgia 30332, USA
                Author notes
                Author information
                http://orcid.org/0000-0001-7045-9229
                Article
                ncomms10106
                10.1038/ncomms10106
                4686835
                26632874
                5e23ac53-4dfc-4132-9f6f-1a6b3dcab27c
                Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 07 September 2015
                : 04 November 2015
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