Faculty Bibliography
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259
MicroRNA regulation of persistent stress-enhanced memory
Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. We previously developed a stress-enhanced fear learning (SEFL) paradigm in inbred mice that produces PTSD-like characteristics in a subset of mice, including persistently enhanced memory and heightened cFos in the basolateral amygdala complex (BLC) with retrieval of the remote (30-day-old) stress memory. Here, the contribution of BLC microRNAs (miRNAs) to stress-enhanced memory was investigated because of the molecular complexity they achieve through their ability to regulate multiple targets simultaneously. We performed small-RNA sequencing (smRNA-Seq) and quantitative proteomics on BLC tissue collected from mice 1 month after SEFL and identified persistently changed microRNAs, including mir-135b-5p, and proteins associated with PTSD-like heightened fear expression. Viral-mediated overexpression of mir-135b-5p in the BLC of stress-resilient animals enhanced remote fear memory expression and promoted spontaneous renewal 14 days after extinction. Conversely, inhibition of BLC mir-135b-5p in stress-susceptible animals had the opposite effect, promoting a resilient-like phenotype. mir-135b-5p is highly conserved across mammals and was detected in post mortem human amygdala, as well as human serum samples. The mir-135b passenger strand, mir-135b-3p, was significantly elevated in serum from PTSD military veterans, relative to combat-exposed control subjects. Thus, miR-135b-5p may be an important therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.
PMID: 31142820
ISSN: 1476-5578
CID: 4174262
Correction: MicroRNA regulation of persistent stress-enhanced memory
A correction to this paper has been published and can be accessed via a link at the top of the paper.
PMID: 31253953
ISSN: 1476-5578
CID: 4174572
An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci
BACKGROUND:Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). METHODS:In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). RESULTS: = 0.042). CONCLUSIONS:The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.
PMCID:7071645
PMID: 32171335
ISSN: 1868-7083
CID: 4353372
Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder
BACKGROUND:Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis. RESULTS:) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region. CONCLUSIONS:This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.
PMCID:6958602
PMID: 31931860
ISSN: 1868-7083
CID: 4264282
MDMA-assisted psychotherapy for posttraumatic stress disorder: A promising novel approach to treatment
PMID: 31455855
ISSN: 1740-634x
CID: 4175062
A Decade of mTBI Experience: What Have We Learned? A Summary of Proceedings From a NATO Lecture Series on Military mTBI
Mild traumatic brain injury (mTBI, also known as a concussion) as a consequence of battlefield blast exposure or blunt force trauma has been of increasing concern to militaries during recent conflicts. This concern is due to the frequency of exposure to improvised explosive devices for forces engaged in operations both in Iraq and Afghanistan coupled with the recognition that mTBI may go unreported or undetected. Blasts can lead to mTBI through a variety of mechanisms. Debate continues as to whether exposure to a primary blast wave alone is sufficient to create brain injury in humans, and if so, exactly how this occurs with an intact skull. Resources dedicated to research in this area have also varied substantially among contributing NATO countries. Most of the research has been conducted in the US, focused on addressing uncertainties in management practices. Development of objective diagnostic tests should be a top priority to facilitate both diagnosis and prognosis, thereby improving management. It is expected that blast exposure and blunt force trauma to the head will continue to be a potential source of injury during future conflicts. An improved understanding of the effects of blast exposure will better enable military medical providers to manage mTBI cases and develop optimal protective measures. Without the immediate pressures that come with a high operational tempo, the time is right to look back at lessons learned, make full use of available data, and modify mitigation strategies with both available evidence and new evidence as it comes to light. Toward that end, leveraging our cooperation with the civilian medical community is critical because the military experience over the past 10 years has led to a renewed interest in many similar issues pertaining to mTBI in the civilian world. Such cross-fertilization of knowledge will undoubtedly benefit all. This paper highlights similarities and differences in approach to mTBI patient care in NATO and partner countries and provides a summary of and lessons learned from a NATO lecture series on the topic of mTBI, demonstrating utility of having patients present their experiences to a medical audience, linking practical clinical care to policy approaches.
PMCID:7477387
PMID: 32982907
ISSN: 1664-2295
CID: 4956462
International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
PMID: 31594949
ISSN: 2041-1723
CID: 4130622
Cohort profile: the Prospective Research In Stress-Related Military Operations (PRISMO) study in the Dutch Armed Forces
PURPOSE/OBJECTIVE:The Prospective Research in Stress-Related Military Operations (PRISMO) study was initiated to gain a better understanding of the long-term impact of military deployment on mental health, and to map the different biological and psychological factors that contribute to the development of stress-related mental health symptoms. PARTICIPANTS/METHODS:The PRISMO cohort consists of a convenience sample of Dutch military personnel deployed to Afghanistan between 2005 and 2008. Baseline data collection resulted in the recruitment of 1032 military men and women. Combat troops as well as non-combat support troops were recruited to increase the representativeness of the sample to the population as a whole. FINDINGS TO DATE/UNASSIGNED:The prevalence of various mental health symptoms increases after deployment in PRISMO cohort members, but symptom progression over time appears to be specific for various mental health symptoms. For post-traumatic stress disorder, we found a short-term symptom increase within 6 months after deployment (8.2%), and a long-term symptom increase at 5 years after deployment (12.9%). Several biological vulnerability factors associated with the development of stress-related conditions after deployment were identified, including predeployment glucocorticoid receptor sensitivity and predeployment testosterone level. Thus far, 34 publications have resulted from the cohort. FUTURE PLANS/UNASSIGNED:Various analyses are planned that will include the prevalence of mental health symptoms at 10 years postdeployment, as well as trajectory analyses that capture the longitudinal development of symptoms. Furthermore, we will use a machine learning approach to develop predictive and network models for several mental health symptoms, incorporating biological, psychological and social factors.
PMID: 30842118
ISSN: 2044-6055
CID: 3724562
International review of psychiatry (Abingdon, UK). 2019:31(1):49-59.DOI: 10.1080/09540261.2019.1602517
Exposure to combat and deployment; reviewing the military context in The Netherlands
This paper reviews the military context of exposure to combat and deployment in Dutch soldiers. It does so by reviewing war victims and military psychiatry after WWII in the Netherlands, and describes Dutch deployments from the late 1970s to the present. 'Who is the Dutch soldier' is asked to articulate the mental load on the individual soldier before, during, and after deployment. The narrative review of this paper allows one to review how the armed forces personnel is challenged in relation to their specific assignment and in what respect the psychological dimensions are addressed and met in the face of risk and adversity. Finally, some critical considerations for future veterans care programmes are raised.
PMID: 31184276
ISSN: 1369-1627
CID: 4174352
Circulating Serum MicroRNAs as Potential Diagnostic Biomarkers of Posttraumatic Stress Disorder: A Pilot Study
Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects (N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of ≥|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings.
PMCID:6883918
PMID: 31824554
ISSN: 1664-8021
CID: 4238832
