Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts.

Pretreatment characteristics associated with symptom reduction during group cognitive processing therapy versus exposure therapy for PTSD: an exploratory study of Veterans.

Exposure and cognitive-based therapies are both effective for PTSD, but knowledge of which intervention is best for which patient is lacking. This lack of knowledge is particularly noticeable for group treatments, as no study has examined whether responses to different group therapies are associated with different pretreatment characteristics. Here, we explored whether pretreatment levels of three types of psychological characteristics-PTSD symptom clusters, posttraumatic cognitions, and emotion regulation difficulties-were associated with symptom reduction during group-delivered cognitive versus exposure-based PTSD treatment.

Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response.

Objective: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution.

Prospective longitudinal assessment of sensorimotor gating as a risk/resiliency factor for posttraumatic stress disorder.

Little is understood about cognitive mechanisms that confer risk and resiliency for posttraumatic stress disorder (PTSD). Prepulse Inhibition (PPI) is a measure of pre-attentional response inhibition that is a stable cognitive trait disrupted in many neuropsychiatric disorders characterized by poor behavioral or cognitive inhibition, including PTSD. Differentiating between PTSD-related phenotypes that are pre-existing factors vs.

Systematic Review and Methodological Considerations for the Use of Single Prolonged Stress and Fear Extinction Retention in Rodents.

Posttraumatic stress disorder (PTSD) is a mental health condition triggered by experiencing or witnessing a terrifying event that can lead to lifelong burden that increases mortality and adverse health outcomes. Yet, no new treatments have reached the market in two decades. Thus, screening potential interventions for PTSD is of high priority.

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice.

Cannabis use is widespread among adolescents and has been associated with long-term negative outcomes on neurocognitive functions. However, the factors that contribute to the long-term detrimental effects of cannabis use remain poorly understood. Here, we studied how Reelin deficiency influences the behavior of mice exposed to cannabis during adolescence.

Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex.

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms.

: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness.

Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states.

Toll-like receptors (TLRs) are a family of pattern recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins comprises an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states.

Effects of military service and deployment on clinical symptomatology: The role of trauma exposure and social support.

The Marine Resiliency Study-II examined changes in symptomatology across a deployment cycle to Afghanistan. U.S.

The relationship between dorsolateral prefrontal activation and speech performance-based social anxiety using functional near infrared spectroscopy.

Functional near-infrared (fNIR) spectroscopy is a promising new technology that has demonstrated utility in the study of normal human cognition. We utilized fNIR spectroscopy to examine the effect of social anxiety and performance on hemodynamic activity in the dorsolateral prefrontal cortex (DLPFC). Socially phobic participants and non-clinical participants with varying levels of social anxiety completed a public speaking task in front of a small virtual audience while the DLPFC was being monitored by the fNIR device.

Fear extinction memory performance in a sample of stable, euthymic patients with bipolar disorder.

Objectives: Affective dysregulation is a core feature of bipolar disorder (BD). Abnormalities in neural circuits underlying affect regulation have been observed in BD, specifically in the structure and function of the amygdala and orbital frontal cortex (OFC). Fear extinction is an automatic affect regulatory process relying on neural circuits that are abnormal in BD.

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice.

Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation.

Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response.

Background: Recent years have seen the emergence of a new paradigm for treatment of anxiety disorders focusing on development of drugs that facilitate psychotherapies via targeted effects on neuroplasticity. One compound that has generated interest in this regard is oxytocin (OT), a mammalian neuropeptide that modulates activity of the neurocircuit mediating fear extinction and memory processes. Recent research in healthy humans has suggested that intranasal OT administered prior to fear extinction training enhances fear extinction performance, supporting its potential to augment exposure-based psychotherapy.

The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury.

Background: Pervasive use of improvised explosive devices (IEDs), rocket-propelled grenades, and land mines in the recent conflicts in Iraq and Afghanistan has brought traumatic brain injury (TBI) and its impact on health outcomes into public awareness. Blast injuries have been deemed signature wounds of these wars. War-related TBI is not new, having become prevalent during WWI and remaining medically relevant in WWII and beyond.

Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model.

Background: This study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model.

Methods: We used behavioral analysis, mass spectrometry, metabolomics, electron microscopy, and western analysis to test the hypothesis that the disturbances in social behavior, novelty preference, metabolism, and synapse structure are treatable with antipurinergic therapy (APT).

Results: Weekly treatment with the purinergic antagonist suramin (20 mg/kg intraperitoneally), started at 9 weeks of age, restored normal social behavior, and improved metabolism, and brain synaptosomal structure.

Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines.

Background: Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms.

Fear conditioning, safety learning, and sleep in humans.

Fear conditioning is considered an animal model of post-traumatic stress disorder. Such models have shown fear conditioning disrupts subsequent rapid eye movement sleep (REM). Here, we provide a translation of these models into humans.

Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy.

Autism spectrum disorders (ASDs) now affect 1-2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive.

Associations between circadian activity rhythms and functional brain abnormalities among euthymic bipolar patients: a preliminary study.

Background: Working memory and underlying functional brain deficits have been observed in euthymic bipolar disorder (BD) patients, though there is heterogeneity in the degree of deficits. Sleep/circadian rhythm abnormalities are thought to be a core component of BD and may explain some of the heterogeneity in functional abnormalities. This preliminary study examined associations between sleep/circadian rhythm abnormalities and functional magnetic resonance imaging (fMRI) brain response on a working memory task among BD patients.

Sleep deprivation impairs performance in the 5-choice continuous performance test: similarities between humans and mice.

Several groups undergo extended periods without sleep due to working conditions or mental illness. Such sleep deprivation (SD) can deleteriously affect attentional processes and disrupt work and family functioning. Understanding the biological underpinnings of SD effects may assist in developing sleep therapies and cognitive enhancers.

Metabolic features of the cell danger response.

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation.