Post-traumatic Stress Disorder Pathology Research Articles

Single-Nucleus Transcriptome Profiling from the Hippocampus of a PTSD Mouse Model and CBD-Treated Cohorts.

Post-traumatic stress disorder (PTSD) is the most common psychiatric disorder after a catastrophic event; however, the efficacious treatment options remain insufficient. Increasing evidence suggests that cannabidiol (CBD) exhibits optimal therapeutic effects for treating PTSD. To elucidate the cell-type-specific transcriptomic pathology of PTSD and the mechanisms of CBD against this disease, we conducted single-nucleus RNA sequencing (snRNA-seq) in the hippocampus of PTSD-modeled mice and CBD-treated cohorts. We constructed a mouse model by adding electric foot shocks following exposure to single prolonged stress (SPS+S) and tested the freezing time, anxiety-like behavior, and cognitive behavior. CBD was administrated before every behavioral test. The PTSD-modeled mice displayed behaviors resembling those of PTSD in all behavioral tests, and CBD treatment alleviated all of these PTSD-like behaviors (n = 8/group). Three mice with representative behavioral phenotypes were selected from each group for snRNA-seq 15 days after the SPS+S. We primarily focused on the excitatory neurons (ExNs) and inhibitory neurons (InNs), which accounted for 68.4% of the total cell annotations. A total of 88 differentially upregulated genes and 305 differentially downregulated genes were found in the PTSD mice, which were found to exhibit significant alterations in pathways and biological processes associated with fear response, synaptic communication, protein synthesis, oxidative phosphorylation, and oxidative stress response. A total of 63 overlapping genes in InNs were identified as key genes for CBD in the treatment of PTSD. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the anti-PTSD effect of CBD was related to the regulation of protein synthesis, oxidative phosphorylation, oxidative stress response, and fear response. Furthermore, gene set enrichment analysis (GSEA) revealed that CBD also enhanced retrograde endocannabinoid signaling in ExNs, which was found to be suppressed in the PTSD group. Our research may provide a potential explanation for the pathogenesis of PTSD and facilitate the discovery of novel therapeutic targets for drug development. Moreover, it may shed light on the therapeutic mechanisms of CBD.

Posttraumatic Stress and Traumatic Brain Injury: Cognition, Behavior, and Neuroimaging Markers in Vietnam Veterans.

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are common in Veterans and linked to behavioral disturbances, increased risk of cognitive decline, and Alzheimer's disease. We studied the synergistic effects of PTSD and TBI on behavioral, cognitive, and neuroimaging measures in Vietnam war Veterans. Data were acquired at baseline and after about one-year from male Veterans categorized into: PTSD, TBI, PTSD+TBI, and Veteran controls without PTSD or TBI. We applied manual tractography to examine white matter microstructure of three fiber tracts: uncinate fasciculus (N = 91), cingulum (N = 87), and inferior longitudinal fasciculus (N = 95). ANCOVAs were used to compare Veterans' baseline behavioral and cognitive functioning (N = 285), white matter microstructure, amyloid-β (N = 230), and tau PET (N = 120). Additional ANCOVAs examined scores' differences from baseline to follow-up. Veterans with PTSD and PTSD+TBI, but not Veterans with TBI only, exhibited poorer behavioral and cognitive functioning at baseline than controls. The groups did not differ in baseline white matter, amyloid-β, or tau, nor in behavioral and cognitive functioning, and tau accumulation change. Progression of white matter abnormalities of the uncinate fasciculus in Veterans with PTSD compared to controls was observed; analyses in TBI and PTSD+TBI were not run due to insufficient sample size. PTSD and PTSD+TBI negatively affect behavioral and cognitive functioning, while TBI does not contribute independently. Whether progressive decline in uncinate fasciculus microstructure in Veterans with PTSD might account for cognitive decline should be further studied. Findings did not support an association between PTSD, TBI, and Alzheimer's disease pathology based on amyloid and tau PET.

Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model

Posttraumatic stress disorder (PTSD) is a complex disorder that involves physiological, emotional, and cognitive dysregulation that may occur after exposure to a life-threatening event. In contrast with the condition of learned fear with resilience to extinction, abnormal fear with impaired fear extinction and exaggeration are considered crucial factors for the pathological development of PTSD. The prefrontal cortex (mPFC) is considered a critical region of top-down control in fear regulation, which involves the modulation of fear expression and extinction. The pathological course of PTSD is usually chronic and persistent; a number of studies have indicated temporal progression in gene expression and phenotypes may be involved in PTSD pathology. In the current study, we use a well-established modified single-prolonged stress (SPS&FS) rat model to feature PTSD-like phenotypes and compared it with a footshock fear conditioning model (FS model); we collected the frontal tissue after extreme stress exposure or fear conditioning and extracted RNA for transcriptome-level gene sequencing. We compared the genetic profiling of the mPFC at early (<2 h after solely FS or SPS&FS exposure) and late (7 days after solely FS or SPS&FS exposure) stages in these two models. First, we identified temporal differences in the expressional patterns between these two models and found pathways such as protein synthesis factor eukaryotic initiation factor 2 (EIF2), transcription factor NF-E2-related factor 2 (NRF2)-mediated oxidative stress response, and acute phase responding signaling enriched in the early stage in both models with significant p-values. Furthermore, in the late stage, the sirtuin signaling pathway was enriched in both models; other pathways such as STAT3, cAMP, lipid metabolism, Gα signaling, and increased fear were especially enriched in the late stage of the SPS&FS model. However, pathways such as VDR/RXR, GP6, and PPAR signaling were activated significantly in the FS model's late stage. Last, the network analysis revealed the temporal dynamics of psychological disorder, the endocrine system, and also genes related to increased fear in the two models. This study could help elucidate the genetic temporal alteration and stage-specific pathways in these two models, as well as a better understanding of the transcriptome-level differences between them.

MicroRNA expression profiles of stress susceptibility and resilience in the prelimbic and infralimbic cortex of rats after single prolonged stress.

The experience of traumatic stress can engender lasting memories associated with the trauma, often resulting in post-traumatic stress disorder (PTSD). However, only a minority of individuals develop PTSD symptoms upon exposure. The neurobiological mechanisms underlying the pathology of PTSD are poorly understood. Utilizing a rat model of PTSD, the Single Prolonged Stress (SPS) paradigm, we were able to differentiate between resilient and susceptible individuals. Fourteen days after the SPS exposure, we conducted the behavioral analyses using Elevated Plus Maze (EPM) and Open Field (OF) tests to identify male rats as trauma resilient or susceptible. We focused on the microRNA (miRNA) profiles of the infralimbic (IL) and prelimbic (PL) cortical regions, known to be crucial in regulating the stress response. Our investigation of stressed rats exposed to the SPS procedure yielded divergent response, and differential expression microRNAs (DEmiRs) analysis indicated significant differences in the IL and PL transcriptional response. In the IL cortex, the GO analysis revealed enriched GO terms in the resilient versus control comparison, specifically related to mitogen-activated protein kinase and MAP kinase signaling pathways for their molecular functions as well as cytosol and nucleoplasm for the biological process. In the susceptible versus resilient comparison, the changes in molecular functions were only manifested in the functions of regulation of transcription involved in the G1/S transition of the mitotic cell cycle and skeletal muscle satellite cell activation. However, no enriched GO terms were found in the susceptible versus control comparison. In the PL cortex, results indicated that the DEmiRs were enriched exclusively in the cellular component level of the endoplasmic reticulum lumen in the comparison between resilient and control rats. Overall, our study utilized an animal model of PTSD to investigate the potential correlation between stress-induced behavioral dysfunction and variations in miRNA expression. The aforementioned discoveries have the potential to pave the way for novel therapeutic approaches for PTSD, which could involve the targeted regulation of transcriptome expression.

Eye-tracking indices of attention allocation and attention bias variability are differently related to trauma exposure and PTSD

Amplified attention allocation to negative information in one’s environment has been implicated in posttraumatic stress disorder (PTSD). Attention bias variability (ABV), the magnitude of attention fluctuation between negative and neutral cues, has also been found to be elevated in PTSD. While eye-tracking methodology has been used in research on attention allocation in PTSD, ABV was only explored using manual reaction-time-based indices. Thirty-seven participants with PTSD, 34 trauma-exposed healthy controls (TEHC), and 30 non-exposed healthy controls (HC) completed an eye-tracking free-viewing task in which matrices comprised of neutral and negatively-valenced faces were presented. Threat-related attention allocation was calculated as the proportion of dwell time (DT%) on negatively-valenced faces. Eye-tracking-based ABV was calculated as the standard deviation of DT% across matrices. DT% on negatively-valenced faces was greater in participants with PTSD compared to both TEHC (p = .036, d = 0.50) and HC (p < .001, d = 1.03), with TEHCs showing a greater attentional bias compared to HCs (p = .001, d = 0.84). Controlling for average fixation duration, ABV was higher in both the PTSD and TEHC groups relative to the HC group (p = .004, d = 0.40), with no difference between the two trauma-exposed groups. Biased attention allocation toward negative social information is related to PTSD pathology, whereas elevated ABV measured with eye-tracking appear to be related to trauma-exposure per-se.

Labelfree mapping and profiling of altered lipid homeostasis in the rat hippocampus after traumatic stress: Role of oxidative homeostasis

Oxidative and lipid homeostasis are altered by stress and trauma and post-traumatic stress disorder (PTSD) is associated with alterations to lipid species in plasma. Stress-induced alterations to lipid and oxidative homeostasis may exacerbate PTSD pathology, but few preclinical investigations of stress-induced lipidomic changes in the brain exist. Currently available techniques for the quantification of lipid species in biological samples require tissue extraction and are limited in their ability to retrieve spatial information. Raman imaging can overcome this limitation through the quantification of lipid species in situ in minimally processed tissue slices. Here, we utilized a predator exposure and psychosocial stress (PE/PSS) model of traumatic stress to standardize Raman imaging of lipid species in the hippocampus using LC-MS based lipidomics and these data were confirmed with qRT-PCR measures of mRNA expression of relevant enzymes and transporters. Electron Paramagnetic Resonance Spectroscopy (EPR) was used to measure free radical production and an MDA assay to measure oxidized polyunsaturated fatty acids. We observed that PE/PSS is associated with increased cholesterol, altered lipid concentrations, increased free radical production and reduced oxidized polyunsaturated fats (PUFAs) in the hippocampus (HPC), indicating shifts in lipid and oxidative homeostasis in the HPC after traumatic stress.

Sex-specific transcriptomic and epitranscriptomic signatures of PTSD-like fear acquisition

SummaryOur understanding of the molecular pathology of posttraumatic stress disorder (PTSD) is evolving due to advances in sequencing technologies. With the recent emergence of Oxford Nanopore direct RNA-seq (dRNA-seq), it is now also possible to interrogate diverse RNA modifications, collectively known as the “epitranscriptome.”. Here, we present our analyses of the male and female mouse amygdala transcriptome and epitranscriptome, obtained using parallel Illumina RNA-seq and Oxford Nanopore dRNA-seq, associated with the acquisition of PTSD-like fear induced by Pavlovian cued-fear conditioning. We report significant sex-specific differences in the amygdala transcriptional response during fear acquisition and a range of shared and dimorphic epitranscriptomic signatures. Differential RNA modifications are enriched among mRNA transcripts associated with neurotransmitter regulation and mitochondrial function, many of which have been previously implicated in PTSD. Very few differentially modified transcripts are also differentially expressed, suggesting an influential, expression-independent role for epitranscriptional regulation in PTSD-like fear acquisition.

Neuronal nitric oxide synthase in dorsal raphe nucleus mediates PTSD-like behaviors induced by single-prolonged stress through inhibiting serotonergic neurons activity

The pathogenesis of post-traumatic stress disorder (PTSD) remains largely unclear. A large body of evidence suggests that the abnormal level of serotonin (5-HT) is closely related to the onset of PTSD. Several reports reveal that nitric oxide (NO) affects extracellular 5-HT levels in various brain regions, but no consistent direction of change was found and the underlying mechanisms remain unknown. The most of serotonergic neurons in dorsal raphe nucleus (DRN), a major source of serotonergic input to the forebrain, co-expresses neuronal nitric oxide synthase (nNOS), a synthase derived nitric oxide (NO) in the central nervous system. Here, we found that the excessive expression of nNOS and thereby the high concentration of NO followed by single-prolonged stress (SPS) caused suppression of the activity of DRN 5-HT neurons, inducing PTSD-like phenotype including increased anxiety-like behaviors, enhanced contextual fear memory, and fear generalization. Our study uncovered an important role of DRN nNOS-NO pathway in the pathology of PTSD, which may contribute to new understanding of the molecular mechanism of PTSD.

Translational relevance of behavioral, neural, and electroencephalographic profiles in a mouse model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a severe, long-term psychological disorder triggered by distressing events. The neural basis and underlying mechanisms of PTSD are not completely understood. Therefore, it is important to determine the pathology of PTSD using reliable animal models that mimic the symptoms of patients. However, the lack of evidence on the clinical relevance of PTSD animal models makes it difficult to interpret preclinical studies from a translational perspective. In this study, we performed a comprehensive screening of the behavioral, neuronal, glial, and electroencephalographic (EEG) profiles in the single prolonged stress and electric foot shock (SPS&S) mouse model. Based on the clinical features of PTSD, we observed fearful and excessive responses to trauma-related environments in the SPS&S mouse model that lasted longer than 14 days. The mice exhibited a defective and strong resistance to the extinction of fear memories caused by auditory cues and also showed enhanced innate fear induced by visual stimuli with concomitant phobias and anxiety. Furthermore, neurons, astrocytes, and microglia in PTSD-related brain regions were activated, supporting abnormal brain activation and neuroimmune changes. EEG assessment also revealed decreased power and impaired coupling strength between cortical regions. These results demonstrated that the SPS&S mouse model recapitulates the behavioral symptoms as well as neural and EEG profiles of PTSD patients, justifying the preclinical use of this mouse model.

Changes in Brain Electrical Activity According to Post-traumatic Stress Symptoms in Survivors of the Sewol Ferry Disaster: A 1-year Longitudinal Study

ObjectiveThe pathology of post-traumatic stress disorder (PTSD) is associated with changes in brain structure and function, especially in the amygdala, medial prefrontal cortex, hippocampus, and insula. Survivors of tragic accidents often experience psychological stress and develop post-traumatic stress symptoms (PTSS), regardless of the diagnosis of PTSD. This study aimed to evaluate electroencephalographic changes according to PTSS in victims of a single traumatic event.MethodsThis study enrolled 60 survivors of the Sewol ferry disaster that occurred in 2014 from Danwon High School and collected electroencephalographic data through 19 channels twice for each person in 2014 and 2015 (mean 451.88 [standard deviation 25.77] days of follow-up). PTSS was assessed using the PTSD Checklist-Civilian Version (PCL-C) and the participants were divided into two groups according to the differences in PCL-C scores between 2014 and 2015. Electroencephalographic data were converted to three-dimensional data to perform low-resolution electrical tomographic analysis.ResultsSignificant electroencephalographic changes over time were observed. The group of participants with worsened PCL-C score showed an increased change of delta slow waves in Brodmann areas 13 and 44, with the largest difference in the insula region, compared to those with improved PCL-C scores.ConclusionOur findings suggests that the electrophysiological changes in the insula are associated with PTSS changes.

Investigating Limbic Grey Matter Microstructure and Macrostructure in Patients With Post-Traumatic Stress Disorder With and Without Psychosis

Post-traumatic stress disorder (PTSD) can present with an array of debilitating symptoms, including psychotic features. The limbic circuit has been largely implicated in the pathology of PTSD, though studies remain inconsistent, with only some results showing reductions in limbic volumes in patients with PTSD. In addition, no study has investigated the association between psychotic symptoms and brain macro- and microstructure in PTSD. The goal of the present study is to compare the macro- and microstructure of the limbic circuit between patients with PTSD, patients with PTSD and psychotic symptoms, and healthy individuals.

The administration of sertraline plus naltrexone reduces ethanol consumption and motivation in a long-lasting animal model of post-traumatic stress disorder

This study was aimed to evaluate the effects of sertraline (STR) and/or naltrexone (NTX) on ethanol consumption and motivation in an animal model of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD).Male C57BL/6J mice were submitted to an intermittent and progressively increasing stressful stimuli simulating PTSD behavioural features. Behavioural alterations were explored by the fear conditioning (FC), novelty suppressed feeding test (NSFT) and acoustic startle response (ASR) paradigms. Afterwards, mice were evaluated in the voluntary ethanol consumption (VC) and the oral ethanol self-administration (OEA) paradigms. The effects of STR (10 mg/kg) and/or NTX (0.7 mg/kg) on ethanol consumption and motivation were analysed in the OEA. Furthermore, relative gene expression analyses of tyrosine hydroxylase (Th), mu-opioid receptor (Oprm1) and 5-hydroxitryptamine transporter (Slc6a4) were performed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) and dorsal raphe nucleus (DR), respectively.PTSD-like mice presented increased fear-related memory, anxiety-like behaviours, and startle response, as well as enhanced ethanol consumption and motivation in the VC and OEA paradigms. Interestingly, STR plus NTX combination significantly reduced ethanol intake and motivation in the OEA. Gene expression analyses revealed reduced Th and Oprm1 whereas Slc6a4 gene expression increased in PTSD-like mice. STR and/or NTX modulated Th and Slc6a4 gene expression changes in PTSD-like mice. Furthermore, NTX increased Oprm1 gene expression revealing a synergistic action when combined with STR.These results provide evidence about the efficacy of the STR plus NTX to attenuate ethanol reinforcement and motivation in an animal model of PTSD and AUD dual pathology.

Phenotypic characterization of frontal cortex microglia in a rat model of post-traumatic stress disorder.

IntroductionPost‐traumatic stress disorder (PTSD) is an anxiety disorder induced by psychologically traumatic events. Using a rat model, this study aimed to determine whether psychological trauma alters relative expression between pro‐inflammatory and anti‐inflammatory markers in microglia. To meet this goal, expression of genes encoding i‐NOS, arginase, TNF‐α, interleukin‐10, CD74, and Mannose Receptor C was analyzed on multiple days following trauma exposure.MethodsSingle‐prolonged stress (SPS) was used to model PTSD in male Sprague‐Dawley rats. Twenty‐four rats (12 Controls and 12 SPS‐exposed) were sacrificed on Days 1, 3, and 7 post‐SPS. Twenty‐four (12 Controls and 12 SPS‐exposed) additional rats were exposed to classical fear conditioning on Day 7, and fear extinction on Days 8, 9, 10, 15, 16, and 17. Freezing behavior was measured to assess fear resolution. Microglial isolates were collected from the frontal cortex, and RNA was extracted. Changes in relative expression of target genes were quantified via RT‐PCR.ResultsSPS rats showed significant decreases in IL‐10 and TNF‐α expression and increases in the i‐NOS:Arginase and TNF‐α:IL‐10 ratios compared to Controls on Day 1, but not on Day 3 or Day 7 for any of the dependent variables. Day 17 SPS rats showed a significant decrease in IL‐10 expression and an increase in the TNF‐α:IL‐10 ratio, further characterized by a significant inverse relationship between IL‐10 expression and fear persistence.ConclusionPsychological trauma impacts the immunological phenotype of microglia of the frontal cortex. Consequently, future studies should further evaluate the mechanistic role of microglia in PTSD pathology.

Sleep, a Governor of Morbidity in PTSD: A Systematic Review of Biological Markers in PTSD-Related Sleep Disturbances.

BackgroundSleep disturbances (SD) are the most impactful and commonly reported symptoms in post-traumatic stress disorder (PTSD). Yet, they are often resistant to primary PTSD therapies. Research has identified two distinct SDs highly prevalent in PTSD; insomnia and nightmares. Those who report SDs prior to a traumatic event are at greater risk for developing PTSD; highlighting that sleep potentially plays a role in PTSD’s pathology. To further understand the pathobiological mechanisms that lead to the development of PTSD, it is first imperative to understand the interplay which exists between sleep and PTSD on a biological level. The aim of this systematic review is to determine if biological or physiological markers are related to SD in PTSD.MethodsA systematic literature search was conducted on the electronic databases; Medline, Embase, AMED and PsycINFO, using Medical Subject Headings and associated keywords.ResultsSixteen studies were included in the final analyses. Physiological makers of autonomic function, and biochemical markers of HPA-axis activity; inflammatory processes; and trophic factor regulation were related to the severity of SDs in PTSD.ConclusionThese findings add to the growing literature base supporting a central focus on sleep in research aiming to define the pathophysiological processes which result in PTSD, as well as emphasising the importance of specifically targeting sleep as part of a successful PTSD intervention strategy. Resolving SDs will not only reduce PTSD symptom severity and improve quality of life but will also reduce all-cause mortality, hospital admissions and lifetime healthcare costs for those with PTSD. Limitations of the current literature are discussed, and key recommendations future research must adhere to are made within.

The Predictive Processing Model of EMDR.

Eye Movement Desensitization and Reprocessing Therapy (EMDR) is an effective treatment for Post-traumatic Stress Disorder (PTSD). The Adaptive Information Processing Model (AIP) guides the development and practice of EMDR. The AIP postulates inadequately processed memory as the foundation of PTSD pathology. Predictive Processing postulates that the primary function of the brain is prediction that serves to anticipate the next moment of experience in order to resist the dissipative force of entropy thus facilitating continued survival. Memory is the primary substrate of prediction, and is optimized by an ongoing process of precision weighted prediction error minimization that refines prediction by updating the memories on which it is based. The Predictive Processing model of EMDR postulates that EMDR facilitates the predictive processing of traumatic memory by overcoming the bias against exploration and evidence accumulation. The EMDR protocol brings the traumatic memory into an active state of re-experiencing. Defensive responding and/or low sensory precision preclude evidence accumulation to test the predictions of the traumatic memory in the present. Sets of therapist guided eye movements repeatedly challenge the bias against evidence accumulation and compel sensory sampling of the benign present. Eye movements reset the theta rhythm organizing the flow of information through the brain, facilitating the deployment of both overt and covert attention, and the mnemonic search for associations. Sampling of sensation does not support the predictions of the traumatic memory resulting in prediction error that the brain then attempts to minimize. The net result is a restoration of the integrity of the rhythmic deployment of attention, a recalibration of sensory precision, and the updating (reconsolidation) of the traumatic memory. Thus one prediction of the model is a decrease in Attention Bias Variability, a core dysfunction in PTSD, following successful treatment with EMDR.

Inflammation and post-traumatic stress disorder.

While post-traumatic stress disorder (PTSD) is currently diagnosed based solely on classic psychological and behavioral symptoms, a growing body of evidence has highlighted a link between this disorder and alterations in the immune and inflammatory systems. Epidemiological studies have demonstrated that PTSD is associated with significantly increased rates of physical comorbidities in which immune dysregulation is involved, such as metabolic syndrome, atherosclerotic cardiovascular disease, and autoimmune diseases. In line with this, a number of blood biomarker studies have reported that compared to healthy controls, individuals with PTSD exhibit significantly elevated levels of proinflammatory markers, such as interleukin-1β, interleukin-6, tumor necrosis factor-α, and C-reactive protein. Moreover, various lines of animal and human research have suggested that inflammation is not only associated with PTSD but also can play an important role in its pathogenesis and pathophysiology. In this review, we first summarize evidence suggestive of increased inflammation in PTSD. We then examine findings that suggest possible mechanisms of inflammation in this disorder in terms of two different but interrelated perspectives: putative causes of increased proinflammatory activities and potential consequences that inflammation generates. Given that there is currently a dearth of treatment options for PTSD, possibilities of new therapeutic approaches using pharmacological and non-pharmacological treatments/interventions that have anti-inflammatory effects are also discussed. Despite the increasing attention given to the inflammatory pathology of PTSD, there remains much to be elucidated, including more detailed mechanisms of inflammation, potential usefulness of inflammatory biomarkers as diagnostic and prognostic markers, and efficacy of novel treatment strategies targeting inflammation.

Updates in PTSD Animal Models Characterization.

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental disorder afflicting more than 7% of the US population and 12% of military service members. Since the Afghanistan and Iraq wars, thousands of US service members have returned home with PTSD. Despite recent progress, the molecular mechanisms underlying the pathology of PTSD are poorly understood. To promote research on PTSD (especially its molecular mechanisms) and to set a molecular basis for discovering novel medications for this disorder, well-validated animal models are needed. However, to develop PTSD animal models is a challenging process, due to predisposing factors such as physiological, behavioral, emotional, and cognitive changes that emerge after trauma. Currently, there is no well-validated animal model of PTSD, although several stress paradigms mimic the behavioral symptoms and neurological alterations seen in PTSD. In this chapter, we will provide an overview of animal models of PTSD including learned helplessness, footshock, restraint stress, inescapable tail shock, single-prolonged stress, underwater trauma, social isolation, social defeat, early-life stress, and predator-based stress. We emphasize rodent models because they reproduce some of the behavioral and biotical phenotypes seen in PTSD. We will also present data showing that homologous biological measures are increasingly incorporated in studies to assess markers of risk and therapeutic response in these models. Therefore, PTSD animal models may be refined in hopes of capitalizing on the understanding of the molecular mechanisms and delivering tools in order to develop new and more efficacious treatments for PTSD.

Posttraumatic stress disorder, social anxiety disorder and childhood trauma: Differences in hippocampal subfield volume

Volume-based hippocampal findings in Social Anxiety Disorder (SAD) and Posttraumatic Stress Disorder (PTSD) have been inconsistent, with very little investigation of hippocampal subfields. We assessed the effects of early childhood trauma on hippocampal subfields in participants with SAD with and without early childhood trauma and PTSD, compared to healthy controls. The sample comprised 26 participants SAD with early childhood trauma, 22 participants with SAD without early childhood trauma, 17 with PTSD secondary to early childhood trauma and 25 control participants. We used Freesurfer version 6 to determine hippocampal subfield volumes. Findings included significant reduction in right parasubiculum volume between the PTSD group secondary to early childhood trauma and the SAD group without early childhood trauma, as well as a significant reduction in left HATA (Hippocampal Amygdala Transition Area) volume between PTSD with early childhood trauma compared to controls, as well as compared to SAD with early childhood trauma. These findings did withstand correction for multiple resting using the false discovery rate. Our findings of an association of reduced volumes in the parasubiculum and HATA regions with PTSD secondary to childhood trauma are interesting. Further work should investigate whether parasubiculum and HATA regional volume reductions in PTSD are a specific effect of early childhood trauma or a specific manifestation of PTSD pathology. Further work should also be undertaken to determine if hippocampal subfield atrophy is associated with SAD in the setting of early childhood maltreatment.

Increased right amygdala metabolite concentrations in the absence of atrophy in children and adolescents with PTSD.

Previous studies have shown that posttraumatic stress disorder (PTSD) is associated with dysfunction of the limbic system, in which the amygdala plays an important role. The purpose of this study was to evaluate whether the neurochemical concentrations assessed by proton magnetic resonance spectroscopy (1H-MRS) in the amygdala are abnormal in children and adolescents with PTSD. Twenty-eight pediatric PTSD patients (11 boys, 17 girls) and 24 matched trauma-exposed control subjects (9 boys, 15 girls) underwent magnetic resonance brain imaging and 1H-MRS of the bilateral amygdalae. The concentrations of N-acetylaspartate (NAA), myo-inositol (mI), total creatine (tCr) and total choline (tCho) in the right amygdala were significantly increased in PTSD patients compared with trauma-exposed control subjects. There were significant group-by-age interactions in the left amygdala NAA and right amygdala mI concentrations: older pediatric patients with PTSD had higher left amygdala NAA concentration and younger patients had higher right amygdala mI concentration than trauma-exposed control subjects. There was also a significant correlation between right mI concentration and time since trauma in PTSD patients. Finally, there was significant group-by-age interaction in the left amygdala volume; intragroup analysis revealed that the right amygdala volume was significantly lower than the left in the PTSD group, but not in the control group. These neurochemical abnormalities of the amygdala may indicate that dysfunctions of both neurons and glial cells are involved in the pathology of pediatric PTSD.

Hippocampal subfield volume alteration in post-traumatic stress disorder: a magnetic resonance imaging study

In the current study, we aim to investigate whether post-traumatic stress disorder (PTSD) is associated with structural alterations in specific subfields of hippocampus comparing with trauma-exposed control (TC) in a relatively large sample. We included 67 PTSD patients who were diagnosed under Diagnostic and Statistical Manual of Mental Disorders (4th Edition) (DSM-Ⅳ) criteria and 78 age- and sex-matched non-PTSD adult survivors who experienced similar stressors. High resolution T1 weighted images were obtained via a GE 3.0 T scanner. The structural data was automatically segmented using FreeSurfer software, and volume of whole hippocampus and subfield including CA1, CA2-3, CA4-DG, fimbria, presubiculum, subiculum and fissure were extracted. Volume differences between the two groups were statistically compared with age, years of education, duration from the events and intracranial volume (ICV) as covariates. Hemisphere, sex and diagnosis were entered as fixed factors. Relationship between morphometric measurements with Clinician-Administered PTSD Scale (CAPS) score and illness duration were performed using Pearson's correlation with SPSS. Comparing to TC, PTSD patients showed no statistically significant alteration in volumes of the whole hippocampus and all the subfields ( P > 0.05). In male patients, there were significant correlations between CAPS score and volume of right CA2-3 ( R2 = 0.197, P = 0.034), right subiculum ( R2 = 0.245, P = 0.016), and duration statistically correlated with right fissure ( R2 = 0.247, P = 0.016). In female patients, CAPS scores significant correlated with volume of left presubiculum ( R2 = 0.095, P = 0.042), left subiculum ( R2 = 0.090, P = 0.048), and left CA4-DG ( R2 = 0.099, P = 0.037). The main findings of the current study suggest that stress event causes non-selective damage to hippocampus in both PTSD patients and TC, and gender-specific lateralization may underlie PTSD pathology.