Single-Prolonged Stress Induces Endoplasmic Reticulum - Dependent Apoptosis in the Hippocampus in a Rat Model of Post-Traumatic Stress Disorder

Background

Our previous research indicated that apoptosis induced atrophy in the hippocampus of post-traumatic stress disorder (PTSD) rats. Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in the development of several disorder diseases. The aim of this study was to investigate whether endoplasmic reticulum-related pathway is involved in single-prolonged stress (SPS) induces apoptosis in the hippocampus of PTSD rats by examining the expression levels of three important indicators in the ER-related apoptotic pathway: Glucose-regulated protein (GRP) 78, caspase-12 and Ca²⁺/CaM/CaMkinaseIIα (CaMkIIα).

Methods

Wistar rats were sacrificed at 1, 4 and 7 days after SPS. SPS is a reliable animal model of PTSD. The apoptotic cells in the hippocampus were assessed by TUNEL method and transmission electron microscopy (TEM). Free intracellular Ca²⁺ concentration was measured. GRP78 expression was examined by immunohistochemistry, western blotting and RT-PCR. mRNA of caspase-12 and CaM/CaMkIIα were determined by RT-PCR.

Results

Our results showed that apoptotic cells were increased in the SPS rats. TEM analysis revealed characteristic morphological changes of apoptosis in these cells. We observed that GRP78 was significantly up-regulated during early PTSD, and then recovered at 7 days after SPS. By RT-PCR, we observed that the change in caspase-12 expression level was similar to that in GRP78. Moreover, the free intracellular Ca²⁺ concentration was significantly higher at 1 day after SPS and decreased in 7 days. CaM expression increased significantly, while CaMKIIα expression decreased significantly in the hippocampus at 1 day after SPS.

Conclusion

SPS induced change in the expression levels of GRP78, caspase-12 and Ca²⁺/CaM/CaMkIIα in the hippocampus of PTSD rats indicated that the endoplasmic reticulum pathway may be involved in PTSD-induced apoptosis.     

Xenon Impairs Reconsolidation of Fear Memories in a Rat Model of Post-Traumatic Stress Disorder (PTSD)

Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation – a state in which recalled memories become susceptible to modification – we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory.     

Influence of Post-Traumatic Stress Disorder on Neuroinflammation and Cell Proliferation in a Rat Model of Traumatic Brain Injury

Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed cell proliferation may evolve into more severe neurodegenerative diseases and psychiatric disorders currently being recognized in traumatized TBI patients.     

Repetitive Transcranial Magnetic Stimulation Ameliorates Anxiety-Like Behavior and Impaired Sensorimotor Gating in a Rat Model of Post-Traumatic Stress Disorder

BackgroundRepetitive transcranial magnetic stimulation (rTMS) has been employed for decades as a non-pharmacologic treatment for post-traumatic stress disorder (PTSD). Although a link has been suggested between PTSD and impaired sensorimotor gating (SG), studies assessing the effects of rTMS against PTSD or PTSD with impaired SG are scarce.AimTo assess the benefit of rTMS in a rat model of PTSD.MethodsUsing a modified single prolonged stress (SPS&S) rat model of PTSD, behavioral parameters were acquired using open field test (OFT), elevated plus maze test (EPMT), and prepulse inhibition trial (PPI), with or without 7 days of high frequency (10Hz) rTMS treatment of SPS&S rats.ResultsAnxiety-like behavior, impaired SG and increased plasma level of cortisol were observed in SPS&S animals after stress for a prolonged time. Interestingly, rTMS administered immediately after stress prevented those impairment.ConclusionStress-induced anxiety-like behavior, increased plasma level of cortisol and impaired PPI occur after stress and high-frequency rTMS has the potential to ameliorate this behavior, suggesting that high frequency rTMS should be further evaluated for its use as a method for preventing PTSD.     

Dysfunction and Post-Traumatic Stress Disorder in Fracture Victims 50 Months after the Sichuan Earthquake

Background

This study aimed to evaluate the effectiveness of a rehabilitation intervention on physical dysfunction (PDF) and post-traumatic stress disorder (PTSD) in fracture victims 50 months after the Sichuan earthquake of 2008 and to identify risk factors for PTSD.

Methods

This is a retrospective cohort study. Four hundred and fifty-nine earthquake-related fracture victims from Mianzhu city, Sichuan Province who did not qualify for disability pension participated. Two hundred and forty-five subjects received regular rehabilitation and 214 did not. Muscle strength, joint range of motion (ROM),sensory function, and sit-to-stand balance capacity were evaluated to assess PDF. The PTSD Checklist-Civilian Version (PCL-C) was administered to screen for PTSD. An ordinary least square regression was used to predict PTSD, and a logistic regression was used to predict PDF. In addition a Least Angle Regression (LARS) was carried out for PTSD to study the effects of rehabilitation and PDF at the same time.

Results

Unadjusted and adjusted group differences in physical dysfunction (p<0.01) and PTSD prevalence (p<0.05) were significant in favor of the rehabilitation group. In addition, being female, average or above family income, having witnessed death and fearfulness were found risk factors for PTSD symptoms 50 months after the earthquake. Both PDF and rehabilitation were selected predictors by LARS demonstrating opposite effects.

Conclusion

PDF and PTSD were significantly reduced by the rehabilitation intervention. Future medical intervention strategies should consider rehabilitation in order to assist survivors in dealing with both physical and psychological effects of natural disaster.     

New Morphofunctional Criteria for Resistance Profile in Post-Traumatic Stress Disorder Models as Adrenal Dysfunction Trigger

Doklady Biological Sciences - For the first time in modeling posttraumatic stress disorder (PTSD), we have described the morphofunctional state of adrenal glands in Wistar rats resistant and...     

The Harmony of Illusions: Inventing Post-Traumatic Stress Disorder

The Harmony of Illusions: Inventing Post-Traumatic Stress Disorder. Allan Young. Princeton, NJ: Princeton University Press, 1995 (cloth and paper),. + 327 pp.     

What Happened in the Hippocampal Axon in a Rat Model of Posttraumatic Stress Disorder

Studies from postmortem and animal models have revealed altered synapse morphology and function in the brain of posttraumatic stress disorder (PTSD). And the effects of PTSD on dendrites and spines have been reported, however, the effection on axon include microtubule (MT) and synaptic vesicles of presynaptic elements remains unknown. Hippocampus is involved in abnormal memory in PTSD. In the present study, we used the single prolonged stress (SPS) model to mimic PTSD. Quantitative real-time polymerase chain reaction (RT-qPCR) and high-throughput sequencing (GSE153081) were utilized to analyze differentially expressed genes (DEGs) in the hippocampus of control and SPS rats. Immunofluorescence and western blotting were performed to examine change in axon-related proteins. Synaptic function was evaluated by measuring miniature excitatory postsynaptic currents (mEPSCs). RNA-sequencing analysis revealed 230 significantly DEGs between the control and SPS groups. Gene Ontology analysis revealed upregulation in axonemal assembly, MT formation, or movement, but downregulation in axon initial segment and synaptic vesicles fusion in the hippocampus of SPS rats. Increased expression in tau, β-tubulin MAP1B, KIF9, CCDC40, DNAH12 and decreased expression in p-tau, stathmin suggested SPS induced axon extension. Increased protein expression in VAMP, STX1A, Munc18-1 and decreased expression in synaptotagmin-1 suggested SPS induced more SNARE complex formation but decreased ability in synaptic vesicle fusion to presynaptic active zone membrane in the hippocampus of SPS rats. Further, low mEPSC frequency in SPS rats indicated dysfunction in presynaptic membrane. These results suggest that axon extension and synaptic vesicles fusion abnormality are involved in dysfunction of PTSD.

     

Meta-Analyses of the 5-HTTLPR Polymorphisms and Post-Traumatic Stress Disorder

Objective

To conduct a meta-analysis of all published genetic association studies of 5-HTTLPR polymorphisms performed in PTSD cases

Methods Data Sources

Potential studies were identified through PubMed/MEDLINE, EMBASE, Web of Science databases (Web of Knowledge, WoK), PsychINFO, PsychArticles and HuGeNet (Human Genome Epidemiology Network) up until December 2011. Study Selection: Published observational studies reporting genotype or allele frequencies of this genetic factor in PTSD cases and in non-PTSD controls were all considered eligible for inclusion in this systematic review. Data Extraction: Two reviewers selected studies for possible inclusion and extracted data independently following a standardized protocol. Statistical analysis: A biallelic and a triallelic meta-analysis, including the total S and S'' frequencies, the dominant (S+/LL and S''+/L''L'') and the recessive model (SS/L+ and S''S''/L''+), was performed with a random-effect model to calculate the pooled OR and its corresponding 95% CI. Forest plots and Cochran''s Q-Statistic and I² index were calculated to check for heterogeneity. Subgroup analyses and meta-regression were carried out to analyze potential moderators. Publication bias and quality of reporting were also analyzed.

Results

13 studies met our inclusion criteria, providing a total sample of 1874 patients with PTSD and 7785 controls in the biallelic meta-analyses and 627 and 3524, respectively, in the triallelic. None of the meta-analyses showed evidence of an association between 5-HTTLPR and PTSD but several characteristics (exposure to the same principal stressor for PTSD cases and controls, adjustment for potential confounding variables, blind assessment, study design, type of PTSD, ethnic distribution and Total Quality Score) influenced the results in subgroup analyses and meta-regression. There was no evidence of potential publication bias.

Conclusions

Current evidence does not support a direct effect of 5-HTTLPR polymorphisms on PTSD. Further analyses of gene-environment interactions, epigenetic modulation and new studies with large samples and/or meta-analyses are required.     

Comparative Analysis of Pathobiochemical Changes in Major Depression and Post-Traumatic Stress Disorder

Biochemistry (Moscow) - Comparative analysis of available literature data on the pathogenetic neuroendocrine mechanisms of depression and post-traumatic stress disorder (PTSD) is provided in this...     

Pet Loss,Complicated Grief,and Post-Traumatic Stress Disorder in Hawaii

We examined the impact of pet/animal death on Complicated Grief (CG) and Post-Traumatic Stress Disorder (PTSD) in relation to demographic variables amongst a diverse population of racial and ethnic groups in Hawaii. Three hundred and fifty-five participants (142 solicited by mail, 213 volunteer college students) completed a 37-item questionnaire, the Inventory of Complicated Grief Revised Short Form (ICG-R-SF) and the PTSD Check-list (PCL), and we assessed relationships between demographic variables such as pet ownership with CG and PTSD scores, to gauge potential at-risk populations. While Filipino populations presented increased, if subclinical, CG and/or PTSD scores, no primary racial/ethnic identity correlated with significant scores, based on the DSM-IV-TR criteria. Individuals who scored higher on questions related to empathy with animals, such as adopting strays, feeling like their pet can sense their mood, integration of animals into the family unit, and feeling over-protective of their pet correlated with higher CG and PTSD scores. We found that 3.8% of participants met the cutoff score for CG and 5.7% met the cutoff score for PTSD, following the death of a pet/animal. There is a need for multicultural awareness regarding both human–pet/animal relationships and bereavement.     

Lasting Consequences of Traumatic Events on Behavioral and Skeletal Parameters in a Mouse Model for Post-Traumatic Stress Disorder (PTSD)

Background

Post-traumatic stress disorder (PTSD) is an anxiety disorder that not only affects mental health, but may also affect bone health. However, there have been no studies to examine the direct relationship between PTSD and bone.

Methodology/Principal Findings

We employed electric shocks in mice to simulate traumatic events that cause PTSD. We also injected the anxiogenic drug FG-7142 prior to electric shocks. Electric shocks created lasting conditioned fear memory in all mice. In young mice, electric shocks elicited not only behavioral response but also skeletal response, and injection of FG-7142 appeared to increase both types of response. For example in behavioral response within the first week, mice shocked alone froze an average of 6.2 sec in 10 sec tests, and mice injected with FG-7142 froze 7.6 sec, both significantly different (P<0.05) from control mice, which only froze 1.3 sec. In skeletal response at week 2, shocks alone reduced 6% bone mineral content (BMC) in total body (P = 0.06), while shocks with FG-7142 injection reduced not only 11% BMC (P<0.05) but also 6% bone mineral density (BMD) (P<0.05). In addition, FG-7142 injection also caused significant reductions of BMC in specific bones such as femur, lumbar vertebra, and tibia at week 3. Strong negative correlations (R² = −0.56, P<0.05) and regression (y = 0.2527−0.0037 * x, P<0.01) between freezing behavior and total body BMC in young mice indicated that increased contextual PTSD-like behavior was associated with reduced bone mass acquisition.

Conclusions/Significance

This is the first study to document evidence that traumatic events induce lasting consequences on both behavior and skeletal growth, and electric shocks coupled with injection of anxiogenic FG-7142 in young mice can be used as a model to study the effect of PTSD-like symptoms on bone development.     

Long-Lasting Effects of Maternal Separation on an Animal Model of Post-Traumatic Stress Disorder: Effects on Memory and Hippocampal Oxidative Stress

Adverse early life events, such as periodic maternal separation, may alter the normal pattern of brain development and subsequently the vulnerability to a variety of mental disorders in adulthood. Patients with a history of early adversities show higher frequency of post-traumatic stress disorder (PTSD). This study was undertaken to verify if repeated long-term separation of pups from dams would affect memory and oxidative stress parameters after exposure to an animal model of PTSD. Nests of Wistar rats were divided into intact and subjected to maternal separation (incubator at 32°C, 3 h/day) during post-natal days 1–10. When adults, the animals were subdivided into exposed or not to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. One month after exposure to the shock, the animals were exposed to a memory task (Morris water maze) and another month later animals were sacrificed and DNA breaks and antioxidant enzymes activities were measured in the hippocampus. Rats exposed to shock or maternal separation plus shock showed long-lasting effects on spatial memory, spending more time in the opposite quadrant of the water maze. This effect was higher in animals subjected to both maternal separation and shock. Both shock and maternal separation induced a higher score of DNA breaks in the hippocampus. No differences were observed on antioxidant enzymes activities. In conclusion, periodic maternal separation may increase the susceptibility to the effects of a stressor applied in adulthood on performance in the water maze. Increased DNA breaks in hippocampus was induced by both, maternal separation and exposure to shock.     

肝癌致创伤后应激障碍的心理咨询探讨

目的:初步探索心理咨询对肝癌所致创伤后应激障碍患者的干预效果。方法:一例肝癌患者接受六次心理咨询服务。采用PTSD症状评估和生活事件症状测评量表,在咨询第一次和第六次对患者实施测评,并收集患者及家属的主观描述。结果:患者经过认知行为、放松和眼动脱敏干预后,其警觉性下降、创伤再体验次数明显减少、睡眠状况改善以及对癌症治疗的管理观念提高,三个月后对患者及家属回访显示,患者症状改善在回访期维持。结论:认知和眼动脱敏疗法对肝癌所致的创伤后应激障碍患者具有潜在的正性干预效果,未来尚需广泛的实证研究。     

Symptoms and Subjective Quality of Life in Post-Traumatic Stress Disorder: A Longitudinal Study

Background

Evidence suggests that post-traumatic stress disorder (PTSD) is associated with substantially reduced subjective quality of life (SQOL). This study aimed to explore whether and how changes in the levels of PTSD symptom clusters of intrusion, avoidance and hyperarousal are associated with changes in SQOL.

Methods

Two samples with PTSD following the war in former Yugoslavia were studied, i.e. a representative sample of 530 people in five Balkan countries and a non-representative sample of 215 refugees in three Western European countries. They were assessed on average eight years after the war and re-interviewed one year later. PTSD symptoms were assessed on the Impact of Event Scale - Revised and SQOL on the Manchester Short Assessment of Quality of Life. Linear regression and a two-wave cross lagged panel analysis were used to explore the association between PTSD symptom clusters and SQOL.

Results

The findings in the two samples were consistent. Symptom reduction over time was associated with improved SQOL. In multivariable analyses adjusted for the influence of all three clusters, gender and time since war exposure, only changes in hyperarousal symptoms were significantly associated with changes in SQOL. The two-wave cross-lagged panel analysis suggested that the link between hyperarousal symptoms and SQOL is bidirectional.

Conclusions

Low SQOL of patients with war-related PTSD is particularly associated with hyperarousal symptoms. The findings suggest a bidirectional influence: a reduction in hyperarousal symptoms may result in improved SQOL, and improvements in SQOL may lead to reduced hyperarousal symptoms.