Pathogenesis Of Post-traumatic Stress Disorder Research Articles

Disrupted brain network topology in pediatric posttraumatic stress disorder: A resting-state fMRI study.

Children exposed to natural disasters are vulnerable to the development of posttraumatic stress disorder (PTSD). Recent studies of other neuropsychiatric disorders have used graph-based theoretical analysis to investigate the topological properties of the functional brain connectome. However, little is known about this connectome in pediatric PTSD. Twenty-eight pediatric PTSD patients and 26 trauma-exposed non-PTSD patients were recruited from 4,200 screened subjects after the 2008 Sichuan earthquake to undergo a resting-state functional magnetic resonance imaging scan. Functional connectivity between 90 brain regions from the automated anatomical labeling atlas was established using partial correlation coefficients, and the whole-brain functional connectome was constructed by applying a threshold to the resultant 90 * 90 partial correlation matrix. Graph theory analysis was then used to examine the group-specific topological properties of the two functional connectomes. Both the PTSD and non-PTSD control groups exhibited "small-world" brain network topology. However, the functional connectome of the PTSD group showed a significant increase in the clustering coefficient and a normalized characteristic path length and local efficiency, suggesting a shift toward regular networks. Furthermore, the PTSD connectomes showed both enhanced nodal centralities, mainly in the default mode- and salience-related regions, and reduced nodal centralities, mainly in the central-executive network regions. The clustering coefficient and nodal efficiency of the left superior frontal gyrus were positively correlated with the Clinician-Administered PTSD Scale. These disrupted topological properties of the functional connectome help to clarify the pathogenesis of pediatric PTSD and could be potential biomarkers of brain abnormalities.

IRE1α-XBP1 Pathway Is Activated Upon Induction of Single-Prolonged Stress in Rat Neurons of the Medial Prefrontal Cortex.

Endoplasmic reticulum stress (ERS) is associated with many nervous system diseases. IRElα is considered as ERS sensor that, upon activation, initiates the nonconventional splicing of the precursor unspliced form of X-box binding protein 1 (XBP1u) messenger RNA (mRNA) to yield an active transcription factor-XBP1s. The goal of this study is to detect whether there is activation of IRE1α-XBP1 pathway in the medial prefrontal cortex (mPFC) of posttraumatic stress disorder (PTSD) model rats. This study adopted single-prolonged stress (SPS) model. Behavioral functions including anxiety-like behavior, exploration behavior, and spatial memory were assessed by open field test and Morris water maze test. We detected the IRE1α and XBP1 by using methods of double-labeling immunofluorescence, Western blot, and quantitative real-time reverse transcription-PCR (qRT-PCR). We also observed neuronal apoptosis by transferase-mediated dUTP Nick-end-labeling (TUNEL) staining and the expression of caspase-12 by qRT-PCR. Our results showed that the expression of IRE1α, XBP1u, and total XBP1 significantly increased at 1day after SPS and then decreased gradually. At the same time, XBP1s appeared and peaked at 4days after SPS, which indicated that IRE1α-XBP1 pathway was activated upon induction of SPS stimulation. We also noted that the mRNA of caspase-12 was upregulated after SPS. Our study preliminarily showed that ERS mediated by IRE1α-XBP1 pathway was closely related to PTSD and it might be a pathogenesis of PTSD.

The neurotrophin BDNF is involved in the development and prevention of stress-induced psychopathologies

The neurotrophin BDNF plays an important role in synaptic plasticity, the survival of neurons, and obviously, in the stress response of the body. We studied the time course of the changes in BDNF expression in the hippocampus and neocortex of rats after their exposure to pathogenic stress in models of endogenous depression and post-traumatic stress disorder (PTSD) and after treatment with hypoxic preconditioning, which prevented the development of anxiety–depressive conditions. Using immunohistochemistry we revealed that the development of experimental anxiety–depressive conditions was accompanied by a significant and stable decrease in the BDNF contents in hippocampal and neocortical neurons. In a model of depressive pathology, hypoxic preconditioning normalized the number of BDNF-expressing neurons early after stress exposure. In a model of PTSD, hypoxic preconditioning substantially and protractedly stimulated BDNF expression in the studied brain structures. Thus, the insufficient expression of this factor in the higher brain structures evidently reflected a maladaptive response to severe stress and may be a general feature of the pathogenesis of both depression and PTSD, whereas the significant and stable upregulation of BDNF expression is involved in the mechanisms of the anxiolytic effects of preconditioning and is important for the prevention of the development of PTSD.

Serum total oxidant and antioxidant status in earthquake survivors with post-traumatic stress disorder.

Oxidative stress has been shown to play an important role in the pathogenesis of post-traumatic stress disorder (PTSD). Although there are some studies on oxidative stress and PTSD, there is no report available on the serum total oxidant and antioxidant status in earthquake survivors with PTSD. Therefore, this study aimed to investigate the serum total oxidant and antioxidant status in earthquake survivors with chronic PTSD. The study group included 45 earthquake survivors with PTSD and 40 earthquake survivors without PTSD. The oxidative status was determined using the total antioxidant status and total oxidant status (TOS) measurements and by calculating the oxidative stress index (OSI). There were no statistically significant differences in the total antioxidant status, TOS, or OSI when comparing individuals with and without PTSD (all, p>0.05). There were no correlations between Clinician-Administered PTSD Scale scores and oxidant and antioxidant stress markers (all, p>0.05). Our results suggest that the total oxidant and antioxidant status may not affect earthquake survivors with PTSD. This is the first study to evaluate the oxidative status in earthquake survivors with PTSD. Further studies are necessary to confirm these findings.

Lycium barbarum polysaccharide improves traumatic cognition via reversing imbalance of apoptosis/regeneration in hippocampal neurons after stress

AimsPrevious studies in our laboratory have demonstrated the increased neuronal apoptosis in the hippocampus and abnormal hippocampal morphology after severe stress, which directly correlates to the pathogenesis of post-traumatic stress disorder (PTSD). This study aims to investigate the effects of Lycium barbarum polysaccharide (LBP) on intrusive memory of posttraumatic stress in rats, and to analyze the mechanism of regeneration/apoptosis balance in the hippocampal neurons. Main methodsThe experimental rats received 20 inescapable electric foot shocks in an enclosed box for six times in three days. The rats were treated by intragastric administration of LBP (20mg/kg/day) for 3days before stress in the stress plus prophylactic group, and for 28days after stress in the stress plus therapeutic group. The emotion, intrusive memory-related behavior (freezing, open field, pain latency, spatial cognition), hippocampus cell morphology, and relation of neurogenesis and apoptosis in dental gyrus of the hippocampus were observed. The hippocampus volume was evaluated by stereology. Meanwhile, the neurogenesis and apoptosis were analyzed with 5-bromo-2′-deoxyuridine and terminal deoxylnucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) method. Key findingsThe treatment of LBP in pre-stress and post-stress had obvious beneficial effect on the behaviors and neurogenesis. The stressed rats showed improvement of intrusive memory related cognition defect, alleviation of the apoptosis in the hippocampus and recovery for the neurogenesis, which was related to the hippocampus volume after LBP treatment. SignificanceLBP treatment might effectively improve the traumatic cognition defect induced by severe stress and be useful for the intrusive memory-related cognition recovery.

Single-prolonged stress activates the transcription factor ATF6α branch of the unfolded protein response in rat neurons of dorsal raphe nucleus.

In our previous studies, we have found that endoplasmic reticulum (ER) stress is associated with post-traumatic stress disorder (PTSD), however, the activation of ER stress sensors in PTSD remains unclear. ATF6 alpha (ATF6α) is an ER-membrane-bound transcription factor and functions as a critical sensor and regulator of ER stress in mammalian cells. The goal of this study is to detect whether there is activation of the transcription factor ATF6α branch of the unfolded protein response in the dorsal raphe nucleus neurons of the rats exposed to single-prolonged stress (SPS), which is a model employed extensively in PTSD study. Our results have demonstrated that SPS activated the ER transmembrane protein ATF6α via its cleavage; and induced the up-regulation of the downstream targets of ATF6α, the mRNA of XBP1 and GRP94. To the best of our knowledge, this is the first study to investigate the relationship between the ATF6α pathways and PTSD, and our results show that SPS activates the ATF6α branch of the ER stress response, which may be contributed to the pathogenesis of PTSD.

Prefrontal GABA and glutathione imbalance in posttraumatic stress disorder: Preliminary findings

Although posttraumatic stress disorder (PTSD) is associated with a variety of structural and functional brain changes, the molecular pathophysiological mechanisms underlying these macroscopic alterations are unknown. Recent studies support the existence of an altered excitation–inhibition balance in PTSD. Further, there is preliminary evidence from blood-sample studies suggesting heightened oxidative stress in PTSD, potentially leading to neural damage through excessive brain levels of free radicals. In this study we investigated PTSD (n=12) and non-PTSD participants (n=17) using single-voxel proton magnetic resonance spectroscopy (MRS) in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). We found significantly higher levels of γ-amino butyric acid (GABA) (a primary inhibitory neurotransmitter) and glutathione (a marker for neuronal oxidative stress) in PTSD participants. Atypically high prefrontal inhibition as well as oxidative stress may be involved in the pathogenesis of PTSD.

Intra-hippocampal administration of ZIP alleviates depressive and anxiety-like responses in an animal model of posttraumatic stress disorder.

BackgroundGiven that impairment of fear extinction has been implicated in the pathogenesis of posttraumatic stress disorder (PTSD), effective pharmacological interventions that facilitate fear extinction may provide alternative strategies to conventional treatment. It is generally accepted that the zeta inhibitory peptide (ZIP), a controversial inhibitor of protein kinase M zeta (PKMζ), could erase certain types of previously established long-term memories. However, it is unclear whether ZIP administration may alleviate PTSD-associated depressive and anxiety-like abnormalities.MethodsHere we developed a re-stressed single-prolonged stress (SPS) paradigm, a modified prevalent animal model of PTSD, and assayed the expressions of PKMζ in the hippocampus after SPS procedure. Next, Seven days prior to re-stress, ZIP was injected into the hippocampus, and the depressive and anxiety-like behavior was examined by the subsequent forced swim (FS), open-field and elevated plus maze (EPM) test.ResultsRats given ZIP prior to FS exhibited a reduction of immobility time in FS test, and more open arms (OA) entries and longer OA duration in EPM. They also spent longer time in the center of the open field.ConclusionsOur results suggested that re-stressed SPS could reproduce behavioral alteration similar to that observed in patients with PTSD, and these behavioral symptoms co-morbid with PTSD could be effectively alleviated by the intro-hippocampal administration of ZIP.

An updated animal model capturing both the cognitive and emotional features of post-traumatic stress disorder (PTSD).

The new-released Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines post-traumatic stress disorder (PTSD) as a “trauma and stressor-related disorder”. PTSD pathogenesis relies on paradoxical changes of emotional memory processing induced by the trauma exposure and associated with emotional dysfunction. Several animal models of PTSD have been validated and are currently used. Each one mimics a particular subset of the disorder with particular emphasis, mainly driven by the past classification of PTSD in the DSM-4, on the emotional features. In view of the recent update in the DSM-5, our aim was to develop, by using well-validated paradigms, a modified model of PTSD able to mimic at the same time both the cognitive and emotional features of the disease. We exposed male rats to either a piece of worn cat collar or to a series of inescapable footshocks paired with a PTSD risk factor, i.e., social isolation. Animals were subsequently re-exposed to the conditioned contexts at different time intervals in order to test memory retention for the stressors. In addition, footshock-exposed rats were tested in the elevated-plus-maze and social interaction tests. We found that rats exposed to a cat collar exhibited an acute fear response that did not lead to enduring memory retention. Conversely, footshock-exposed rats expressed a successful retention of the stressful experience at 1, 7, 14, 21 and 56 post-exposure days. Footshock-exposed rats displayed an anxious behavioral profile in the social interaction test and a significantly reduced locomotor activity in the elevated-plus-maze test. These dysfunctions were not observed when animals were socially housed, thus highlighting a social buffering effect in the development of the pathology. Our results underline the good validity of a footshock-based paradigm paired with social isolation as a PTSD animal model, able to mimic at the same time both some of the enduring cognitive and emotional facets of the pathology.

Involvement of Anomalous Apoptosis in Impairments to Synaptic Plasticity in Post-Traumatic Stress Disorder

Enzyme-linked immunosorbent assay was used to measure levels of apoptosis and synaptic plasticity marker proteins, i.e., annexin A5 and complexin 2 respectively, as well as the proinflammatory cytokine tumor necrosis factor α (TNF-α), in serum from patients with post-traumatic stress disorder (PTSD) in comparison with healthy subjects. Correlations between these parameters were studied. The results obtained here showed that annexin A5 and complexin 2 concentrations in PTSD patients were significantly lower than normal, while TNF-α levels were higher. PTSD patients showed a positive correlation between annexin A5 and complexin 2 levels on the one hand, and a negative correlation between annexin A5 and TNF-α levels on the other. These data lead to the conclusion that the pathogenesis of PTSD is characterized by reduced apoptosis associated with defects in synaptic plasticity. It is suggested that anomalous apoptosis may also be among the factors supporting the development of the chronic inflammation typical of the pathogenesis of PTSD.

Effect of Glucose-Regulated Protein 94 and Endoplasmic Reticulum Modulator Caspase-12 in Medial Prefrontal Cortex in a Rat Model of Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is an anxiety disorder caused by a life-threatening traumatic experience, which affects a patient's quality of life and social stability. The objective of this study was to investigate the change of the glucose-regulated protein (GRP) 94 and apoptosis-related caspase-12 expression in medial prefrontal cortex (mPFC) in rats to determine whether endoplasmic reticulum apoptosis pathway plays an important role in single-prolonged stress (SPS), a well-established PTSD animal model, and therefore to provide experimental evidence to reveal PTSD pathogenesis. A total of 120 healthy male Wistar rats were selected for this study, randomly divided into a normal control group and SPS groups of 1, 4, 7, 14, and 28 days. Behavioral studies of the learning and memory capabilities of rats were observed by using Morris water maze. Morphological changes were detected using transmission electron microscopy (TEM). Immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction (RT-PCR) were used to detect the expressions of caspase-12 and GRP94 expressions in mPFC. Our results showed that compared with control groups, after the SPS exposure, the average escape latency was prolonged in place navigation test (P < 0.05), and swimming time in the third quadrant in spatial probe test shortened. The morphological change of mPFC in each SPS group bears typical apoptotic characteristics. The expressions of GRP94 and caspase-12 gradually increased on 1 and 4 days, peaked on 7 days after the SPS exposure, and then decreased. These results suggest that SPS exposure can induce apoptotic neurons and a change of caspase-12 and GRP94 expression in the mPFC, which may be one of the pathogenesis of mPFC abnormal function in PTSD.

The adaptive role of the CREB and NF-κB neuronal transcription factors in post-stress psychopathology models in rats

We studied the dynamics of the activation of the CREB and NF-κB transcription factors in areas of the rat brain after exposure to pathogenic psycho-emotional stress in the model of endogenous depression and the model of posttraumatic stress disorder (PTSD), as well as after application of hypoxic preconditioning, which prevents the formation of anxiety-depressive pathologies in these models. The development of anxiety-depressive pathology in both models was associated with reduced (10 times lower than the control maximum) or basal levels of the activating transcription factors CREB and NF-κB in the hippocampus and the neocortex. However, in the hypothalamus, NF-κB overactivation (up to an 18-fold increase above the control level) was detected in the model of depression. Therefore the lack of activation of these factors in the extra-hypothalamic areas of the brain may be a common component of the pathogenesis of both depression and PTSD, while NF-κB overactivation in the neurosecretory centers of the hypothalamus is obviously involved in the development of depressive conditions. Antidepressant and anxiolytic actions of hypoxic preconditioning were accompanied by a mild 2- to 6-fold increase in CREB and NF-κB levels in the neurons of the brain in both stress paradigms. Obviously, the maintenance of optimum activity of transcription factors in the neurons of the brain plays an important role in nonspecific compensatory processes that enhance the adaptive potential of the brain under stress conditions.

Treatment of trauma with lithium to forestall the development of posttraumatic stress disorder by pharmacological induction of a mild transient amnesia

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder that develops after exposure to trauma. Symptoms include persistent reexperiencing, persistent avoidance, persistent numbing, and persistent hyperarousal. Subsequent to trauma exposure, the onset of symptoms of an acute stress reaction can typically develop over varying amounts of time from days to months. Current pharmacotherapies for PTSD are available after symptoms manifest, and primarily consist of selective serotonin reuptake inhibitor (SSRI) antidepressants. There are currently no FDA approved pharmacological interventions available for the treatment of acutely traumatized individuals to forestall the development of PTSD after trauma and prior to the onset of symptoms.A prominent model of PTSD developed by Roger Pitman attributes the pathogenesis of PTSD to over-consolidated traumatic memories that are mediated by endogenous stress hormones released with trauma and after trauma.The molecular processes of memory consolidation in neurons are mediated by intracellular signaling pathways. One secondary messenger signaling pathway with a putative role in long-term potentiation (LTP) is the inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) secondary messenger system.Lithium, a treatment for bipolar disorder, and a pharmacotherapy that is associated with inducing transient impairments in cognition, memory, and learning, is an inhibitor of inositol monophosphatase (IMP), an enzyme in the IP3 and DAG secondary messenger pathway.I am advancing the hypothesis that the administration of lithium for a brief interval to traumatized individuals at risk for PTSD within the time period after trauma and prior to the onset of symptoms could potentially forestall the development of PTSD by disrupting LTP. I am proposing that this treatment will reduce the incidence of PTSD and reduce the severity of symptoms in those who eventually develop PTSD.

Increased Neuronal Apoptosis in Medial Prefrontal Cortex is Accompanied with Changes of Bcl-2 and Bax in a Rat Model of Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by traumatic experience, which affects a patient's quality of life and social stability. The objective of this study was to determine the apoptosis-related genes B-cell lymphoma 2 (Bcl-2) and BCL2-associated X (Bax) expressions and medial prefrontal cortex (mPFC) neuronal apoptosis after PTSD in rat model and therefore to provide experimental evidence to reveal PTSD pathogenesis. The single-prolonged stress (SPS) method was used to set up the rat PTSD models. Chemiluminescence was used to determine serum corticosterone levels. Neuronal apoptosis was detected using transmission electron microscopy, Hoechst staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Immunohistochemistry, immunofluorescence, RT-PCR, and Western blot were used to detect the expressions of Bcl-2 and Bax protein in mPFC. Our results showed an increased mPFC neuronal apoptosis after SPS stimulation. The number of apoptotic cells peaked on day 7. The expressions of Bcl-2 and Bax peaked on days 4 and 7. The Bcl-2/Bax ratio elevated on days 1 and 4 but decreased markedly on day 7. These results indicated that SPS stimulation increased the number of apoptotic neurons, up-regulated the expressions of Bcl-2 and Bax, and altered the Bcl-2/Bax ratio in the mPFC of PTSD rats.

Study of the variations in apoptotic factors in hippocampus of male rats with posttraumatic stress disorder

Background:Post-traumatic stress disorder (PTSD) is a stress-related psychosomatic disorder caused by occurrence of a traumatic event and the hippocampus volume of the patients with Post-traumatic stress disorder decreased. However, the mechanisms that cause such damage are not well-understood. The aim of this study is to detect the expression of apoptosis-related Bax, Bcl-2, Caspase-3 and Insulin-like growth Factor-I proteins in the hippocampus region in the Predatory stress rats.Materials and Methods:A total of 70 male wistar rats were divided into Predatory stress groups of 1d, 2d, 3d, 7d, 14d, 30d and a normal control group (N = 10). Rats were subjected to 5 min of predatory stress and then exposed to the elevated plus-maze (EPM). Serum corticosterone and Insulin-like growth factor-1 level of Hippocampus were measured by ELISA technique. The expression of Bax, Bcl-2, and Caspase-3 were detected by western blotting.Results:Rats spent significantly more time in closed arms of the elevated plus maze (EPM) than control group after exposure to stress. Serum levels of corticosterone significantly increased at 2d-3d. The expression of hippocampal IGF-1 was significantly up-regulated at 1d-2d after stress. Both Bax and the ratio of Bax/Bcl-2 significantly peaked at Predatory stress 2d-14d. Caspase3 was significantly active among 2d-30 compared to the normal control.Conclusion:The activation of caspase-3 in the stress groups indicates that apoptosis may be one of the reasons inducing hippocampus atrophy and play roles in the pathogenesis of PTSD. Increase in hippocampus levels of IGF-1 during early PTSD might be involved in the early molecular inhibitory mechanism of apoptosis in PTSD.

The Role of BDNF-TrkB Signaling in the Pathogenesis of PTSD.

Posttraumatic Stress Disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. The majority of individuals with PTSD often have comorbid psychiatric conditions such as major depression, generalized anxiety disorder, and substance use disorders, and are at increased risk for suicide. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. One promising target for modulation is Tropomyosin Receptor Kinase B (TrkB), the receptor for Brain-Derived Neurotrophic Factor (BDNF), a signaling pathway important for neuronal plasticity, survival, and growth. The following discusses how genetic and environmental alterations to this signaling pathway may contribute to anatomical and functional changes in the hippocampus, amygdala, anterior cingulate cortex, ventromedial prefrontal cortex, and the nucleus accumbens. Changes in these brain regions may in turn contribute to the predisposition to or maintenance of some of the clinical manifestations of PTSD, including intrusive memories, hyperarousal, increased fear, and emotional numbing.

1178 – Correlation study of apoptosis-related genes bcl-2, bax and ptsd in rat medial prefrontal cortex neuronal apoptosis

Post-traumatic stress disorder (PTSD) is a significant problem,The medial prefrontal cortex (mPFC) is known to be significantly involved in emotional adjustment. To discuss the issue of post-traumatic stress disorder (PTSD) rat apoptosis-related genes Bcl-2, Bax and medial prefrontal cortex (mPFC) neuronal apoptosis, and to provide experimental evidence to reveal PTSD pathogenesis. The single-prolonged stress(SPS) method was used to set up the rat PTSD models There were five groups after SPS 1 day 4 days 7 days 14 days groups and control group Serum corticosterone level was determined with chemiluminescence, mPFC neuronal apoptosis changes and detection of apoptotic index were detected with transmission electron microscopy, hoechst 33342 staining and in situ nick end labeling method (TUNEL) staining. Immunohistochemistry, immunofluorescence, RT-PCR and western blotting were used to detect the expressions of Bcl-2 and Bax in the medial prefrontal cortex neuronal. PTSD rat mPFC neuron cell apoptosis, the number of apoptotic cells gradually increased with time and reached a peak at 7 days after SPS stimulates. Bcl-2 expression reached a peak at 4d and Bax expression reached a peak at 7d after SPS stimulates, Bcl-2/Bax ratio transient increased and then gradually decreased, reached a lowest point in seventh days after SPS stimulates. The expression of apoptosis related genes Bcl-2 and Bax increase and their ratio imbalances are likely to be one of the reasons that lead to PTSD in rat mPFC neurons apoptosis, which may provide the pathophysiology basis for PTSD.

Alterations in the cortical thickness and the amplitude of low-frequency fluctuation in patients with post-traumatic stress disorder

The core neuropsychological processes underlying post-traumatic stress disorder (PTSD) have yet to be elucidated, and the association between anatomical and functional deficits in PTSD remains largely unknown. The aim of our study was to investigate the alterations in cortical thickness and amplitude of low-frequency fluctuation (ALFF) in PTSD patients resulting from motor vehicle accidents (MVCs), and to explore the association of cortical thickness and ALFF with the severity of PTSD symptoms. A total of 20 PTSD patients and 20 healthy controls were recruited and examined by high-resolution structural MRI combined with resting-state fMRI. The results showed significant decrease in cortical thickness in the left BA10, BA32 and BA45 and the right superior temporal gyrus in PTSD patients. The ALFF value in PTSD patients increased significantly in the left BA10 and BA32 and the right cerebellum. Linear regression revealed that decreased cortical thickness and increased ALFF in the BA10 were associated with the increased PTSD scores. These findings suggest that the structural integrity and resting-state function in the BA10 play an important role in the pathogenesis of PTSD.

Long-Lasting Hippocampal Synaptic Protein Loss in a Mouse Model of Posttraumatic Stress Disorder

Despite intensive research efforts, the molecular pathogenesis of posttraumatic stress disorder (PTSD) and especially of the hippocampal volume loss found in the majority of patients suffering from this anxiety disease still remains elusive. We demonstrated before that trauma-induced hippocampal shrinkage can also be observed in mice exhibiting a PTSD-like syndrome. Aiming to decipher the molecular correlates of these trans-species posttraumatic hippocampal alterations, we compared the expression levels of a set of neurostructural marker proteins between traumatized and control mice at different time points after their subjection to either an electric footshock or mock treatment which was followed by stressful re-exposure in several experimental groups. To our knowledge, this is the first systematic in vivo study analyzing the long-term neuromolecular sequelae of acute traumatic stress combined with re-exposure. We show here that a PTSD-like syndrome in mice is accompanied by a long-lasting reduction of hippocampal synaptic proteins which interestingly correlates with the strength of the generalized and conditioned fear response but not with the intensity of hyperarousal symptoms. Furthermore, we demonstrate that treatment with the serotonin reuptake inhibitor (SSRI) fluoxetine is able to counteract both the PTSD-like syndrome and the posttraumatic synaptic protein loss. Taken together, this study demonstrates for the first time that a loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice. Further studies will have to reveal whether these findings are transferable to PTSD patients.

One's sex, sleep, and posttraumatic stress disorder

Women are approximately twice as likely as men to develop posttraumatic stress disorder (PTSD) after trauma exposure. Mechanisms underlying this difference are not well understood. Although sleep is recognized to have a critical role in PTSD and physical and psychological health more generally, research into the role of sleep in PTSD sex differences has been only recent. In this article, we review both animal and human studies relevant to sex differences in sleep and PTSD with an emphasis on the roles of sex hormones. Sleep impairment including insomnia, trauma-related nightmares, and rapid-eye-movement (REM) sleep fragmentation has been observed in individuals with chronic and developing PTSD, suggesting that sleep impairment is a characteristic of PTSD and a risk factor for its development. Preliminary findings suggested sex specific patterns of sleep alterations in developing and established PTSD. Sleep maintenance impairment in the aftermath of trauma was observed in women who subsequently developed PTSD, and greater REM sleep fragmentation soon after trauma was associated with developing PTSD in both sexes. In chronic PTSD, reduced deep sleep has been found only in men, and impaired sleep initiation and maintenance with PTSD have been found in both sexes. A limited number of studies with small samples have shown that sex hormones and their fluctuations over the menstrual cycle influenced sleep as well as fear extinction, a process hypothesized to be critical to the pathogenesis of PTSD. To further elucidate the possible relationship between the sex specific patterns of PTSD-related sleep alterations and the sexually dimorphic risk for PTSD, future studies with larger samples should comprehensively examine effects of sex hormones and the menstrual cycle on sleep responses to trauma and the risk/resilience for PTSD utilizing various methodologies including fear conditioning and extinction paradigms and animal models.