Model Of Posttraumatic Stress Disorder Research Articles

Low emotional contagious behavior induces PTSD susceptibility in observers and is related to the regulation of oxytocin receptor in mice.

Post-traumatic stress disorder (PTSD) is a serious psychiatric disorder that occurs after an individual has witnessed or experienced a major traumatic event. Emotional contagion seems to play an important role in witnessing trauma, highlighting the importance of understanding the neurobiological consequences of psychological or emotional stress and its impact on the individual's mental health. Therefore, understanding the relationship between emotional contagion and PTSD susceptibility and the abnormal neurobiological and behavioral changes behind it could help find effective molecular treatment targets. The formalin pain test was used to distinguish the level of emotional contagion in observer mice, dividing them into quartiles according to their pain response. The upper and lower quartiles were the emotional contagion-prone (ECP) and -resistant (ECR) groups, respectively. The vicarious social defeat stress (VSDS) procedure was used to establish PTSD models in mice with various emotional contagion levels when witnessing stress. Open field, elevated plus maze, social interaction test, and forced swimming test were used to examine PTSD-like symptoms. Changes in the medial prefrontal cortex (mPFC) mRNA expression of brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OTR) were detected by qPCR, and their protein levels were analyzed by Western blot and immunofluorescence staining. The formalin pain test induced emotional contagion behaviors in mice between the ECP and ECR levels. The VSDS procedure resulted in PTSD symptoms in mice; mice in the lowest quartile were characterized by high levels of anxiety, depression, and social avoidance behaviors, such as decreased autonomous activity and residence time in the open field test or open arms position and increased immobility time and social avoidance behavior. These were accompanied by reduced OTR and BDNF protein expression levels and fluorescence intensity, as well as reduced OTR and BDNF mRNA levels in the mPFC. Emotional contagion can induce PTSD-like behavior in mice that witnessed stress. Low emotional contagion behavior increased PTSD susceptibility in the observer mice and might be related to the regulation of their oxytocin receptors.

Prediction models for post-traumatic stress disorder in family members of ICU patients: A systematic review.

Several predictive models have been developed for post-traumatic stress disorder (PTSD) in intensive care unit (ICU) family members. However, significant differences persist across related studies in terms of literature quality, model performance, predictor variables and scope of applicability. This study aimed to systematically review risk prediction models for PTSD in family members of ICU patients, to make recommendations for health care professionals in selecting appropriate predictive models. China National Knowledge Infrastructure, VIP database, Wanfang database, SinoMed, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library, Embase and OVID were searched from inception to 1 May 2024. Two independent researchers conducted literature screening, data extraction and applied a risk of bias assessment tool for predictive models to evaluate included studies. The systematic review was registered on PROSPERO (registration number: CRD42024560815). Seventeen studies were included, with sample sizes ranging from 32 to 2734. Incidence rates of outcomes ranged from 1.6% to 63.6%. The most frequently used predictors were relative's female sex, longer duration of ICU stay, patient's death in the ICU and type of relationship with the patient. Two models reported area under the receiver operating characteristic curve (AUC) values ranging from 0.73 to 0.74; only three models reported calibration, and one study conducted internal validation. Overall, the 17 studies showed good applicability but exhibited a high risk of bias, particularly in data analysis. Research on predictive models for PTSD risk in family members of ICU patients is in the developmental stage. Future studies should validate existing models or develop high-performance localized predictive models. PTSD can have a significant impact on the families of ICU patients, making early identification of high-risk populations essential for health care professionals to implement timely interventions.

The Association Between Peritraumatic Dissociation and Race-Based Trauma Symptoms: The Role of Negative Cognitions

ABSTRACT Peritraumatic dissociation is a risk factor for the development of Post-Traumatic Stress Disorder (PTSD). Per the cognitive model of PTSD and empirical research, cognitive appraisals mediate the relationship between peritraumatic dissociation and PTSD. Racial trauma has recently been conceptualized as a psychological sequelae to racism and discrimination that involves a posttraumatic stress reaction to experiences of racism and discrimination. Given the theoretical parallels between PTSD and racial trauma, we hypothesized that negative cognitions would intervene in the relationship between peritraumatic dissociation and racial trauma. To test this hypothesis, we examined whether negative cognitions about the self and the world and self-blame intervened in the relationship between peritraumatic dissociation and racial trauma among 220 minoritized participants. The results indicated that negative views about the self (b = .24) and the world (b = .18), but not self-blame intervened in the relationship between peritraumatic dissociations and racial trauma. These findings provide some insight regarding how negative cognitions relate to peritraumatic dissociations and racial trauma, allowing for a discussion of potential treatment implications.

The clinically relevant MEK inhibitor mirdametinib combined with D-cycloserine and prediction error disrupts fear memory in PTSD models

This study establishes mirdametinib as the first MEK inhibitor that can undergo clinical development for psychiatric indications such as post-traumatic stress disorder (PTSD). PTSD is characterized by persistent traumatic memories with limited effective treatment options. A body of evidence suggests that memory storage is dynamic and constantly updated through post-retrieval modification a process termed reconsolidation. Although ERK/MAPK signaling plays a central role in fear memory consolidation, no clinically translatable MEK inhibitor has been tested in experimental models or in clinical trials to disrupt this process. Furthermore, there is need to develop pharmacological and behavioral strategies to labilize the memory to make it susceptible for disruption. Here, we disrupted fear memory reconsolidation with the clinically relevant MEK inhibitor mirdametinib in C57BL/6 mice and tested memory destabilization strategies using an auditory fear conditioning paradigm, with drugs administered following reactivation of memory. We found prediction error effective in labilizing weak fear memory and combined D-cycloserine (DCS) and predication error effective in labilizing strong fear memory. Mirdametinib disrupted the weak fear memory and reduced ERK phosphorylation in lateral amygdala when coupled with prediction error at the time of memory reactivation but required coordinated combination of DCS, prediction error and mirdametinib to disrupt strong fear memory. Barnes maze spatial memory test and open field test revealed that mirdametinib did not affect retrieval of other forms (spatial) of long-term memory and locomotor activity. Furthermore, the effect of mirdametinib was specific to reconsolidation as it had no effect on fear memory when given without reactivation. These translational findings identify a new drug that can be adapted for the treatment of PTSD.

New Insights into Contradictory Changes in Brain-Derived Neurotrophic Factor (BDNF) in Rodent Models of Posttraumatic Stress Disorder (PTSD).

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that may develop after experiencing traumatic events. Preclinical studies use various methods to induce PTSD-like models such as fear-conditioning, single-prolonged stress (SPS), restraint stress, and social defeat. Brain-derived neurotrophic factor (BDNF) is a crucial neurotrophin in mood regulation. Evidence shows BDNF changes in different neuropsychiatric disorders particularly PTSD. This review examined BDNF alterations in preclinical rodent models of PTSD where we demonstrated a wide range of paradoxical changes in BDNF. We found that the fear-conditioning model produced the most inconsistent alterations in BDNF, and suggest that conclusions drawn from these changes be approached with caution. We suggest that BDNF maladaptive changes in social defeat and restraint stress models may be related to the duration of stress, while the SPS model appears to have more consistent results. Ultimately, we propose that evaluating BDNF alterations in the process of treating PTSD symptoms may not be a reliable factor.

Exploring the Anxiolytic Potential of NPY by a Dipeptidyl Peptidase-IV Inhibitor in an Animal Model of PTSD.

The regulatory neuropeptide Y (NPY) is implicated in anxiety and post-traumatic stress disorder (PTSD)-related behaviors. NPY exerts its effects through 5 receptor subtypes, with Y1 and Y2 receptors being predominantly expressed in the rat brain. Activation of Y1 by full-length NPY1-36 induces anxiolytic effects, whereas Y2 binds truncated peptides, eliciting region-specific anxiogenic responses. Dipeptidyl peptidase-IV (DPP-IV) cleaves NPY, thereby modulating its functionality. Sitagliptin, a DPP-IV inhibitor (DPP-IV-I), inhibits the degradation of various vasoactive peptides, including cerebral NPY. As such, the therapeutic potential of DPP-IV-I following a traumatic event remains inconclusive. We assessed the effects of a highly selective DPP-IV-I, administered either shortly after the stressor or intermittently over 3 days, on behavioral outcomes using the predator scent stress (PSS) model of PTSD. Rats exposed to PSS or sham-PSS received a single dose of sitagliptin (10 or 30mg/kg) or saline 1 hour post-exposure, or repeated doses over 3 days (20mg/kg). Behavioral outcomes were evaluated using the elevated plus maze and acoustic startle response at 7 days post-exposure. Additionally, rats exposed to PSS or sham-PSS were treated with sitagliptin (30mg/kg) or saline, and their brains were prepared for immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Sitagliptin did not attenuate anxiety-related behaviors or PTSD-related behavior prevalence compared to saline. Notably, the 30mg/kg dose increased NPY levels in several brain regions without affecting NPY-Y1 levels. The findings suggest that sitagliptin-induced upregulation of NPY levels shortly after PSS is insufficient to prevent the development of post-traumatic responses. The effectiveness of NPY signaling may be influenced by factors beyond peptide concentration alone, potentially limiting its therapeutic efficacy. Activation of NPY-Y1 receptors, rather than merely increasing NPY levels, appears to be crucial for modulating anti-anxiety and post-traumatic responses.

Effects of electroacupuncture at auricular points on excitability of glutamatergic neurons in the anterior cingulate cortex of posttraumatic stress disorder mice

To elucidate the relationship between the auricular point stimulation and the activity of glutamatergic neurons in the anterior cingulate cortex (ACC) from the perspective of intrinsic excitability plasticity of neurons in mice with posttraumatic stress disorder (PTSD), so as to explore the underlying mechanisms of acupuncture at auricular points in improving emotional diseases induced by PTSD. C57BL/6J male mice were randomly divided into control, PTSD model, sham electroacupuncture (EA), and EA groups, with 5 mice in each group. The glutamatergic neurons were labelled by injection of AAV2/9-CaMKⅡα-EGFP viral fluid into the bilateral ACC. Fourteen days after the injection, the PTSD model was established by single prolonged stress (restraint stress, forced swimming, ether exposure) and plantar electrical shock. EA (2 Hz/15 Hz, 1 mA) was applied to bilateral "Xin" points and the center of auriculae of auricular concha area for 30 min, once daily for 7 days. Mice of the sham EA group were anesthetized for 30 min per day for 7 days, but no EA treatments were given. The anxiety-like behavior of mice was evaluated by open field (OF) and elevated plus maze (EPM) tests after 2 weeks of modeling. The whole-cell patch-clamp method was used to record the intrinsic excitability level of ACC glutamatergic neurons. Compared with the control group, the dwell time and locomotor distance in the central area of the OF, the dwell time and entry times percentage in the open arms of the EPM in the model group were significantly reduced (P<0.001, P<0.01). At the same time, the intrinsic excitability of ACC glutamatergic neurons in model mice was suppressed, presenting as enhanced rheobase currents (P<0.01) and decreased spike number (P<0.05, P<0.01, P<0.001). Compared with the model group, the dwell time and locomotor distance in the central area of the OF, the dwell time and entry times percentage in the open arms of the elevated plus maze were significantly increased (P<0.001, P<0.01), and the intrinsic excitability of ACC glutamatergic neurons was significantly improved, presenting as reduced rheobase currents (P<0.05) and an increased spike number (P<0.05) in the EA group. Compared with the sham EA group, the dwell time and locomotor distance in the central area of the OF, the dwell time and entry times percentage in the open arms of the EPM were significantly increased (P<0.001, P<0.01) in the EA group, and the intrinsic excitability of ACC glutamatergic neurons was significantly improved, presenting as reduced rheobase currents (P<0.01) and an increased spike number (P<0.05). EA of auricular points can effectively alleviate the anxiety-like behavior of PTSD mice and increase the intrinsic excitability level of glutamatergic neurons in ACC, which may be one of the neural mechanisms of auricular point stimulation in the treatment of emotional diseases.

Effects of Shugan Tiaoshen acupuncture on anxiety-like behavior and PKC/ERK/CREB pathway in the bed nucleus of the stria terminalis in rats with post-traumatic stress disorder

To observe the effect of Shugan Tiaoshen acupuncture (acupuncture for soothing the liver and regulating the spirit) on the protein kinase C/extracellular signal-regulated kinase/cAMP response element-binding protein (PKC/ERK/CREB) signaling pathway in the bed nucleus of the stria terminalis (BNST) of rats with post-traumatic stress disorder (PTSD), and to explore the mechanism of acupuncture on alleviating anxiety and fear in PTSD. Fifty SPF-grade male SD rats were randomly divided into a blank group (10 rats) and a PTSD model group (40 rats). The PTSD model was induced by using a combination of closed electric shock and forced exhaustive swimming. Thirty successfully modeled rats were randomly assigned to a model group, a medication group, and an acupuncture group, with 10 rats in each group. The rats in the medication group were treated with paroxetine hydrochloride solution by gavage, once daily for 12 consecutive days. The rats in the acupuncture group were treated with acupuncture at "Baihui" (GV 20) and bilateral "Neiguan" (PC 6), "Shenmen" (HT 7), "Taichong" (LR 3). "Baihui" (GV 20) was needled daily, while the other acupoints were alternately needled on the left side on odd days and the right side on even days, once daily for 12 consecutive days. Anxiety and fear behaviors changes were assessed by using the open field test and elevated plus maze test. Histological changes in the BNST were observed by using HE staining and Nissl staining. The expression of PKC, phosphorylated PKC (p-PKC), ERK1/2, phosphorylated ERK1/2 (p-ERK1/2), and p-CREB proteins in the BNST were detected by using Western blot. Compared with the blank group, the model group showed decreased time and total distance spent in the center of the open field and on the open arms of the elevated plus maze (P<0.05); the BNST tissues in the model group exhibited a reduced number of neurons, disorganized cell arrangement, cell shrinkage, nuclear condensation, abnormal neuronal structure, uneven Nissl staining, and reduced Nissl bodies. The model group showed increased protein expression of p-PKC and p-PKC/PKC ratio (P<0.05) and decreased protein expression of p-ERK1/2, p-CREB, and p-ERK1/2/ERK1/2 ratio (P<0.05). Compared with the model group, the medication group and the acupuncture group showed increased time and total distance spent in the center of the open field and on the open arms of the elevated plus maze (P<0.05); the BNST tissues showed increased number of neurons, more organized cell arrangement, improved neuronal structure, and increased Nissl bodies; the medication group and the acupuncture group also showed decreased p-PKC protein expression and p-PKC/PKC ratio (P<0.05) and increased p-ERK1/2, p-CREB protein expression, and p-ERK1/2/ERK1/2 ratio (P<0.05). Shugan Tiaoshen acupuncture could alleviate anxiety and fear behaviors in PTSD rats, and improve neuronal damage in the BNST. The mechanism may be related to the regulation of the PKC/ERK/CREB signaling pathway in the BNST.

Female Wistar Kyoto More Immobile rats with genetic stress hyper-reactivity show enhanced contextual fear memory without deficit in extinction of fear.

The prevalence of post-traumatic stress disorder (PTSD) is higher in females than males, but pre-clinical models are established almost exclusively in males. This study is aimed to investigate the stress-enhanced fear learning model of PTSD in females. The model mirrors PTSD symptomology in males, whereby prior stress leads to extinction resistant exaggerated contextual fear memory. As stress reactivity is highly relevant to the study and risk for PTSD, females of the stress hyper-reactive Wistar Kyoto More Immobile (WMI) and its nearly isogenic control the Wistar Kyoto Less Immobile (WLI) strains were employed. Prior studies have shown WMI females presenting unchanged or enhanced fear memory in the stress-enhanced fear learning paradigm compared WLIs. The present study confirmed the enhanced fear memory following contextual fear conditioning in WMIs compared to WLI females, but this increased fear memory was neither exaggerated by prior stress nor showed extinction deficit. The novel stressor of a glucose challenge test resulted in subtle strain- and prior stress-induced differences in plasma glucose responses. However, fasting plasma corticosterone levels were lower, and rose slower in response to glucose challenge in WMI females, suggesting a PTSD-like dysfunctional stress response. Hippocampal expressions of genes relevant to both learning and memory and the stress response were decreased in stressed WMIs compared to WLI females, further suggesting a marked dysregulation in stress-related functions like in PTSD. Thus, although WMI females do not show extinction-resistant enhanced fear memory, they do present other characteristics that are relevant to PTSD in women.

Single Intranasal Administration of Ucn3 Affects the Development of PTSD Symptoms in an Animal Model.

Post-traumatic stress disorder (PTSD) is a multifactorial psychological disorder that affects different neurotransmitter systems, including the central CRH system. CRH acts via the CRHR1 and CRHR2 receptors, which exert opposite effects, i.e., anxiogenic or anxiolytic. The aim of this work was to investigate how intranasal administration of the CRHR2-specific agonist urocortin 2 (Ucn2) or urocortin 3 (Ucn3) affects manifestations of PTSD in a single prolonged stress (SPS) animal model of PTSD. Elevated plus maze (EPM) and open field (OF) tests were used to assess anxiety-like behavior. Changes in the gene expressions of CRH, CRHR1, CRHR2, glucocorticoid receptor (GR), and FKBP5 were measured in brain regions (BNST, amygdala, and PVN) responsible for modulating the stress response. The SPS animals spent less time in the OF central zone and were less mobile than the controls; however, the Ucn3 treatment reversed this effect. SPS decreased the GR and FKPB5 mRNA levels in the PVN. Ucn3 suppressed the effect of SPS on FKBP5 mRNA expression in the PVN and increased FKBP5 mRNA in the BNST and PVN compared to the stressed animals. We demonstrate that Ucn3 has the potential to ameliorate anxiety-like behavior in SPS animals and also to affect the neuroendocrine system in the BNST and PVN. In addition, we confirm the important role of CRHR2 signaling in mediating the stress response.

Cannabidiol Modulates Neuroinflammatory Markers in a PTSD Model Conducted on Female Rats.

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition closely linked to neuroinflammation, with a higher prevalence in women. Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown promise as a potential treatment for PTSD. In this study, we used a PTSD model in which female rats were subjected to a severe foot shock followed by contextual situational reminders (SRs). Testing was conducted one month after exposure. The rats received daily CBD injections for three weeks during the SRs, from days 7 to 28. Two days after the final SR, the rats underwent five extinction trials, followed by the forced swim test (FST). After a five-day rest period, the rats were sacrificed, and brain tissues from the medial prefrontal cortex (mPFC) and ventral subiculum (vSUB) were analyzed for inflammatory markers. Chronic CBD treatment reversed impairments in fear extinction caused by shock and SR. It also reduced learned helplessness in the FST and decreased the upregulation of mPFC-il1β induced by shock and SRs. Additionally, exposure to shock and SRs downregulated mPFC-il6 while upregulating vSUB-il6. CBD treatment further downregulated il6 expression in the vSUB compared to the vehicle groups. Our findings show that CBD effectively inhibited the development of PTSD-like behaviors and suppressed neuroinflammation in the mPFC.

A prediction model of PTSD in the Israeli population in the aftermath of october 7th, 2023, terrorist attack and the Israel–Hamas war

BackgroundOn October 7th, 2023, a mass terror attack was launched by Hamas militants, which was followed by the Israel-Hamas war. These events constitute a nationwide trauma with major ramifications for public mental health. This article presents an evidence-based model for the prediction of the prevalence of posttraumatic stress disorder (PTSD) related to the terrorist attack and the war.Main body: The creation of the model consisted of several steps. Firstly, the Israeli population was divided into six groups based on the intensity, context, and type of traumatic exposure (direct exposure to terror, close proximity to terror, soldiers in combat and support units, intense exposure to rocket attacks, moderate exposure to rocket attacks, and indirectly affected communities), and the population size of each group was assessed using official national databases. Secondly, an estimation of the expected prevalence of PTSD in each of the exposure groups was based on a review of the relevant literature. A random-effects meta-analysis of the prevalence rates was conducted separately per each exposure group. Finally, the predicted number of PTSD causalities in the population was calculated by multiplying the group size and the PTSD prevalence estimation. Based on population size and estimated PTSD prevalence within each exposure category, the model predicts that approximately 5.3% (N = 519,923) of the Israeli population (95% confidence interval, 1.64–9%), may develop PTSD as a result of the terrorist attack and the war.ConclusionsThe predicted number of individuals with PTSD following mass trauma is expected to be considerable. The presented model can assist policymakers, clinicians, and researchers in preparing and devising adequate interventions for the mental health needs of large populations. Moreover, this model can be applied in other instances of mass-trauma exposure.

H2S improves hippocampal synaptic plasticity in SPS rats via PI3K/AKT signaling pathway

Post-traumatic stress disorder (PTSD) is a severe mental illness that could impose heavy burdens on individuals and society, but effective and precise treatment modalities are unknown. The level of hydrogen sulfide (H2S) in the brain plays an important role in psychiatric diseases. However, it is still unclear whether PTSD exposure could affect the level of H2S and whether there is a correlation between H2S levels and the pathogenesis of PTSD. In this study, we selected single prolonged stress (SPS) as a PTSD model and found that SPS exposure decreased the endogenous H2S content accompanied by abnormal behavioral changes and dysregulation of the hippocampal synaptic plasticity in SPS rats. We further found that the exogenous administration of H2S could alleviate PTSD-like behaviors and improve hippocampal synaptic plasticity in SPS rats. In addition, we further used the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 to interfere with the PI3K/AKT/BDNF signaling pathway. It was found that LY294002 significantly blocked the anti-anxiety effect and the improvement in synaptic plasticity derived from the exogenous administration of H2S in SPS rats. These results suggested that the endogenous H2S content was decreased in SPS rats, and that the exogenous administration of H2S could ameliorate abnormal disorders and improve hippocampal synaptic plasticity by mediating the PI3K/AKT pathway.

The effects of apelin-13 in a mouse model of post-traumatic stress disorder.

The objective is to investigate the effects of apelin-13 in models of post-traumatic stress disorder (PTSD). Mature male CD1 mice were subjected to the single prolonged stress method to induce PTSD-related behaviors. These behaviors were then evaluated using the elevated plus maze test, Morris water maze test, and open field test. Hippocampal neural cell death was assessed using propidium iodide labeling. The expression of hippocampal autophagy pathway-associated proteins was determined through immunoblotting analysis, and LC3 levels were also measured via quantitative real-time reverse transcription-PCR. The results demonstrate that administration of apelin-13 suppressed PTSD-induced hippocampal neural cell death and alleviated PTSD-related behaviors in mice. Additionally, PTSD led to an up-regulation of LC3 and FoxO3a, and down-regulation of P62, p-PI3K, p-Akt, and p-FoxO3a in the hippocampus. However, these changes were reversed by apelin-13 treatment. These findings support the hypothesis that apelin-13 prevents the development of PTSD-like behavior and inhibits autophagy of neuronal cells in a mouse model of PTSD. Apelin-13 may hold potential as a therapeutic agent for PTSD in clinical applications.

Unraveling the Liver-Brain Axis: Resveratrol's Modulation of Key Enzymes in Stress-Related Anxiety.

Stress-related anxiety disorders and anxiety-like behavior in post-traumatic stress disorder (PTSD) are associated with altered neurocircuitry pathways, neurotransmitter systems, and the activities of monoamine and glucocorticoid-metabolizing enzymes. Resveratrol, a natural polyphenol, is recognized for its antioxidant, anti-inflammatory, and antipsychiatric properties. Previous studies suggest that resveratrol reduces anxiety-like behavior in animal PTSD models by downregulating key enzymes such as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and monoamine oxidases (MAOs). However, the underlying mechanisms remain unclear. In this study, we explored the efficacy of resveratrol in treating stress-induced anxiety using a chronic predator stress model in rats. Resveratrol was administered intraperitoneally at 100 mg/kg following a 10-day stress exposure, and anxiety behavior was assessed with an elevated plus maze. Our results indicated that stress-related anxiety correlated with increased activities of brain MAO-A, MAO-B, and hepatic 11β-HSD-1, alongside elevated oxidative stress markers in the brain and liver. Resveratrol treatment improved anxiety behavior and decreased enzyme activities, oxidative stress, and hepatic damage. We demonstrate that resveratrol exerts antianxiogenic effects by modulating glucocorticoid and monoamine metabolism in the brain and liver. These findings suggest resveratrol's potential as a therapeutic agent for anxiety disorders, warranting further clinical investigation.

The epigenetic changes are affected by sex and valproic acid treatment in a rat model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) presents distinct sex-specific differences in both symptom expression and treatment outcomes, with the underlying biological mechanisms still remain unclear. Epigenetic modifications, particularly histone acetylation, have been increasingly recognized as critical factors in the pathophysiology of PTSD. Valproic acid (VPA), a potent histone deacetylase (HDAC) inhibitor, has shown promise in modulating epigenetic responses and improving therapeutic outcomes is PTSD, though its effect may differ between sexes.This study aimed to explore the sex-specific epigenetic changes in response to trauma and the impact of VPA treatment in a rat model of PTSD induced by predator scent stress. Sprague-Dawley rats of both sexes were randomly assigned to stressed and non-stressed groups and treated with either VPA (100 mg/kg) or vehicle. Anxiety levels were assessed using the elevated plus maze, followed by analysis of histone H3 and H4 acetylation, HDAC activity, and c-fos expression in the hippocampus.Our findings revealed that traumatic stress led to increased freezing time and anxiety levels, with more pronounced effects observed in females. Additionally, we have identified sex-specific differences in hippocampal epigenetic modifications; stressed females exhibited higher H3 acetylation, and VPA-treated stressed males showed increased H4 acetylation.These results highlight the importance of considering sex differences in the epigenetic mechanism underlying PTSD and suggest that personalized therapeutic approaches may be necessary to address these complexities.

Effects of voluntary, involuntary exercise and sertraline on anxiety, social and cognitive behavior in female rat model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is considered as a complex syndrome comprising extremely severe anxiety levels, social-interpersonal dysfunction, and cognitive impairment that may be based on severe traumatic events. Although PTSD is more prevalent in females than in males, most preclinical studies have been carried out in males. The present study investigated the effects of voluntary and involuntary exercise, as well as sertraline on behavioral deficits in a female nonhuman animal model of PTSD using the single-prolonged stress (SPS) paradigm. Female adult rats were exposed to SPS protocol (2-hour restrain, 20-minute forced swimming, 15-minute rest, and 2–3 minute diethyl ether exposure) and were then kept undisturbed. Following a 7-day undisturbed period, animals were subjected to a 10 min restraint (re-stress). SPS rats were treated with voluntary wheel running or moderate treadmill exercise (5 days/week) and/or the administration of sertraline (10 mg/kg/day) for four consecutive weeks. Behavioral assessments were conducted using the Elevated Plus Maze (EPM) test for anxiety, the Three-Chamber Social Test (3-CST) for social interaction, and the Morris Water Maze (MWM) test for spatial memory. Involuntary exercise combined with sertraline significantly increased time spent in the open arms of the EPM test (P < 0.001), and interaction with new rats in 3-CST (P < 0.001) compared to SPS rats. The voluntary exercise plus sertraline group showed a significant increase in entries into the training platform during the probe phase of the MWM test (P < 0.001) compared to SPS rats. Overall, sertraline combined with involuntary exercise was more effective than voluntary exercise plus sertraline in enhancing social interaction and reducing anxiety in the SPS model of PTSD. Conversely, voluntary exercise combined with sertraline provided greater benefits for spatial memory enhancement in female rats.

Effects of early life stress paired with adolescent alcohol consumption on two-bottle choice alcohol drinking behaviors in mice.

In humans, early life stress (ELS) is associated with an increased risk for developing both alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). We previously used an infant footshock model that produces stress-enhanced fear learning (SEFL) in rats and mice and increases aversion-resistant alcohol drinking in rats to explore this shared predisposition. The goal of the current study was to extend this model of comorbid PTSD and AUD to male and female C57BL/6J mice. Acute ELS was induced using 15 footshocks on postnatal day (PND) 17. In adulthood, alcohol drinking behavior was tested in one of three two-bottle choice drinking paradigms. In continuous access, mice were given 24 h access to 5% or 10% ethanol and water for five consecutive drinking sessions each. In limited access drinking in the dark, mice were given 2 h of access to 15% ethanol and water across 15 sessions 3 h into the dark cycle. In intermittent access, mice were presented with 20% ethanol and water Monday, Wednesday, and Friday, for four consecutive weeks. In a fifth week of intermittent access drinking, increasing concentrations of quinine (10 mg/L, 100 mg/L, and 200 mg/L) were added to the ethanol to test aversion-resistant drinking. Intermittent access drinking was tested with and without a period of adolescent drinking (PND 35). Infant footshock did not alter drinking in the continuous or limited access tasks. Adult consumption and preference were lower in the intermittent access task when adolescent drinking was included and there were ELS-induced differences in consumption of quinine-adulterated ethanol in females. Our results demonstrate that infant footshock followed by a period of adolescent drinking is a viable model of comorbid PTSD and AUD in rats and mice.

A Baseline Model of PTSD From the ACES Cohort.

Post-traumatic stress disorder (PTSD) is a primary military psychiatric condition with complex etiology including strong genetic and/or environmental influences. Environmental influences and demographics can play a role in supporting underlying genetic traits for clinical utility evaluation as risk modifying factors. We are undertaking an IRB approved study to evaluate polygenic scores of PTSD risk in the adverse childhood experience and serotonin (ACES) transporter cohort. Baseline demographic characteristics and statistical modeling of 291 active duty service members from ACES cohort were used and excluded individuals with traumatic brain injury-induced loss of consciousness, pre-deployment PTSD or anxiety disorder, and pre-deployment prescription of antidepressants or psychoactive medications. Summary of categorical and numerical variables were evaluated using chi-square and t-test, respectively. We model PTSD risk and associated scores using linear and logistic regressions. The ACES subset was 79.1% males, multi-ancestry, and mean age of 38.3 years. Most PTSD individuals received behavioral therapy (89.6%) and/or prescribed antidepressants (67%) had higher scores in ACES, combat exposure scales, PTSD checklist military version, neurobehavioral symptom inventory, Pittsburg sleep quality index, insomnia severity index, and composite autonomic symptom score surveys and were less likely to expect future deployment. A positive correlation between age, total months deployed, ACES, CES, PCL-M, and positive-PTSD diagnosis were consistent but not in older individuals, who were more likely and frequently deployed although increasing risk for combat exposure. Demographic characteristics of the ACES cohort fit a coherent model of risk for PTSD to evaluate polygenic scores. Additional research is merited to understand PTSD effects on these confounding factors.

Effects of the combination of bone marrow stromal cells and exercise on corticosterone, BDNF, IGF-1, and anxiety-like behaviour in a rat model of post-traumatic stress disorder: Comparable effects of exercise

Aim Post-traumatic stress disorder (PTSD) requires more effective treatment options with fewer side effects. Stem cell therapy, as a novel approach, has been investigated in the treatment of various diseases, including brain disorders. This study investigated the effects of bone marrow stromal cells (BMSCs) and the combination of BMSCs with exercise on corticosterone, BDNF and IGF-1, and anxiety-like behaviours in a male rat model of PTSD. Methods Male adult Wistar rats were subjected to PTSD induced by the single prolonged stress (SPS) model. 7 days after SPS, BMSCs were injected intravenously. The exercise started on day 11 and continued for 4 weeks. On day 40th, anxiety behaviour, corticosterone, BDNF, and IGF-1 were tested. p < 0.05 was considered as a significant level. Results The study showed that a combination of BMSCs and exercise significantly reduced anxiety-related behaviours, and alterations in BDNF, IGF-1, and corticosterone levels. Also, BMSCs alone significantly reduced some of the PTSD-induced impairments. However, exercise alone showed greater efficiency in comparison with BMSCs alone. Conclusion According to the results, although combination therapy effectively improved PTSD-related complications, exercise had relatively comparable effects on PTSD. Exercise has the potential to enhance the efficacy of BMSC therapy. Further research is required to determine whether BMSC therapy is sufficiently efficacious and safe in clinical settings.