Rat Model Of Post-traumatic Stress Disorder Research Articles

GABAergic interneurons in the hippocampal CA1 mediate contextual fear generalization in PTSD rats.

Fear overgeneralization is widely accepted as a pathogenic marker of post-traumatic stress disorder (PTSD). Recently, GABAergic interneurons have been regarded as key players in the regulation of fear memory. The role of hippocampal GABAergic interneurons in contextual fear generalization of PTSD remains incompletely understood. In the present study, we established a rat model of PTSD with inescapable foot shocks (IFS) and observed the loss of GABAergic interneuron phenotype in the hippocampal cornu ammonis-1 (CA1) subfield. To determine whether the loss of GABAergic interneuron phenotype was associated with fear generalization in PTSD rats, we used adeno-associated virus (AAV) to reduce the expression of GAD67 in CA1 and observed its effect on fear generalization. The results showed that the reduction of GAD67 in CA1 enhanced contextual fear generalization in rats. We investigated whether the PERK pathway was involved in the GABAergic interneuron injury. Increased expression of p-PERK, CHOP, and Caspase12 in GABAergic interneurons of PTSD rats was observed. Then, we used salubrinal, an endoplasmic reticulum stress inhibitor, to modulate the PERK pathway. The salubrinal treatment significantly protected the GABAergic interneurons and relieved fear generalization in PTSD rats. In addition, the results showed that salubrinal down-regulated the expression of CHOP and Caspase12 in GABAergic interneurons of PTSD rats. In conclusion, this study provided evidence that the loss of GABAergic interneuron phenotype in CA1 may contribute to contextual fear generalization in PTSD. The PERK pathway is involved in the GABAergic interneuron injury of PTSD rats and modulating it can protect GABAergic interneurons and constrain contextual fear generalization.

Psilocybe cubensis extract potently prevents fear memory recall and freezing behavior in short- but not long-term in a rat model of posttraumatic stress disorder.

Psilocybe cubensis is a species of psilocybin mushroom (magic mushroom) of moderate potency whose principal active compounds are psilocybin and psilocin. Recent studies have shown the significant procognitive and mood-enhancer effects of Psilocybe cubensis. However, evidence is so limited, especially in preclinical studies. We aimed to investigate the effect of Psilocybe cubensis extract on posttraumatic stress disorder (PTSD)-like behavior, pain perception, locomotor activity, and anxiety in a rat model of PTSD. Male rats were exposed to three consecutive shocks (0.8 mA, 3 s interval) paired with three sounds broadcasted 3 s before delivering shocks (75 dB, 3 s). After 1, 3, or 21 days, freezing rate was measured in the fear-conditioning apparatus. Open filed test and hot plate were used to assess locomotor activity and anxiety, and pain subthreshold, respectively. Psilocybe cubensis was injected intraperitoneal at the dose of 25 mg/kg (single administration) before (pretrain) or after (posttrain) shocks, or before the test (pretest). Results showed psilocybin potently alleviated PTSD symptom is short- but not long-term after the induction of PTSD. Psilocybe cubensis decreased locomotor activity only in a short period after administration. Psilocybe cubensis also increased pain subthreshold and decreased anxiety. In conclusion, Psilocybe cubensis effects on PTSD-like behavior and locomotor activity seem to be remained in short-term, while Psilocybe cubensis effects on pain subthreshold and anxiety remained long-term. This is the first study evaluating the effect of Psilocybe cubensis on PTSD-like behavior in rats in three different time protocols (1, 3, and 21 days after fear conditioning). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Artemisinin reduces PTSD-like symptoms, improves synaptic plasticity, and inhibits apoptosis in rats subjected to single prolonged stress.

Post-Traumatic Stress Disorder (PTSD) is a chronic mental disorder characterized by symptoms of panic and anxiety, depression, impaired cognitive functioning, and difficulty in social interactions. While the effect of the traditional Chinese medicine artemisinin (AR) on PTSD is unknown, its therapeutic benefits have been demonstrated by studies on models of multiple neurological disorders. This study aimed to extend such findings by investigating the effects of AR administration on a rat model of PTSD induced by a regimen of single prolonged stress (SPS). After rats were subjected to the SPS protocol, AR was administered and its impact on PTSD-like behaviors was evaluated. In the present study, rats were subjected to a multitude of behavioral tests to evaluate behaviors related to anxiety, memory function, and social interactions. The expression of hippocampal synaptic plasticity-related proteins was detected using Western blot and immunofluorescence. The ultrastructure of synapses was observed under transmission electron microscopy. The apoptosis of hippocampal neurons was examined with Western blot, TUNEL staining, and HE staining. The results showed that AR administration alleviated the PTSD-like phenotypes in SPS rats, including behavior indicative of anxiety, cognitive deficits, and diminished sociability. AR administration was further observed to improve synaptic plasticity and inhibit neuronal apoptosis in SPS rats. These findings suggest that administering AR after the onset of severe traumatic events may alleviate anxiety, cognitive deficits, and impaired social interaction, improve synaptic plasticity, and diminish neuronal apoptosis. Hence, the present study provides evidence for AR's potential as a multi-target agent in the treatment of PTSD.

Effects and mechanisms of salidroside on the behavior of SPS-induced PTSD rats

Post-traumatic stress disorder (PTSD) is a complex mental disorder, closely associated with stress and traumatic events. Salidroside (Sal) has been reported to possess neuroprotective effects. However, the behavioral effects and mechanisms of Sal on PTSD remain unknown. In this study, we utilized a rat model of PTSD induced by single prolonged stress (SPS) and administered Sal intraperitoneally (25, 50, 75 mg/kg/d) for 14 days. We then examined the behavioral effects and underlying mechanisms of Sal on SPS-induced PTSD rats. Our findings demonstrated that Sal alleviated anxiety-like behavior and spatial learning and memory impairment in SPS-induced PTSD rats. Furthermore, Sal treatment preserved the histomorphology of the hippocampal region. It was observed that Sal protected against hippocampal neuronal apoptosis in PTSD rats by reducing the number of TUNEL-positive cells and modulating apoptosis-related proteins (Bcl-2 and Bax). Additionally, Sal inhibited the activation of the NF-κB/iNOS/COX-2 signaling pathway in the hippocampus of PTSD rats, thereby suppressing the release of inflammatory factors (TNF-α and IL-1β) and the activation of microglia. Notably, Sal increased the expression of synapse-associated proteins PSD95 and Synapsin I in the hippocampus, while also enhancing dendritic density in the region. In conclusion, our results demonstrated that Sal could attenuate SPS-induced PTSD-like behaviors by inhibiting hippocampal neuronal apoptosis, enhancing hippocampal synaptic plasticity, and reducing neuroinflammatory responses. These findings may provide a foundation for the potential clinical application of Sal in the treatment of PTSD.

Oxidative stress mediates hippocampal neuronal apoptosis through ROS/JNK/P53 pathway in rats with PTSD triggered by high-voltage electrical burn.

The pathogenesis of post-traumatic stress disorder (PTSD) triggered by high-voltage electrical burn (HVEB) remains unclear and the oxidative stress plays a role in this process. The purpose of this study is to investigate the underlying mechanism of oxidative stress mediates hippocampal neuronal apoptosis in rats with PTSD triggered by HVEB. The PTSD rat model was developed by stimulating with high voltage electricity and screened using behavioral performance including Morris water maze (MWM), elevated plus-maze (EPM) and open-field test (OFT). The reactive oxygen species (ROS) generation was measured by DHE fluorescence staining or flow cytometry. Western blotting assay was used to detect the proteins of p-JNK, JNK, P53, PUMA, Bcl-2 and Bax in hippocampal tissue or HT22 cells treated with electrical stimulation. The serum MDA and 8-OHdG levels were increased (P < 0.001), while the activities of SOD and CAT were decreased (P < 0.001) significantly in patients with HVEB. Behavioral test results showed that high-voltage electric stimulation induced the PTSD-like symptoms and the ROS-JNK-P53 pathway was involved in the neuronal apoptosis in rats with PTSD induced by HVEB. In vitro experiments further confirmed the electrical stimulation induced neuronal apoptosis through ROS/JNK/P53 signaling pathway and the antioxidant NAC could rescued the ROS generation, activation of JNK/P53 proteins and improved the cell apoptosis rate in HT22 cells. Finally, the JNK inhibitor SP600125 could significantly inhibited the percentage of HT22 cell apoptosis induced by electrical stimulation (P < 0.001). These results indicated that oxidative stress mediates hippocampal neuronal apoptosis through ROS/JNK/P53 pathway in rats with PTSD triggered by HVEB.

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

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

Anandamide Hydrolysis Inhibition Modulates Stress Markers via Beta-Catenin in the PFC in A Rat Model Of PTSD

Post-traumatic stress disorder (PTSD) involves dysregulation of stress modulators, particularly corticotrophin-releasing factor (CRF) and glucocorticoid receptor. Endocannabinoid )ECB( signaling usually serves to inhibit the stress response and has been suggested as a potential target for PTSD treatment. The Wnt/β-catenin pathway was found to play a significant role in anxiety and depression. We examined the expression of stress markers in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in a rat model for PTSD, and whether the stress-buffering effects of enhancing ECB signaling are mediated via β-catenin in the mPFC. Rats were exposed to the shock and reminders model for PTSD and injected with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.4 mg/kg.). URB597 was found to normalize the dysregulation in stress markers in the mPFC and BLA as well as the anxiogenic phenotype. Importantly, downregulation by viral-mediated gene transfer of β-catenin in the mPFC blocked the stress-buffering effects of URB597 on CRF, a key modulator of the stress response, as well as on CB1r and β-catenin protein levels. We suggest a novel mechanism for the stress-buffering effects of FAAH inhibition on CRF that is dependent on β-catenin activation in the mPFC in a PTSD rat model.

Early- and late-phase changes of brain activity and early-phase neuromodulation in the posttraumatic stress disorder rat model

Posttraumatic stress disorder (PTSD) is a complex syndrome that may occur after life-threatening events. Fear memory abnormalities may play vital roles in the pathogenesis of PTSD. Previous work has found that fear memories are not rigid; the retrieval of fear memories may change over time. Furthermore, prior studies suggest that theta wave (4 Hz) activity is highly correlated with fear expression in an animal model. However, the relationship between pathological fear memory and potential brain wave features in PTSD remains largely uncharacterized. Here, we hypothesized that after traumatic stress exposure, the longitudinal dynamics of abnormal fears in PTSD animal models could be reflected by the measurement of local field potentials (LFPs). Using a well-established modified single-prolonged stress and footshock (SPS & FS) PTSD rat model, animals were restrained for 2 h and subsequently subjected to 20 min of forced swimming, then exposed to diethyl ether until they lost consciousness and placed in a conditioning chamber for fear conditioning. To characterize the temporal changes, we characterized freezing behavior brain wave features during the conditioning chamber re-exposure in the early (10 and 30 min; 2, 4, and 6 h) and late (day 1, 3, 7, and 14) phases after traumatic stress exposure. Our results indicate that SPS & FS rats showed co-morbid PTSD phenotypes including significantly higher levels of anxiety-, depression-, and anhedonia-like behaviors, and impaired fear extinction. Delta wave (0.5–4 Hz) suppression in the medial prefrontal cortex, amygdala, and ventral hippocampus occurred 10 and 30 min after traumatic stress, followed by continuous delta wave activity from 2 h to day 14, correlating with fear levels. tDCS reduced delta activity and alleviated PTSD-like phenotypes in the SPS & FS group. In this study, profiling abnormal fears with brain wave correlates may improve our understanding of time-dependent pathological fear memory retrieval in PTSD and facilitate the development of effective intervention strategies.

Sodium aescinate improve behavioral performance by inhibiting dorsal raphe nucleus NLRP3 inflammasome in Post-traumatic stress disorder Rat Model

Growing evidence suggest that NLRP3 inflammasome activation in hippocampus and amygdala is involved in the pathophysiology of PTSD. Our previous studies have demonstrated that apoptosis of dorsal raphe nucleus (DRN) contributes to the pathological progression of PTSD. Recent studies by others have shown that in brain injury sodium aescinate (SA) has a protective effect on neurons by inhibiting inflammatory response pathways, thereby relieving symptoms. Here, we extend the therapeutic effects of SA to PTSD rats. We found that PTSD was associated with significant activation of the NLRP3 inflammasome in DRN, whereas administration of SA significantly inhibited DRN NLRP3 inflammasome activation and reduced DRN apoptosis level. SA also improved learning and memory ability and reduced anxiety and depression level in PTSD rats. In addition, NLRP3 inflammasome activation in DRN of PTSD rats impaired mitochondria function by inhibiting ATP synthesis and increasing ROS production, whereas SA can effectively reverse the pathological progression of mitochondria. We recommend SA as a new candidate for the pharmacological treatment of PTSD.

Inhibition of mGluR5 alters BDNF/TrkB and GLT-1 expression in the prefrontal cortex and hippocampus and ameliorates PTSD-like behavior in rats.

Post-traumatic stress disorder (PTSD) is a prevalent and debilitating psychiatric disorder. However, its specific etiological mechanism remains unclear. Previous studies have shown that traumatic stress changes metabotropic glutamate receptor 5 (mGluR5) expression in the hippocampus (HIP) and prefrontal cortex (PFC). More importantly, mGluR5 expression is often accompanied by alterations in brain-derived neurotrophic factor (BDNF). Furthermore, BDNF/tropomyosin-associated kinase B (TrkB) signaling plays multiple roles, including roles in neuroplasticity and antidepressant activity, by regulating glutamate transporter-1 (GLT-1) expression. This study aims to explore the effects of inhibiting mGluR5 on PTSD-like behaviors and BDNF, TrkB, and GLT-1 expression in the HIP and PFC of inevitable foot shock (IFS)-treated rats. Seven-day IFS was used to establish a PTSD rat model, and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (10mg/kg, intraperitoneal injection) was used to inhibit the activity of mGluR5 during IFS in rats. After modeling, behavioral changes and mGluR5, BDNF, TrkB, and GLT-1 expression in the PFC and HIP were examined. First, the IFS procedure induced PTSD-like behavior. Second, IFS increased the expression of mGluR5 and decreased BDNF, TrkB, and GLT-1 expression in the PFC and HIP. Third, the mGluR5 antagonist blocked the above behavioral and molecular alterations. mGluR5 was involved in IFS-induced PTSD-like behavior by changing BDNF, TrkB, and GLT-1 expression.

Male and female impairments in odor span are observed in a rat model of PTSD.

Posttraumatic stress disorder (PTSD) is associated with neural and behavioral alterations in response to trauma exposure, including working memory impairments. Rodent models of PTSD have not fully investigated chronic or reactive working memory deficits, despite clinical relevance. The present study uses footshock to induce a posttraumatic stress state in male and female rats and evaluates the effect of footshock and trauma-paired odor cues on working memory performance in the odor span task. Results demonstrate the emergence of chronic deficits in working memory among animals exposed to footshock by 3 wk after traumatic stress. The presentation of a trauma-paired odor cue was associated with further decrement in working memory performance for male animals. Furthermore, anxiety-like behaviors associated with the PTSD-like phenotype could predict the degree of working memory impairment in response to the trauma-paired odor cue. This study enhances validation of an existing rodent model of PTSD through replication of the clinical observations of working memory deficits associated with PTSD and provides novel insight into effects in female rodents. This will facilitate work to probe underlying mechanistic dysregulation of working memory following footshock trauma exposure and future development of novel treatment strategies.

The role of hippocampal CaMKII in resilience to trauma-related psychopathology

Traumatic stress exposure can form persistent trauma-related memories. However, only a minority of individuals develop post-traumatic stress disorder (PTSD) symptoms upon exposure. We employed a rat model of PTSD, which enables differentiating between exposed-affected and exposed-unaffected individuals. Two weeks after the end of exposure, male rats were tested behaviorally, following an exposure to a trauma reminder, identifying them as trauma 'affected' or 'unaffected.' In light of the established role of hippocampal synaptic plasticity in stress and the essential role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in hippocampal based synaptic plasticity, we pharmacologically inhibited CaMKII or knocked-down (kd) αCaMKII (in two separate experiments) in the dorsal dentate gyrus of the hippocampus (dDG) following exposure to the same trauma paradigm. Both manipulations brought down the prevalence of 'affected' individuals in the trauma-exposed population. A day after the last behavioral test, long-term potentiation (LTP) was examined in the dDG as a measure of synaptic plasticity. Trauma exposure reduced the ability to induce LTP, whereas, contrary to expectation, αCaMKII-kd reversed this effect. Further examination revealed that reducing αCaMKII expression enables the formation of αCaMKII-independent LTP, which may enable increased resilience in the face of a traumatic experience. The current findings further emphasize the pivotal role dDG has in stress resilience.

Chronic fluoxetine enhances extinction therapy for PTSD by evaluating brain glucose metabolism in rats: an [18F]FDG PET study.

Recent studies suggest that selective serotonin reuptake inhibitors (SSRIs) and exposure therapies have been used to reduced footshock-induced posttraumatic stress disorder (PTSD) symptoms. However, the therapeutic effect of the combination of SSRIs treatment with exposure therapy remains a matter of debate. This study aimed to evaluate these therapeutic effect through the behavioural and the neuroimaging changes by positron emission tomography (PET) in model rats. Pavlovian fear conditioning paradigm to establish model rats, and serial PET imaging with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was performed during the control, fear-conditioning, and extinction-retrieval phases. The expression of c-Fos was used to identify neural activity. We report that fear conditioning increased glucose metabolism in the right amygdala and left primary visual cortex but decreased glucose metabolism in the left primary somatosensory cortex. After extinction retrieval, there was increased [18F]FDG uptake in the left striatum, left cochlear nucleus and right primary visual cortex but decreased uptake in the anterior cingulate cortex in the extinction group. Fluoxetine increased [18F]FDG uptake in the left hippocampus and right primary visual cortex but decreased uptake in the bilateral primary somatosensory cortex, left primary/secondary motor cortex and cuneiform nucleus. The combined therapy increased [18F]FDG uptake in the left hippocampus, left striatum, right insular cortex, left posterior parietal cortex, and right secondary visual cortex but reduced uptake in the cerebellar lobule. c-Fos expression in the hippocampal dentate gyrus and anterior cingulate cortex in the fluoxetine and combined groups was significantly higher than that in the extinction group, with no significant difference between the two groups. Chronic fluoxetine enhanced the effects of extinction training in a rat model of PTSD. In vivo PET imaging may provide a promising approach for evaluation chronic fluoxetine treatment of PTSD.

Protective effects of glucocorticoid receptor antagonist Mifepristone on fear memory extinction impairment in a rat model of PTSD

IntroductionCentral glucocorticoid receptor (GR) has been found to play an important role in the interpretation of cognitive abnormalities of posttraumatic stress disorder (PTSD), particularly focused on the extinction failure of fear memory. Potential of using GR antagonist as a pharmacological agent to prevent PTSD-related fear memory disruption is worth investigating.ObjectivesWe aimed to examine whether GR antagonist Mifepristone (RU486) administered before single prolonged stress (SPS) can prevent rats from fear memory extinction impairment.MethodsIn the present study, SPS was employed in rats to induce a rodent model of PTSD. 60 minutes before SPS, RU486 (20 mg/kg) was administered by intraperitoneal injection. Seven days after SPS, rats received a protocol of behavioral testing to measure their abilities of specific fear memory (by a cue-dependent fear conditioning paradigm) and nonspecific spatial memory (by T-maze). Neurochemically, we measured plasma corticosterone with or without dexamethasone suppression, activation ratio of GR and levels of norepinephrine, dopamine, and serotonin in amygdala, paraventricular nucleus, dorsal and ventral hippocampus.ResultsOur results found that RU486 exerted protective effects on SPS-induced fear extinction impairment. Corticosterone of SPS-RU486 rats was less suppressed by dexamethasone. GR became less activated in dorsal hippocampus of SPS-RU486 rats.ConclusionsThe findings supported the utility of GR antagonism in preventing the development of PTSD.DisclosureNo significant relationships.

Detection of Microstructural Medial Prefrontal Cortex Changes Using Magnetic Resonance Imaging Texture Analysis in a Post-Traumatic Stress Disorder Rat Model.

BackgroundRadiomics is characterized by high-throughput extraction of texture features from medical images and the mining of information that can potentially be used to define neuroimaging markers in many neurological or psychiatric diseases. However, there have been few studies concerning MRI radiomics in post-traumatic stress disorder (PTSD). The study's aims were to appraise changes in microstructure of the medial prefrontal cortex (mPFC) in a PTSD animal model, specifically single-prolonged stress (SPS) rats, by using MRI texture analysis. The feasibility of using a radiomics approach to classify PTSD rats was examined.MethodsMorris water maze and elevated plus maze were used to assess behavioral changes in the rats. Two hundred and sixty two texture features were extracted from each region of interest in T2-weighted images. Stepwise discriminant analysis (SDA) and LASSO regression were used to perform feature selection and radiomics signature building to identify mPFC radiomics signatures consisting of optimal features, respectively. Receiver operating characteristic curve plots were used to evaluate the classification performance. Immunofluorescence techniques were used to examine the expression of glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) in the mPFC. Nuclear pycnosis was detected using 4′,6-diamidino-2-phenylindole (DAPI) staining.ResultsBehavioral results indicated decreased learning and spatial memory performance and increased anxiety-like behavior after SPS stimulation. SDA analysis showed that the general non-cross-validated and cross-validated discrimination accuracies were 86.5% and 80.4%. After LASSO dimensionality reduction, 10 classification models were established. For classifying PTSD rats between the control and each SPS group, these models achieved AUCs of 0.944, 0.950, 0.959, and 0.936. Among four SPS groups, the AUCs were 0.927, 0.943, 0.967, 0.916, 0.932, and 0.893, respectively. The number of GFAP-positive cells and intensity of GFAP-IR within the mPFC increased 1 day after SPS treatment, and then decreased. The intensity of NeuN-IR and number of NeuN-positive cells significantly decreased from 1 to 14 days after SPS stimulation. The brightness levels of DAPI-stained nuclei increased in SPS groups.ConclusionNon-invasive MRI radiomics features present an efficient and sensitive way to detect microstructural changes in the mPFC after SPS stimulation, and they could potentially serve as a novel neuroimaging marker in PTSD diagnosis.

Akut topiramat uygulamasının sıçanlardaki travma sonrası stres bozukluğu üzerine etkileri

Purpose: The aim of this study was to investigate the effects of acute systemic topiramate administration on anxiety index and freezing time, plasma estrogen and progesterone levels, and salivary gland immunoglobulin A in a post-traumatic stress disorder rat model.&#x0D; Materials and Methods: A total of eighteen female Wistar rats used in the study were exposed to predatory odor stress. One week later, saline was administered to the control group and 15 µM and 30 µM topiramate to the treatment groups, after which the animals were exposed to the trauma reminder and their behavior was monitored in the elevated plus maze. At the end of the experiment, blood samples were taken, animals were sacrificed, salivary glands were removed immediately after.&#x0D; Results: Topiramate suppressed anxiety index and freezing time in rats with post-traumatic stress disorder at both 15 µM and 30 µM doses compared to the control group. A positive correlation was observed between plasma estrogen level and anxiety index in the control group, and topiramate suppressed this correlation in a dose-dependent manner. Topiramate did not change the plasma progesterone level, but suppressed the salivary gland immunoglobulin A level at the low dose.&#x0D; Conclusion: These findings obtained in our study indicate that topiramate may be effective in the treatment of post-traumatic stress disorder.

Effect of acupuncture on endoplasmic reticulum stress-related factors in hippocampus of post-traumatic stress disorder rats

To observe the effect of acupuncture on endoplasmic reticulum stress-related molecules glucose regulated protein 78 kD (GRP78), C/EBP homologous protein (CHOP), cysteinyl aspartate specific proteinase-12 (Caspase-12) and cysteinyl aspartate specific proteinase-3 (Caspase-3)in the hippocampus of rats with post-traumatic stress disorder, so as to explore the possible mechanism of acupuncture in treating post-traumatic stress disorder (PTSD). Twenty-eight SD rats were randomly divided into normal control, model, acupuncture and sertraline groups, with 7 rats in each group. The PTSD rat model was established by single prolonged stress. After modeling, acupuncture was applied to "Baihui" (GV20) and "Dazhui" (GV14) for rats of the acupuncture group for 10 min, once a day for 7 days. Sertraline (10 mg/kg) was given by gavage to rats of the sertraline group daily for 7 days. Rats' behavior was assessed by open field test and novelty-suppressed test. The mRNA expression levels of GRP78 and CHOP in the hippocampus were detected by real-time PCR. The expression le-vels of Caspase-12 and Caspase-3 in the hippocampus were detected by Western blot. Compared with the normal control group, the rearing and crossing times were decreased (P<0.05), the time remaining in the central zone and the total distance of movement were significantly reduced (P<0.01, P<0.05), the time of entering the central area for the first time was significantly increased (P<0.01), the latency of the novelty-suppressed feeding was significantly increased (P<0.05) in the model group, meanwhile the expression level of GRP78 and CHOP mRNAs, Caspase-12 and Caspase-3 proteins in the hippocampus were increased (P<0.05, P<0.01). In comparison with the model group, the crossing times, the time remaining in the central zone and total distance of movement were increased significantly (P<0.05, P<0.01), while the time of entering the central area for the first time, the expression levels of GRP78 and CHOP mRNAs, and Caspase-12 protein in the hippocampus were obviously decreased (P<0.05, P<0.01) in the acupuncture and sertraline groups. In addition, the rearing times were increased significantly (P<0.05), the latency of the novelty-suppressed feeding and the expression of Caspase-3 were decreased significantly (P<0.05) in the sertraline group than in the model group. Acupuncture can significantly down-regulate the expression of endoplasmic reticulum stress-related molecules GRP78, CHOP and Caspase-12 in PTSD rats, which may be one of the mechanisms of acupuncture in treating PTSD.

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex.

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.

Activated cell-cycle CDK4/CyclinD1-pRB-E2F1 signaling pathway is involved in the apoptosis of dorsal raphe nucleus in the rat model of PTSD

Dysregulation of the dorsal raphe nucleus (DRN) has been revealed to contribute to cognitive and arousal impairments associated with post-traumatic stress disorder (PTSD) in an animal model. In our research an acute exposure to single prolonged stress (SPS) was used to establish PTSD rat model and the effects related to cell-cycle signaling pathway in DRN were examined. Apoptosis in DRN was detected by TUNEL staining, showing that DRN apoptosis number was sharply increased after SPS. SPS triggered cell-cycle CDK4/CyclinD1-pRB-E2F1 signal pathway. Treatment with CDK4 inhibitor Abemaciclib successfully attenuated the DRN apoptosis and rescued decreased spatial learning and memory abilities in SPS rats, indicating that activation of CDK4/CyclinD1-pRB-E2F1 pathway was involved in DRN apoptosis, which may be one of the pathogenesis for PTSD.

Quantitative Proteomics Analysis of Susceptibility and Resilience to Stress in a Rat model of PTSD

Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder and sometimes deadly consequence of exposure to severe psychological trauma. However, there has been little known about the definitive molecular changes involved in determining vulnerability to PTSD. In the current study, we used proteomics to quantify protein changes in the hippocampus of foot shocks rats. A total of 6151 proteins were quantified and 97 proteins were significantly differentially expressed. The protein-protein interaction (PPI) analysis showed that oxidation-reduction process and glutathione homeostasis may be the potential key progress of being vulnerable to PTSD. The Gene Ontology analysis revealed enriched GO terms in the protein groups of Susceptible group vs Control group rats for glutathione binding,oligopeptide binding,modified amino acid binding,and glutathione transferase activity for their molecular functions (MF) and in the process of cellular response to toxic substance,xenobiotic metabolic process, urea metabolic process, and response to drug for the biological process (BP).SIGNIFICANCE:In recent years, there has been a growing interest in mental illness associated with trauma exposure. We found that stress susceptibility was associated with increased expression of arginase 1 indicated as a potential treatment target. Our results also proposed that carbonic anhydrases 3 could be a biomarker for the development of PTSD. This research helps to explain the potential molecular mechanism in PTSD and supply a new method for ameliorating PTSD.