Single Prolonged Stress Research Articles

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.

Effect of chronic alcohol exposure and single-prolonged stress on conditioned fear behavior

The present study investigated the impact of chronic intermittent ethanol (CIE) exposure and single-prolonged stress (SPS) on the acquisition of fear memories in both male and female Wistar rats. Adult rats were first subjected to CIE by vapor inhalation followed by SPS. Following a subsequent 8-day incubation period, the rats underwent a Pavlovian fear conditioning procedure (tone-shock pairings) followed by cued-tone extinction training, and then testing of extinction recall memory and fear renewal memory. In control animals that had not been exposed to either CIE or SPS, female rats exhibited significantly lower levels of freezing compared to male rats during tone-shock pairings. This lower level of freezing in female rats during conditioning was associated with an increased speed of movement compared to males. Also compared to males, female rats exhibited lower levels of fear extinction, recall, and renewal. Exposure to CIE, SPS, or CIE+SPS had no effect on freezing during the cued-conditioning, extinction, or extinction recall phases of the testing procedure in either sex. In fear renewal, CIE exposure decreased freezing in male but not female rats, while SPS increased freezing in female but not male rats. CIE exposure significantly reduced freezing during the fear renewal phase. Taken together, these results provide further evidence that male and female rats adopt different avoidance strategies for threat responding. These results also revealed that prior exposure to CIE, SPS, or CIE+SPS had minimal effects on threat responding using conditioned freezing as an indicator of fear responsivity.

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.

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.

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.

Probiotic treatment improves post-traumatic stress disorder outcomes in mice

Post-traumatic stress disorder (PTSD) is a mental disorder resulting from traumatic events which are characterized primarily by anxiety and depressive disorder. In this study, we determine the role of gut bacteria in PTSD. PTSD-like symptoms were produced by single prolonged stress (SPS). SPS animals showed increased levels of anxiety as measured by the elevated plus maze test, while depressive behaviour was confirmed using sucrose preference, force swim, and tail suspension tests. Gut dysbiosis was confirmed in PTSD animals by next-generation sequencing of 16 s RNA of faecal samples, while these animals also showed increased intestinal permeability and altered intestinal ultrastructure. Probiotic treatment increases beneficial microbiota, improves intestinal health and reduces PTSD-associated anxiety and depression. We also found a decrease in cortical BDNF levels in PTSD animals, which was reversed after probiotic administration. Here, we establish the link between gut dysbiosis and PTSD and show that probiotic treatment may improve the outcome of PTSD like symptoms in mice.

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.

Central innate immunization induces tolerance against post-traumatic stress disorder-like behavior and neuroinflammatory responses in male mice

Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder associated with abnormally elevated neuroinflammatory responses. Suppression of neuroinflammation is considered to be effective in ameliorating PTSD-like behaviors in rodents. Since pre-stimulation of microglia prior to stress exposure can prevent neuroinflammation, we hypothesized that pre-stimulation of microglia may prevent PTSD in animals. The results show that a single injection of a classical immune stimulant, lipopolysaccharide (LPS), at 50, 100 or 500, but not 10 μg/kg, one day before stress exposure, prevented the anxiety- and fear-like behaviors induced by modified single prolonged stress (mSPS). The time-dependent analysis shows that a single injection of LPS (100 μg/kg) either one or five, but not ten, days before stress prevented mSPS-induced anxiety- and fear-like behaviors. A second low-dose LPS injection 10 days after the first injection or a repeated LPS injection (4 × ) 10 days before stress induced tolerance to mSPS. Mechanistic studies show that a single injection of LPS one day before stress stimulation prevented mSPS-induced increases in levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 mRNA in the hippocampus and medial prefrontal cortex. Inhibition of microglia by pretreatment with minocycline or depletion of microglia by PLX3397 abolished the preventive effect of low-dose LPS pre-injection on mSPS-induced anxiety- and fear-like behavior and neuroinflammatory responses. These results suggest that pre-stimulation of microglia may prevent the development of PTSD-like behaviors by attenuating the development of neuroinflammatory responses. This could help to develop new strategies to prevent the damaging effects of harmful stress on the brain.

Ketamine alleviates PTSD-like effect and improves hippocampal synaptic plasticity via regulation of GSK-3β/GR signaling of rats

BackgroundEach year, 3–4% of the global population experiences post-traumatic stress disorder (PTSD), a chronic mental disorder with significant social and economic repercussions. Although it has been shown that ketamine can effectively alleviate PTSD symptoms in individuals, the specific mechanism of action underlying its anti-PTSD effects remains unclear. In this study, we investigated how a single, low dose of ketamine affected the glycogen synthase kinase 3β (GSK-3β)/glucocorticoid receptor (GR) signaling pathway in a single prolonged stress (SPS)-induced PTSD rat model. MethodsAfter establishing the model, stress-related behavioral alterations in the rats were assessed following intraperitoneal injections of ketamine (10 mg/kg) and GSK-3β antagonist SB216763 (5 mg/kg). In the hippocampus, alterations in the expression of specific proteins implicated in PTSD development, such as GR, brain-derived neurotrophic factor (BDNF), GSK-3β, and phosphorylated glycogen synthase kinase 3β (p-GSK-3β), were assessed. We also measured changes in the mRNA expression levels of GR, BDNF, GSK-3β, FK501 binding protein 51 (FKBP5), and corticotropin-releasing hormone (CRH), as well as synaptic ultrastructure, in the hippocampus, and measured changes in corticosterone levels in the blood. ResultsSPS induced anxiety-like and depression-like behaviors in rats and induced morphological changes in synapse, which were accompanied by higher GSK-3β protein expression and conversely, decreased expression of GR, BDNF, p-GSK-3β, FKBP5 and CRH. Intraperitoneal administration of ketamine (10 mg/kg) after SPS prevented SPS-induced anxiety-like behaviors. Most importantly, ketamine attenuated SPS-induced dysfunctions in GSK-3β/GR signaling and synaptic deficits. Furthermore, treatment with a GSK-3β inhibitor played the same effect as ketamine on behavioral changes of SPS model rats. ConclusionSingle doses of ketamine effectively ameliorate SPS-induced anxiety-like symptoms, potentially by improving synaptic plastic in the hippocampus by regulating GSK-3β/GR signaling.

Effects and mechanisms of electroacupuncture on fear extinction and sleep phase in single prolonged stress mice

To observe the effects of electroacupuncture (EA) on fear extinction and sleep phase in single prolonged stress (SPS) mice, and explore its mechanism in view of the expression of relevant synaptic proteins. Thirty-two C57BL/6J male mice were randomly divided into a control group, a model group, an EA group and a paroxetine (PRX) group, with 8 mice in each one. Modified SPS method was used to establish PTSD model in the model group, the EA group and the PRX group. Seven days after modeling completion, in the EA group, the intervention was delivered at "Baihui" (GV 20) and bilateral "Zusanli" (ST 36), with disperse-dense wave, 3 Hz/15 Hz in frequency and 1 mA in current intensity, for 30 min. In the PRX group, paroxetine solution (2.5 g/L) was administered intragastrically (10 mg/kg). The intervention was given once daily and for consecutive 10 days in the above two groups. The fear conditioning task and the elevated plus-maze test were adopted to evaluate the fear extinction and anxiety of the mice in each group. Using Medusa electroencephalogram (EEG) and electromyography (EMG) recording system from rats and mice, the sleep phase was determined in the mice. With Western blot method adopted, the protein expression of the postsynaptic density protein 95 (PSD95), activity-regulated cytoskeleton-associated protein (ARC), brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartic acid receptor 2A (GluN2A), N-methyl-D-aspartic acid receptor 2B (GluN2B) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor 1 (GluA1) in the hippocampus was detected in the mice. Compared with the control group, the freezing time for the fear re-exposure in 3 min to 15 min and the fear extinction in 0 min to 3 min were prolonged (P<0.05), the fear extinction index decreased (P<0.05), and the open arm time (OT) of the elevated plus-maze was shortened (P<0.05) in the model group. When compared with the model group, in the EA group and the PRX group, the freezing time for the fear re-exposure in 3 min to 6 min and 12 min to 15 min, as well as the fear extinction in 0 min to 3 min was shortened (P<0.05), the fear extinction index increased (P<0.05); the OT in elevated plus-maze was longer in the mice of the EA group (P<0.05). The period of wake (Wake) was prolonged (P<0.05), the non-rapid eye movement period (NREM) and the total sleep time (Sleep) were reduced in the model group (P<0.05) in comparison with the control group. Compared with the model group, the Wake was declined (P<0.05), and the NREM and Sleep increased in the EA group and the PRX group (P<0.05). When compared with the control group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus decreased (P<0.05), and that of GluN2B increased (P<0.05) in the model group. In the EA group and the PRX group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus was elevated (P<0.05), and that of GluN2B reduced (P<0.05) when compared with the model group. Electroacupuncture at "Baihui" (GV 29) and "Zusanli" (ST 36) can ameliorate anxiety-like behavior, fear extinction disorder and abnormal sleep phase in SPS mice, which may be related to the regulation of synaptic transmission and synaptic plasticity expression in the hippocampus.

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.

DCC, a potential target for controlling fear memory extinction and hippocampal LTP in male mice receiving single prolonged stress

Post-traumatic stress disorder (PTSD) is a severe stress-dependent psychiatric disorder characterized by impairment of fear memory extinction; however, biological markers to determine impaired fear memory extinction in PTSD remain unclear. In male mice with PTSD-like behaviors elicited by single prolonged stress (SPS), 19 differentially expressed proteins in the hippocampus were identified compared with controls. Among them, a biological macromolecular protein named deleted in colorectal cancer (DCC) was highly upregulated. Specific overexpression of DCC in the hippocampus induced similar impairment of long-term potentiation (LTP) and fear memory extinction as observed in SPS mice. The impairment of fear memory extinction in SPS mice was improved by inhibiting the function of hippocampal DCC using a neutralizing antibody. Mechanistic studies have shown that knocking down or inhibiting μ-calpain in hippocampal neurons increased DCC expression and induced impairment of fear memory extinction. Additionally, SPS-triggered impairment of hippocampal LTP and fear memory extinction could be rescued through activation of the Rac1–Pak1 signaling pathway. Our study provides evidence that calpain-mediated regulation of DCC controls hippocampal LTP and fear memory extinction in SPS mice, which likely through activation of the Rac1–Pak1 signaling pathway.

Hominis Placenta modulates PTSD-like behaviors in SPSS-induced PTSD mice: Regulating energy metabolism and neuronal activity

The symptoms of post-traumatic stress disorder (PTSD) include re-experiencing trauma, avoidance behaviors, negative alterations in cognition and mood. However, the underlying molecular mechanisms are unclear. Dysfunction of hypothalamic-pituitary-adrenal axis (HPA-axis) and dysregulation of glutamatergic and GABAergic systems were shown during PTSD. Therefore, regulating hormonal change or glutamate energy metabolism are considered as a therapeutic approach to alleviate this condition. Herbal medicine may be effective in treating PTSD due to its ability to target multiple underlying mechanisms with various compounds. Hominis placenta (HP) is a traditional medicine widely used in East Asia for various conditions. However, the effect on PTSD has not been clarified. We aimed to investigate the effects of HP treatment in single-prolonged stress with shock (SPSS)-induced PTSD mice and explore its possible mechanisms. HP treatment at ST36 acupoints, combined with herbal medicine and acupuncture point stimulation, was applied three times/week for 2 weeks. HP treatment effectively alleviated anxiety and cognitive decline in SPSS-induced PTSD mice, as detected by Open field and the Y-maze test. Additionally, HP decreased the corticosterone levels and proinflammatory cytokines in the serum, modulated brain energy metabolism, and inhibited glutamate excitotoxicity, while regulating neuronal activity through modulating brain-derived neurotrophic factor (BDNF) levels, as demonstrated by western blot and immunohistochemistry, and flow cytometry analyses. These findings reveal that HP treatment effectively alleviates PTSD-like behaviors by regulating energy metabolism and neuronal activity though modulation of the HPA-axis and BDNF levels in PTSD mice, indicating that HP treatment is a promising therapeutic approach for PTSD.

Inhibition of 5-HT alleviates PTSD-like behaviors and promotes hippocampal neuroplasticity by modulating hippocampal autophagy in rats.

5-Hydroxytryptamine (5-HT) plays a substantial role in mitigating depression and anxiety. However, the potential effects of 5-HT against posttraumatic stress disorder (PTSD) and its underlying mechanisms remain unclear. Elevated plus maze test evaluates anxiety-related behaviors, and the open field test is used to assess overall activity levels and anxiety. Inflammatory cytokine levels were determined using ELISA. The levels of 5-HT and dopamine were measured using HPLC. mRNA and protein levels were examined by PCR and Western blot, respectively. Rats exposed to single prolonged stress (SPS) exhibited typical PTSD-like phenotypes, with decreased levels of 5-HT in the hippocampus and significant reductions in its downstream targets, brain-derived neurotrophic factor (BDNF) and TrkB. In addition, it was discovered that the autophagy signaling pathway might be involved in regulating hippocampal BDNF in rats exposed to SPS. Subsequent treatment with an intracerebral injection of sh-SERT significantly inhibited anxiety and cognitive dysfunction in rats. Moreover, sh-SERT treatment was observed to substantially reverse the increase in autophagy signaling protein expression and consequently improve the expression of BDNF and TrkB proteins, which had been reduced. The current study demonstrates that sh-SERT exhibits significant anti-PTSD effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.NEW & NOTEWORTHY The study demonstrated that sh-SERT exhibits significant anti-posttraumatic stress disorder (PTSD) effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.

Sex-specific alterations in visual properties induced by single prolonged stress model

Patients with post-traumatic stress disorder (PTSD) exhibit sex differences in symptomology, with women more likely to report higher rates of intrusive and avoidance symptoms than men, underscoring the need for sex-informed approaches to research and treatment. Our study delved into the sex-specific aspects of stress-induced visual impairments using the single prolonged stress (SPS) model, a partially validated rodent model for PTSD. Male SPS mice exhibit heightened optimal spatial frequency (SF) of primary visual cortex (V1) neurons, while female counterparts exhibit decreased optimal temporal frequency (TF) of V1 neurons. This phenomenon persisted until the 29th day after SPS modeling, and it may be the physiological basis for the observed increase in visual acuity in male SPS mice in visual water task. Furthermore, our study found that corticotropin-releasing factor receptor 1 regulated optimal TF and optimal SF of V1 in mice, but did not exhibit sex differences. These findings indicated that severe stress induces sex-specific effects on visual function.

The Effectiveness of the Single Object Burying Test in Assessing Hypervigilance-like Behavior in the Single Prolonged Stress Model of Post-Traumatic Stress Disorder (PTSD) in Male Sprague Dawley Rats

Abstract Introduction Post-traumatic stress disorder (PTSD) is recognized nowadays as a major public health issue. It arises as a long-term reaction to severe stressors considered to be life-threatening. It’s characterized by intrusive symptoms, avoidance, and hypervigilance. Although its prevalence is rather high, the mechanisms behind this serious condition are little understood, and its treatment is currently challenging. To get insights into this disorder, a variety of PTSD models were developed in the last 15 years as well as several tests have been proposed to assess the PTSD-like behaviors in these animal models. The single object burying test (OBT) was used to examine the hypervigilant behavior in electric shock animal model of PTSD. To the best of our knowledge, no prior studies have utilized the OBT to assess hypervigilance in the traditional single prolonged stress (SPS) animal model of PTSD. Our study aims to compare the behavioral response of the SPS-exposed and SPS-unexposed rats in the OBT. Methods This study employed the single prolonged stress (SPS) model to induce PTSD in male Sprague-Dawley rats (n = 12 rats, divided as control group = 6 rats, and SPS group = 6 rats) to investigate whether the single object burying test can detect the hypervigilance like behavior in the SPS rats as compared to control group. Parameters used are the percentage of time spent manipulating the object and the percentage of time spent burying the object. Results SPS rats demonstrated decrease in the percentage of time spent manipulating the object and increase in the percentage of time spent burying the object as compared to control group in the OBT. These responses are interpreted as hypervigilance like behavior. Conclusion The OBT can be considered a successful test in assessing hypervigilance of the rats exposed to the SPS animal model of PTSD

Activation of GPER1 by G1 prevents PTSD-like behaviors in mice: Illustrating the mechanisms from BDNF/TrkB to mitochondria and synaptic connection.

G1 is a specific agonist of G protein-coupled estrogen receptor 1 (GPER1), which binds and activates GPER1 to exert various neurological functions. However, the preventive effect of G1 on post-traumatic stress disorder (PTSD) and its mechanisms are unclear. To evaluate the protective effect of G1 against synaptic and mitochondrial impairments and to investigate the mechanism of G1 to improve PTSD from brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling. This study initially detected GPER1 expression in the hippocampus of single prolonged stress (SPS) mice, utilizing both Western blot and immunofluorescence staining. Subsequently, the effects of G1 on PTSD-like behaviors, synaptic, and mitochondrial functions in SPS mice were investigated. Additionally, the involvement of BDNF/TrkB signaling involved in the protection was further confirmed using GPER1 antagonist and TrkB inhibitor, respectively. The expression of GPER1 was reduced in the hippocampus of SPS mice, and G1 treatment given for 14 consecutive days significantly improved PTSD-like behaviors in SPS mice compared with model group. Electrophysiological local field potential (LFP) results showed that G1 administration for 14 consecutive days could reverse the abnormal changes in the gamma oscillation in the CA1 region of SPS mice. Meanwhile, G1 administration for 14 consecutive days could significantly improve the abnormal expression of synaptic proteins, increase the expression of mitochondria-related proteins, increase the number of synapses in the hippocampus, and ameliorate the damage of hippocampal mitochondrial structure in SPS mice. In addition, G15 (GPER1 inhibitor) and ANA-12 (TrkB inhibitor) blocked the ameliorative effects of G1 on PTSD-like behaviors and aberrant expression of hippocampal synaptic and mitochondrial proteins in SPS mice and inhibited the reparative effects of G1 on structural damage to hippocampal mitochondria, respectively. G1 improved PTSD-like behaviors in SPS mice, possibly by increasing hippocampal GPER1 expression and promoting BDNF/TrkB signaling to repair synaptic and mitochondrial functional impairments. This study would provide critical mechanism for the prevention and treatment of PTSD.

Alcohol-exacerbates post-traumatic stress psychiatric behavior and its neuropathological sequalae in experimental mice: preventive effects of morin

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are very prevalent and co-occurring. It is unclear how alcohol exacerbates PTSD predicaments owing to less characterized pathophysiological mechanisms. Also, studies on pharmacological agents that can effectively reverse PTSD-AUD comorbidity have, to date, been scarce. Hence, we designed a methodological approach to investigate the pathophysiological mechanisms and pharmacological outcomes of morin, a neuroprotective flavonoid in mice. After 7 days of PTSD following single-prolonged stress (SPS) induction in mice, the PTSD mice were exposed to intermittent binge ethanol administration using ethanol (2g/kg, oral gavage) every other day, alongside daily morin (50 and 100mg/kg) or fluoxetine (10mg/kg) from days 8-21. The consequences of PTSD-AUD behavior, hypothalamic-pituitary-adrenal-axis (HPA-axis) dysfunction, neurochemistry, oxidative/nitrergic stress, and inflammation were evaluated in the prefrontal-cortex (PFC), striatum, and hippocampus of mice. The exacerbated anxiety-like behavior, and spatial/non-spatial memory deficits, with general depressive phenotypes and social stress susceptibility by SPS-ethanol interaction, were alleviated by morin and fluoxetine, evidenced by reduced corticosterone release and adrenal hypertrophy. SPS-ethanol exacerbates dopamine, serotonin, and glutamic acid decarboxylase alterations, and monoamine oxidase-B and acetylcholinesterase hyperactivities in the striatum, PFC, and hippocampus, respectively, which were prevented by morin. Compared to SPS-ethanol aggravation, morin prevented TNF-α, and IL-6 release, malondialdehyde and nitrite levels, with improved antioxidant (glutathione, superoxide-dismutase, catalase) levels in the hippocampus, PFC, and striatum. Overall, these findings suggest that AUD exacerbated PTSD might be primarily connected, among other mechanisms, with aggravated HPA-axis dysfunction, upregulated neurochemical degradative enzymes, enhancement of oxidative/nitrergic stress and neuroinflammation, stereo-selectively in the mice brains, which morin abated via the preventive mechanisms.

Involvement of dysregulated hippocampal histone H3K9 methylation at the promoter of the BDNF gene in impaired memory extinction

RationaleSince the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Impaired extinction of fear memory (EFM) is one of the core symptoms of PTSD and is associated with stress-induced epigenetic change in gene expression.ObjectivesIn this study, we examined whether the involvement of histone H3 lysine 9 dimethylation (H3K9me2) in EFM is mediated through brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and whether BIX01294, a selective G9a and GLP histone methyltransferase inhibitor, could be treatment for impaired EFM in an animal model of PTSD.MethodsThe single prolonged stress (SPS) paradigm was used to model PTSD. We measured BDNF mRNA levels by RT-PCR, and H3K9me2 levels in the BDNF gene promoters by chromatin immunoprecipitation-qPCR. After undergoing contextual fear conditioning and hippocampal injection of BIX01294, male rats were subjected to extinction training and extinction testing and their freezing times and BDNF mRNA levels were measured.ResultsCompared to sham rats, SPS rats showed decreased BDNF mRNA levels 2 h after extinction training, no significant changes in levels of global H3K9me2 prior to extinction training, and increased levels of H3K9me2 in BDNF gene promoter IV, but not in BDNF gene promoter I. Administration of BIX01294 ameliorated the decrease in BDNF mRNA levels 2 h after extinction training and subsequently alleviated impaired EFM in extinction tests in SPS rats.ConclusionWe conclude that reduced hippocampal levels of BDNF mRNA due to increase in H3K9me2 levels may play a role in PTSD-associated EFM impairment, and BIX01294 could be a PTSD treatment option.

Diosgenin reverses posttraumatic stress disorder in mice by augmenting neurochemical release and inhibiting HPA axis dysfunction, oxidative stress, and neuroinflammation

Post-traumatic stress disorder (PTSD) is a mental disorder linked to neurochemical, hypothalamic-pituitary-adrenal (HPA)-axis dysregulations, inflammatory and pro-oxidant challenges in response to traumatic events. It is one of the leading causes of neurocognitive declines, hence prompting the need for a pharmacological intervention. However, the impact of diosgenin, a naturally occurring steroidal saponin with adaptogenic-like action, on PTSD-induced neuropsychiatric disturbances and its underlying mechanisms are unknown. In this study, we investigated the outcome of diosgenin treatment in a multimodal traumatic, single prolonged stress (SPS)-induced PTSD in mice. Following the SPS-induced 7 days of PTSD, mice (n = 9) were thereafter treated with diosgenin (25 and 50 mg/kg) or fluoxetine (10 mg/kg) orally from days 8–20 (14 days). Locomotory, cognitive-, depressive- and anxiety-like behaviors were investigated. We assayed for changes in adrenal weight, serum glucose and corticosterone concentrations. Neurochemical, inflammatory, oxido-nitrergic dysfunctions and monoamine oxidase-B and acetylcholinesterase activities, were measured in the striatum, prefrontal-cortex and hippocampus. The results revealed that the SPS challenge inhibited locomotor, spatial/non-spatial memory functions, increased anxiety and depressive-like features, which were reversed by diosgenin. Diosgenin reduced SPS-induced increased monoamine oxidase-B, acetylcholinesterase activities, TNF-α, IL-6, malondialdehyde and nitrite levels in the striatum, prefrontal-cortex and hippocampus. Antioxidants such as glutathione, superoxide-dismutase, and catalase levels in SPS-mice brains were increased by diosgenin. Moreover, diosgenin attenuated SPS-induced hyper-HPA-axis mediation of PTSD by decreasing serum corticosterone, glucose levels and adrenal gland hypertrophy. Herewith, we suggest that diosgenin convenes adaptogenic-like protection against mice exposed to PTSD by enhancing antioxidant machinery, neurochemical modulations, and inhibition of oxido-nitrergic, inflammatory, and HPA-axis dysfunctions.