Electroacupuncture modulates glutamate neurotransmission to alleviate PTSD-like behaviors in a PTSD animal model.

Post-traumatic stress disorder (PTSD) is a mental disorder that develops after exposure to a traumatic event. Owing to the relatively low rates of response and remission with selective serotonin reuptake inhibitors as the primary treatment for PTSD, there is a recognized need for alternative strategies to effectively address the symptoms of PTSD. Dysregulation of glutamatergic neurotransmission plays a critical role in various disorders, including anxiety, depression, PTSD, and Alzheimer's disease. Therefore, the regulation of glutamate levels holds great promise as a therapeutic target for the treatment of mental disorders. Electroacupuncture (EA) has become increasingly popular as a complementary and alternative medicine approach. It maintains the homeostasis of central nervous system (CNS) function and alleviates symptoms associated with anxiety, depression, and insomnia. This study investigated the effects of EA at the GV29 (Yintang) acupoint three times per week for 2 weeks in an animal model of PTSD. PTSD was induced using single prolonged stress/shock (SPSS) in mice, that is, SPS with additional foot shock stimulation. EA treatment significantly reduced PTSD-like behavior and effectively regulated serum corticosterone and serotonin levels in the PTSD model. Additionally, EA treatment decreased glutamate levels and glutamate neurotransmission-related proteins (pNR1 and NR2B) in the hippocampus of a PTSD model. In addition, neuronal activity and the number of Golgi-impregnated dendritic spines were significantly lower in the EA treatment group than in the SPSS group. Notably, EA treatment effectively reduced glutamate-induced excitotoxicity (caspase-3, Bax, and pJNK). These findings suggest that EA treatment at the GV29 acupoint holds promise as a potential therapeutic approach for PTSD, possibly through the regulation of NR2B receptor-mediated glutamate neurotransmission to reduce PTSD-like behaviors.

Electroacupuncture alleviates PTSD-like behaviors by modulating hippocampal synaptic plasticity via Wnt/ß-catenin signaling pathway.

Abnormalities in hippocampal synaptic plasticity contribute to the pathogenesis of post-traumatic stress disorder (PTSD). The Wnt/ß-catenin signaling pathway is critical for the regulation of synaptic plasticity. PTSD symptoms can be alleviated by correcting impaired neural plasticity in the hippocampus (Hipp). Electroacupuncture (EA) has a therapeutic effect by relieving PTSD-like behaviors. However, little is known about whether the Wnt/ß-catenin pathway is involved in EA-mediated improvements of PTSD symptoms. In this study, we found that enhanced single prolonged stress (ESPS)-induced PTSD led to abnormal neural plasticity, characterized by the decline of dendritic spines, the expression of postsynaptic density 95 (PSD95), and synaptophysin (Syn) in the stressed Hipp along with the reduction of Wnt3a and ß-catenin, and increased GSK-3ß. EA significantly alleviated PTSD-like behaviors, as assessed by the open field test, elevated platform maze test and conditioning fear test. This was paralleled by correcting abnormal neural plasticity by promoting the expression of PSD95 and Syn, as well as the number of dendritic spines in the Hipp. Importantly, EA exerted anti-PTSD effects by augmenting the expression levels of Wnt3a and ß-catenin, and decreasing that of GSK-3ß. The effects mediated by EA were abolished by XAV939, an inhibitor of the Wnt/ß-catenin pathway. This suggests that EA relieved ESPS-induced PTSD-like behaviors, which can largely be ascribed to impaired neural plasticity in the Hipp. These findings provide new insights into possible mechanisms linking neural plasticity in the Hipp as potential novel targets for PTSD treatment in EA therapy.

Effects of acupuncture on regulating the hippocampal inflammatory response in rats exposed to post-traumatic stress disorder.

Data from clinical and experimental studies have verified the efficacy and safety of acupuncture in the treatment of post-traumatic stress disorder (PTSD). However, the concrete mechanism has not been well elucidated. The stress-induced activation of inflammatory response is involved in the development and pathogenesis of PTSD. Here, we aimed to investigate the effects of acupuncture on regulating the hippocampal inflammatory response in rats exposed to PTSD. Forty male rats were randomly divided into control, model, acupuncture and sertraline group. Within 1 day after adaptive feeding, all rats were exposed to single prolonged stress (SPS), except for the rats in the control group. Rats in acupuncture group were exposed to acupuncture intervention at the acupoints of Baihui (GV20) and Yintang (GV29), 20 min once per day for 15 days. Rats in sertraline group were exposed to a suspension of sertraline and distilled water (0.2 mg/ml), once per day for 15 days continuously. Body weight and elevated plus maze experiment were detected at different time-points to evaluate the behavioral changes of rats. HE staining method was used to observe the basic pathological morphological changes in hippocampus. Immunofluorescence staining method was used to observe the activation of hippocampal microglia. The content of IL-6 and IL-1ß in serum were detected by ELISA method. Compared with the control group, the body weight of rats in model group significantly decreased on 8 days, and the percentage of time in open arms and open arm entries decreased significantly on 15 days after SPS procedures, which indicated that SPS induced PTSD-like behavior in rats. Acupuncture exerted therapeutic effect. Simultaneously, the result of HE staining confirmed that SPS induced hippocampal morphological changes in SPS rats. Notably, acupuncture reversed the reduction and pathological injury to some extent. The results have also shown that acupuncture intervention effectively reversed the activated microglia of the hippocampus in rats. Moreover, the expression of IL-1ß in serum was significantly decreased by acupuncture intervention. In summary, the present study demonstrated that the role of acupuncture in eliminating PTSD-like behavior might be connected with reversing the pathological process of the inflammatory response mediated by the activation of microglia induced by SPS.

Curculigoside rescues hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.

Chronic traumatic stress results in various psychiatric disorders, especially posttraumatic stress disorder (PTSD). Previous study demonstrated that curculigoside (CUR) a component of Rhizoma Curculiginis prevented fear extinction and stress-induced depression-like behaviors. However, its effects on PTSD and the mechanisms are still not completely clear. In this study, we observed typical PTSD-like phenotypes, synaptic deficit, and reduction of BDNF/TrkB signaling pathway in mice receiving modified single prolonged stress and electrical stimulation (SPS&S). By contrast, systemic administration of CUR blocked PTSD-like phenotypes and synaptic deficits, including reduction of BDNF/TrkB signaling pathway, GluA1 and Arc expression. Importantly, CUR reversed the impairment of PKA signaling pathway elicited by PTSD. We further confirmed that the effects of CUR on synaptic function were through PKA signaling pathway, as H-89, an inhibitor of PKA blocked the effect of CUR on behavioral changes and BDNF/TrkB signaling pathway. Thereafter, we verified that CUR on synaptic function were through PKA pathway using direct intracerebral injection of CUR and H-89. Direct intracerebral injection of CUR activated PKA/CREB/BDNF/TrkB, which was blocked by H-89. Additionally, the docking results showed high binding energies of CUR with A2AR, AC, PRKACA, and PRKAR1A, which might indicate that CUR functions through regulating PKA signaling pathway. In conclusion, CUR prevented the behavioral changes and hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.

Ginsenoside Rg3 modulates spatial memory and fear memory extinction by the HPA axis and BDNF-TrkB pathway in a rat post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a serious mental disorder that can develop after exposure to extreme stress. Korean red ginseng, whose major active component is ginsenoside Rg3 (Rg3), is a widely used traditional antioxidant that has anti-inflammatory, anti-apoptotic and anxiolytics effects. This study investigated whether the administration of Rg3 ameliorated the memory deficit induced by a single prolonged stress (SPS) in rats. Male rats were dosed with Rg3 (25 or 50 mg/kg) once daily for 14 days after exposure to SPS. Rg3 administration improved fear memory and spatial memory might be involved in modulating the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and monoamine imbalance in the medial prefrontal cortex and hippocampus. It also increased the reduction in the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) mRNAs expression, and the ratio of p-Akt/Akt in the hippocampus. Thus, Rg3 exerted memory-improving actions might be involved in regulating HPA axis and activating BDNF-TrkB pathway. Our findings suggest that Rg3 could be useful for preventing traumatic stress, such as PTSD.

The Anxiolytic-Like Effects of Protocatechuic Acid in an Animal Model of Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a serious psychiatric disorder characterized by impaired fear extinction, depression, and anxiety caused by dysregulation of the hypothalamic-pituitary-adrenal axis and an imbalance of monoamines. Protocatechuic acid (PCA; 3,4-dihydroxybenzoic acid), a major polyphenol metabolite, has various pharmacological effects, such as anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective activities. In this study, the efficacy of PCA for fear extinction, antidepressant, and anxiolytic effects in PTSD-mediated psychiatric disorders, were evaluated by exposing rats to single prolonged stress (SPS). Male rats were administered PCA (100 or 200 mg/kg) once daily for 14 days after exposure to SPS. PCA significantly decreased situational fear, depressive and anxiety-like behaviors, and corticosterone levels. In addition, PCA regulated the imbalance of serotonin and norepinephrine in the fear circuit region (i.e., the medial prefrontal cortex and hippocampus [Hipp]), and suppressed the decrease in brain-derived neurotrophic factor mRNA expression in the Hipp. The results showed that PCA administration improves freezing behavior and has antidepressant and anti-anxiety effects through modulation of the serotonergic nervous system and monoamines in rats. These results indicated that PCA may be useful as a food ingredient to prevent PTSD.

Anshen Dingzhi prescription in the treatment of PTSD in mice: Investigation of the underlying mechanism from the perspective of hippocampal synaptic function.

BACKGROUND: Anshen Dingzhi prescription (ADP) is an important prescription for the treatment of mental diseases in traditional Chinese medicine and is widely used to treat neuropsychiatric disorders. PURPOSE: To explore the ameliorative effect of ADP on post-traumatic stress disorder (PTSD)-like behaviors in mice and determine the underlying mechanism. METHODS: The constituents of ADP were analyzed by UPLC-Q-TOF/MS. The PTSD-like behaviors of mice subjected to single prolonged stress (SPS) were evaluated using behavioral tests. Potential pathological changes in the hippocampus were assessed by hematoxylin and eosin (H&E) staining. Western blotting and immunohistochemistry (IHC) were employed to detect the expression of proteins involved in relevant signaling pathways. RESULTS: Five quality control markers (ginsenoside Rg1, ginsenoside Rb1, tenuifolin, poricoic acid B, and α-asarone) were detected in the ADP solution. The ginsenoside Rg1 content in ADP was found to be 0.114 mg/g. Mice subjected to SPS showed obvious fear generalization and anxiety-like behaviors. ADP treatment prevented the behavioral changes caused by exposure to SPS. Compared with control animals, the number of normal pyramidal cells in the hippocampal CA1 region of mice exposed to SPS was decreased and the number of degenerating pyramidal cells was increased; however, ADP administration could counteract these effects. Furthermore, the protein expression of BDNF, p-TrkB, µ-calpain, PSD95, GluN2A, GluA1, p-AKT, p-mTOR, and ARC was decreased, while that of PTEN and GluN2B was increased in the hippocampus of mice subjected to SPS compared with that in control animals; however, these changes in protein expression were reversed following ADP treatment. Importantly, the ameliorative effect of ADP on PTSD-like behaviors and synaptic protein expression were inhibited by rapamycin administration. CONCLUSIONS: ADP administration improves PTSD-like behaviors in mice and this effect may be mediated through an mTOR-dependent improvement in synaptic function in the hippocampus.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The effects of laser stimulation at acupoint ST36 on anxiety-like behaviors and anterior cingulate cortex c-Fos expression in a rat post-traumatic stress disorder model.

Post-traumatic stress disorder (PTSD) is a mental disorder that is linked with the onset of multiple anxiety-like behaviors. This study was designed to assess how these behaviors and anterior cingulate cortex (ACC) c-Fos expression were impacted by 10.6-µm laser stimulation at acupoint ST36 a rat model of PTSD. A rat model of PTSD was prepared via prolonged exposure of animals to a stressor, followed by a 7-day period during which animals were allowed to rest undisturbed in their cages. Rats were randomized into four experimental groups (n = 12/group): the control, PTSD, LS, and sham LS groups. Control group animals were not subjected to SPS procedures prior to behavioral testing. LS and sham LS animals were administered LS treatment at bilateral ST36 acupoints or non-acupoints, respectively, for a 7-day period. Animals were then assessed for performance in elevated plus maze (EPM) tests and open-field tests (OFT), and their plasma corticosterone levels were measured. In addition, c-Fos-positive nuclei in the ACC were detected via immunohistochemical staining. Relative to sham LS treatment and PTSD model control rats, LS was associated with increased time spent in both open EPM test arms and in the central area in the OFT (P < 0.05). The PTSD model group exhibited a significant reduction in ACC c-Fox expression, while LS treatment significantly increased this expression (P < 0.001). In addition, a correlation was detected between anxiety-like behaviors and altered ACC neuronal activation. The results of this study indicate that LS at acupoint ST36 can have a previously unreported effect on anxiety-like behaviors in the context of PTSD, with ACC neuronal activation potentially being implicated as a driver of this effect.

Yoga for veterans with PTSD: Cognitive functioning, mental health, and salivary cortisol.

Objective: Research indicates that cognitive functioning is negatively impacted by exposure to chronic stress due to overactivation of the stress response. Yoga has demonstrated benefits when practiced by individuals diagnosed with posttraumatic stress disorder (PTSD). This quasi-experimental pilot study examined the impact of a yoga intervention on cognitive functioning, symptoms of PTSD, and the biological stress response in Veterans diagnosed with PTSD. Method: Cognitive functioning, self-report measures of mental health symptoms, and salivary cortisol were measured within two weeks prior to beginning and following completion of a 10-week yoga protocol. Veterans with PTSD participated in gender-specific groups of the yoga intervention. Paired t tests and correlational analyses were used to analyze quantitative data. Results: Statistically significant improvements were observed between baseline and postintervention scores on measures of response inhibition, PTSD, depression, sleep, quality of life, and subjective neurocognitive complaints. Positive correlations were found between baseline and postintervention changes in sleep and depression, and between change in cortisol output and a measure of life satisfaction. Statistically significant differences (baseline to postintervention) for other objective measures of cognitive performance and cortisol were not detected. Conclusions: Results provide preliminary support for the practice of yoga to improve cognitive functioning (response inhibition) related to symptoms of PTSD while also improving mental health symptoms, sleep, and quality of life. Positive correlations affirm the role of sleep in mood symptoms and indicate the need for further examination of the role of cortisol in life satisfaction. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Neuroendocrine biomarkers of prolonged exposure treatment response in military-related PTSD.

Posttraumatic stress disorder (PTSD) is associated with dysregulation of the neuroendocrine system, including cortisol, allopregnanolone, and pregnanolone. Preliminary evidence from animal models suggests that baseline levels of these biomarkers may predict response to PTSD treatment. We report the change in biomarkers over the course of PTSD treatment. Biomarkers were sampled from individuals participating in (1) a randomized controlled trial comparing a web-version of Prolonged Exposure (Web-PE) therapy to in-person Present-Centered Therapy (PCT) and (2) from individuals participating in a nonrandomized effectiveness study testing PE delivered in-person as part of an intensive outpatient PTSD program. We found that higher cortisol reactivity during script-driven imagery was associated with higher baseline PTSD severity and that baseline allopregnanolone, pregnanolone, and cortisol reactivity were associated with PTSD treatment responder status over the course of intensive outpatient treatment. These findings demonstrate that peripherally assessed biomarkers are associated with PTSD severity and likelihood of successful treatment outcome of PE delivered daily over two weeks. These assessments could be used to determine which patients are likely to respond to treatment and which patients require augmentation to increase the likelihood of optimal response to PTSD treatment.

Electroacupuncture ameliorates post-traumatic stress disorder in rats via a mechanism involving the BDNF-TrkB signaling pathway.

Post-traumatic stress disorder (PTSD) is a mental health condition triggered by a terrifying event, causing flashbacks, nightmares and severe anxiety. It develops in individuals who have experienced a shocking, scary, or dangerous event. Electroacupuncture is reported to be effective for the treatment of PTSD. The present study was carried out to investigate the protective effect of electroacupuncture in a rat model of PTSD, and the mechanism involved. Specific-pathogen-free male Sprague Dawley rats (n = 30) weighing 180 - 220 g (mean weight = 200 ± 20 g) were randomly assigned to three groups of ten rats each: control group, single-prolonged stress (SPS) group, and treatment group. The treatment group rats received electroacupuncture. Changes in PTSD-like behavior were assessed using locomotor activity, elevated plus-maze (EPM) and fear conditioning tests. The mRNA and protein expressions of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) were determined using real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting, respectively. Co-immunoprecipitation (Co-IP) was used to measure BDNF and TrkB binding interaction, while chromatin immunoprecipitation (ChIP) was used to evaluate the binding between cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and its target genes. Electroacupuncture significantly increased locomotor activity and exploratory behavior, but significantly reduced general fear and anxiety in SPS rats (p < 0.05). It also significantly upregulated the mRNA and protein expressions of BDNF and TrkB, and increased the binding of BDNF to its receptor TrkB (p < 0.05). Electroacupuncture significantly increased the binding of CREB to BDNF promoter region (p < 0.05). Electroacupuncture ameliorates PTSD in rats via a mechanism involving the BDNF-TrkB signaling pathway.

Investigating the role of the amygdala orexin receptor 1 in memory acquisition and extinction in a rat model of PTSD.

Understanding the mechanisms underlying memory is essential for the treatment of post-traumatic stress disorder (PTSD). Orexin, as a lateral hypothalamic (LH) neuropeptide, interferes with the stages of memory, primarily through the orexin receptor1 (Orx1R). The aim of this study was to evaluate the effects of amygdala Orx1R in the acquisition and extinction processes of PTSD modeled in animals. In three experiments, rats were divided into three groups: control (Naïve), shock (receiving a foot shock), and PTSD (experiencing Single prolonged stress (SPS) method). The first experiment aimed to evaluate LH activity in PTSD modeled rats. The second and third experiments aimed to evaluate the effects of Orx1R in the acquisition and extinction of fear memory in PTSD modeled animals. SB334867 (SB) or its solvent was microinjected into the amygdala and the rats were subjected to conditioning thereafter. In the second group, we used a single injection after conditioning. In the third group, we used three consecutive injections (one after each memory test). Some behaviors and Orx1R expression were evaluated. The freezing response was significantly longer in the PTSD group than on the control. Similarly, anxiety and sensitized fear were also intensified. CFos expression levels in LH was higher in the PTSD group. Inhibition of Orx1R in the amygdala significantly decreased memory acquisition, diminished anxiety, and decreased the sensitized fear in the SB group. Applying SB to the amygdala after each fear memory test significantly decreased freezing. Expression of Orx1R was significantly higher following fear conditioning. These results indicate a likely involvement of the orexin and amygdalar Orx1R in memory acquisition and in extinction of PTSD.

The effects of eicosapentaenoic acid dietary supplementation on behavioral parameters and expression of hippocampal brain-derived neurotrophic factor in an animal model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a trauma- and stressor-related disorder, characterized by bi-directional symptomatic manifestations of increase in both hyperarousal/hypervigilance and numbing/avoidance. In our previous reports, we have proposed an animal model of PTSD using avoidance/escape task sessions in the shuttle box after delivering an inescapable foot-shock traumatization in the same box (Wakizono et al., 2007), and demonstrated the efficacy of 2-week administration of antidepressant on the hyperarousal/hypervigilant behavioral parameters (Sawamura et al., 2004) in the model. In this study, we observed a partial but significant efficacy of oral supplementation of eicosapentaenoic acid (EPA) for five weeks on the numbing/avoidance behavior in the experimental model. Additionally, western blot analyses using brain-derived neurotrophic factor (BDNF) monoclonal antibody revealed a decreased expression of BDNF protein, in the hippocampal region of the rats, due to foot-shock traumatization and a significantly increased expression of BDNF protein after oral EPA supplementation. The results indicate a possibility that alteration of the numbing/avoidance behavior parallels the expression of hippocampal BDNF in the rat brain. The present study suggests a possibility that EPA supplementation in the treatment of PTSD ameliorates persistent numbing/avoidance symptoms. (185 words).

Repeated caffeine administration aggravates post-traumatic stress disorder-like symptoms in rats.

BACKGROUND: Caffeine is the widely consumed central nervous system stimulant in form of coffee and other beverages. However, the repeated administration of caffeine induces anxiety, disturbance in hypothalamic-pituitary-adrenal (HPA) axis and psychiatric symptoms in humans. As much evidence links PTSD to HPA axis dysfunction, and anxiety is a hallmark symptom, repeated and/or large doses of caffeine may exacerbate symptoms of PTSD. OBJECTIVE: In our present study, we evaluated the effect of repeated administration of caffeine on stress re-stress (SRS) model of PTSD. METHODS: As per the protocol, male rats were restrained for 2 h followed by 20 min forced swim and halothane anaesthesia on day 2 (D-2). Then the rats were re-stressed (forced swim) at 6-days interval between D-8 to D-32. After exposure to SRS, depressive, anxiety-like behaviour, and cognitive functions were evaluated by forced swim test (FST), elevated plus maze (EPM) and Y-maze tests respectively. Caffeine (10, 20 and 30 mg/kg, i.p.) dosing was started from D-8 and continued up to D-32. The corticosterone level was measured in plasma followed by serotonin and glucocorticoid receptor (GR) and mineralocorticoid receptors (MR) estimation in hippocampus (HIP), prefrontal cortex (PFC) and amygdala (AMY). RESULTS: SRS-induced depressive and anxiety-like behaviour was aggravated by caffeine at dose of 20 and 30 mg/kg. Caffeine (30 mg/kg) treated control animals showed depressive, anxiety-like behaviour and cognitive impairments. SRS-induced decrease in plasma corticosterone level and increase in serotonin (5HT) levels in the PFC, HIP and AMY were not altered by caffeine. Caffeine did not modulate the SRS-induced decrease in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). In contrast, caffeine per se decreased GR and MR expression and their ratio in unstressed animals. CONCLUSION: Repeated intake of caffeine aggravates PTSD-like symptoms in stress-exposed rats and induces PTSD-like symptoms in unstressed rats by altering the expression of glucocorticoid receptors.

Temporal effect of electroacupuncture on anxiety-like behaviors and c-Fos expression in the anterior cingulate cortex in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychiatric disease which leads to a series of anxiety-like behaviors. In this study, we investigated the temporal effects of electroacupuncture (EA) at acupoint ST36 on anxiety-like behaviors and the expression of c-Fos in the anterior cingulate cortex (ACC) in a rat model of PTSD. PTSD was induced by a single prolonged stress procedure comprising three stages: restraint for 2 h, forced swim for 20 min, and pentobarbital sodium anesthesia. EA at acupoint ST36 was performed from 7:00-9:00 once a day for 7 consecutive days. Open field test (OFT) and elevated plus maze (EPM) test were used to assess the success of the model and evaluate anxiety-like behaviors. Immunohistochemistry was used to detect Fos-positive nuclei in the ACC. We observed that EA performed from 7:00-9:00 was associated with significantly more time spent in the center area during the OFT and in the open arm during the EPM, as well as lower corticosterone response compared with that of regular EA (P < 0.05). PTSD rats expressed significantly less c-Fos in the ACC. Timed EA significantly increased c-Fos expression in the ACC. The effect of timed EA acting on PTSD rats was linked to altered neuronal activation in the ACC. Compared to regular EA, timed EA exhibited superior therapeutic effects by attenuating anxiety-like behaviors in PTSD rats. These results emphasize the association between temporal parameters of EA manipulation and acupuncture effects. Timed acupuncture therapy may be a novel therapeutic application in the treatment of PTSD.

Pretreatment cortisol predicts trauma-focused psychotherapy response in youth with (partial) posttraumatic stress disorder.

BACKGROUND: Despite availability of effective trauma-focused psychotherapies, treatment non-response in youth with (partial) posttraumatic stress disorder remains substantial. Studies in adult PTSD have suggested that cortisol is associated with treatment outcome. Furthermore, cortisol prior to treatment could be used to predict treatment success. However, there is a lack of comparable studies in youth with (partial) PTSD. The objective of the current study was therefore to test whether cortisol prior to treatment would differ between treatment responders and non-responders and would positively predict the extent of clinical improvement in youth with (partial) PTSD. METHODS: Youth aged 8-18 with PTSD (79.2%) or partial PTSD (20.8%) were treated with 8 sessions of either trauma-focused cognitive behavioral therapy (TF-CBT) or eye movement desensitization and reprocessing (EMDR). Prior to treatment initiation, salivary cortisol was measured in treatment responders (n = 23) and treatment non-responders (n = 30) at 10 and 1 min before and 10, 20 and 30 min after personalized trauma script driven imagery (SDI). The cortisol stress response (>1.5 nmol/L increase from baseline) and basal cortisol secretion was assessed during the SDI procedure. We hypothesized that treatment responders would display higher cortisol levels caused by increased cortisol reactivity prior to trauma-focused psychotherapy relative to psychotherapy non-responders and higher cortisol levels would positively predict the extent of clinical improvement. RESULTS: Script driven imagery did not induce a cortisol stress response in all but two participants. Prior to treatment responders showed significantly higher basal cortisol secretion during SDI compared to treatment non-responders. This effect remained significant after controlling for gender. Higher pre-treatment basal cortisol secretion further positively predicted the extent of clinical improvement during trauma-focused psychotherapy. CONCLUSION: Because SDI failed to provoke a cortisol stress response in our sample, the question if cortisol reactivity differs between treatment responders and non-responders remains inconclusive. However, our results do suggest that higher pretreatment basal cortisol secretion forms a potential indicator of prospective trauma-focused psychotherapy response in youth with (partial) PTSD. Although, the amount of uniquely explained variance in clinical improvement by pre-treatment cortisol secretion is limited and still renders insufficient basis for clinical applicability, these findings do suggest directions for future studies to delineate the mechanisms of treatment success in youth with (partial) PTSD.

Increase of precuneus metabolism correlates with reduction of PTSD symptoms after EMDR therapy in military veterans: an 18F-FDG PET study during virtual reality exposure to war.

PURPOSE: The prevalence of posttraumatic stress disorder (PTSD) is higher among veterans, and can lead to disastrous consequences such as suicide. Eye movement desensitization and reprocessing (EMDR) is recommended in first-line psychotherapies for PTSD. Virtual reality exposure (VRE) coupled with 18F-FDG PET imaging can highlight the activated brain regions during stress exposure. The objective of this study is to identify, after EMDR therapy, the regions of brain metabolism that evolve during the stress exposure of a war scene with symptomatic remission in a group of military veterans suffering from PTSD, and to secondarily search for predictive metabolic features. METHODS: We recruited 15 military veterans suffering from PTSD who performed an 18F-FDG PET sensitized by the exposure to a virtual war scene, before (T0) and after (T1) EMDR therapy. Statistical parametric mapping was used to compare brain metabolism before and after treatment and to study correlations between metabolism and evolution scores on PTSD clinical scales (PTSD Checklist Scale, PCLS; Clinician-Administered PTSD Scale, CAPS). RESULTS: The metabolic activity of the precuneus was increased after EMDR therapy (p < 0.005 uncorrected, k > 180) and correlated with clinical improvement with the CAPS scale (r = -0.73 and p < 0.001). Moreover, the precuneus metabolic value before therapy predicted the clinical improvement on the PCLS scale (T1-T0) after EMDR (r = -0.667 and p < 0.006). CONCLUSION: The clinical improvement in military patients with PTSD after EMDR is related to increased precuneus metabolism upon VR stress exposure.

Deconstructing the Gestalt: Mechanisms of Fear, Threat, and Trauma Memory Encoding.

Threat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits underlying the "engram" of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.

Single prolonged stress PTSD model triggers progressive severity of anxiety, altered gene expression in locus coeruleus and hypothalamus and effected sensitivity to NPY.

PTSD is heterogeneous disorder that can be long lasting and often has delayed onset following exposure to a traumatic event. Therefore, it is important to take a staging approach to evaluate progression of biological mechanisms of the disease. Here, we begin to evaluate the temporal trajectory of changes following exposure to traumatic stressors in the SPS rat PTSD model. The percent of animals displaying severe anxiety on EPM increased from 17.5% at one week to 57.1% two weeks after SPS stressors, indicating delayed onset or progressive worsening of the symptoms. The LC displayed prolonged activation, and dysbalance of the CRH/NPY systems, with enhanced CRHR1 gene expression, coupled with reduced mRNAs for NPY and Y2R. In the mediobasal hypothalamus, increased CRH mRNA levels were sustained, but there was a flip in alterations of HPA regulatory molecules, GR and FKBP5 and Y5 receptor at two weeks compared to one week. Two weeks after SPS, intranasal NPY at 300 µg/rat, but not 150 µg which was effective after one week, reversed SPS triggered elevated anxiety. It also reversed SPS elicited depressive/despair symptoms and hyperarousal. Overall, the results reveal time-dependent progression in development of anxiety symptoms and molecular impairments in gene expression for CRH and NPY systems in LC and mediobasal hypothalamus by SPS. With longer time afterwards only a higher dose of NPY was effective in reversing behavioral impairments triggered by SPS, indicating that therapeutic approaches should be adjusted according to the degree of biological progression of the disorder.