Cheonwangbosimdan mitigates post-traumatic stress disorder-like behaviors through GluN2B-containing NMDA receptor antagonism in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cheonwangbosimdan (CWBSD), a herbal medicine traditionally used for anxiety, insomnia, depression, and heart palpitations, has been reported to have anti-anxiety, antidepressant, cognitive improvement, and neuroprotective effects. AIM OF THE STUDY: The purpose of this study was to determine if CWBSD could affect post-traumatic stress disorder (PTSD)-like behaviors because it has prioritized clinical use over mechanism study. MATERIALS AND METHODS: A single prolonged stress (SPS) mouse model, a well-established animal model of PTSD, was used to investigate whether standardized CWBSD could mitigate PTSD-like behaviors through robust behavioral tests, including the elevated plus-maze test and marble burying test for measuring anxiety-like behaviors, the splash test, forced swimming test, and tail suspension test for evaluating depression-like behaviors, and the Y-maze test and novel object recognition test for assessing cognitive function. Additionally, a fear extinction test was employed to determine whether CWBSD might reverse fear memory extinction deficits. Amygdala tissue was isolated from SPS-treated mouse brain and subjected to Western blotting or quantitative PCR to explore mechanisms by which CWBSD could mitigate PTSD-like behaviors. RESULTS: CWBSD ameliorated emotional impairments and cognitive dysfunction in an SPS-induced PTSD-like mouse model. It also mitigated deficits in abnormal fear memory extinction. Protein expression levels of N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) and phosphorylation levels of Ca2+/calmodulin-dependent protein kinase II in the amygdala were increased in SPS model mice and normalized by CWBSD. Additionally, co-administration of CWBSD and GluN2B-containing NMDA receptor antagonist, ifenprodil, at each sub-effective dose promoted fear memory extinction. CONCLUSIONS: CWBSD can alleviate SPS-induced PTSD-like behaviors by normalizing GluN2B-containing NMDA receptor activity in the amygdala. Therefore, CWBSD could be a promising candidate for PTSD treatment with fewer adverse effects and better efficacy than existing therapies.

Medicinal cannabis oil improves anxiety-like and depressive-like behaviors in CCS mice via the BDNF/TRPC6 signaling pathway.

BACKGROUND: Post-traumatic stress disorder (PTSD) refers to a chronic impairing psychiatric disorder occurring after exposure to the severe traumatic event. Studies have demonstrated that medicinal cannabis oil plays an important role in neuroprotection, but the mechanism by which it exerts anti-PTSD effects remains unclear. METHODS: The chronic complex stress (CCS) simulating the conditions of long voyage stress for 4 weeks was used to establish the PTSD mice model. After that, behavioral tests were used to evaluate PTSD-like behaviors in mice. Mouse brain tissue index was detected and hematoxylin-eosin staining was used to assess pathological changes in the hippocampus. The indicators of cell apoptosis and the BDNF/TRPC6 signaling activation in the mice hippocampus were detected by western blotting or real-time quantitative reverse transcription PCR experiments. RESULTS: We established the PTSD mice model induced by CCS, which exhibited significant PTSD-like phenotypes, including increased anxiety-like and depression-like behaviors. Medicinal cannabis oil treatment significantly ameliorated PTSD-like behaviors and improved brain histomorphological abnormalities in CCS mice. Mechanistically, medicinal cannabis oil reduced CCS-induced cell apoptosis and enhanced the activation of BDNF/TRPC6 signaling pathway. CONCLUSIONS: We constructed a PTSD model with CCS and medicinal cannabis oil that significantly improved anxiety-like and depressive-like behaviors in CCS mice, which may play an anti-PTSD role by stimulating the BDNF/TRPC6 signaling pathway.

Single-Nucleus Transcriptome Profiling from the Hippocampus of a PTSD Mouse Model and CBD-Treated Cohorts.

Post-traumatic stress disorder (PTSD) is the most common psychiatric disorder after a catastrophic event; however, the efficacious treatment options remain insufficient. Increasing evidence suggests that cannabidiol (CBD) exhibits optimal therapeutic effects for treating PTSD. To elucidate the cell-type-specific transcriptomic pathology of PTSD and the mechanisms of CBD against this disease, we conducted single-nucleus RNA sequencing (snRNA-seq) in the hippocampus of PTSD-modeled mice and CBD-treated cohorts. We constructed a mouse model by adding electric foot shocks following exposure to single prolonged stress (SPS+S) and tested the freezing time, anxiety-like behavior, and cognitive behavior. CBD was administrated before every behavioral test. The PTSD-modeled mice displayed behaviors resembling those of PTSD in all behavioral tests, and CBD treatment alleviated all of these PTSD-like behaviors (n = 8/group). Three mice with representative behavioral phenotypes were selected from each group for snRNA-seq 15 days after the SPS+S. We primarily focused on the excitatory neurons (ExNs) and inhibitory neurons (InNs), which accounted for 68.4% of the total cell annotations. A total of 88 differentially upregulated genes and 305 differentially downregulated genes were found in the PTSD mice, which were found to exhibit significant alterations in pathways and biological processes associated with fear response, synaptic communication, protein synthesis, oxidative phosphorylation, and oxidative stress response. A total of 63 overlapping genes in InNs were identified as key genes for CBD in the treatment of PTSD. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the anti-PTSD effect of CBD was related to the regulation of protein synthesis, oxidative phosphorylation, oxidative stress response, and fear response. Furthermore, gene set enrichment analysis (GSEA) revealed that CBD also enhanced retrograde endocannabinoid signaling in ExNs, which was found to be suppressed in the PTSD group. Our research may provide a potential explanation for the pathogenesis of PTSD and facilitate the discovery of novel therapeutic targets for drug development. Moreover, it may shed light on the therapeutic mechanisms of CBD.

Generalized fear after acute stress is caused by change in neuronal cotransmitter identity.

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. In this study, we show that generalized fear in mice results from a transmitter switch from glutamate to γ-aminobutyric acid (GABA) in serotonergic neurons of the lateral wings of the dorsal raphe. Similar change in transmitter identity was found in the postmortem brains of individuals with posttraumatic stress disorder (PTSD). Overriding the transmitter switch in mice prevented the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors mediated the switch, and prompt antidepressant treatment blocked the cotransmitter switch and generalized fear. Our results provide important insight into the mechanisms involved in fear generalization.

CK2 negatively regulates the extinction of remote fear memory.

Cognitive behavioral therapy, rooted in exposure therapy, is currently the primary approach employed in the treatment of anxiety-related conditions, including post-traumatic stress disorder (PTSD). In laboratory settings, fear extinction in animals is a commonly employed technique to investigate exposure therapy; however, the precise mechanisms underlying fear extinction remain elusive. Casein kinase 2 (CK2), which regulates neuroplasticity via phosphorylation of its substrates, has a significant influence in various neurological disorders, such as Alzheimer's disease and Parkinson's disease, as well as in the process of learning and memory. In this study, we adopted a classical Pavlovian fear conditioning model to investigate the involvement of CK2 in remote fear memory extinction and its underlying mechanisms. The results indicated that the activity of CK2 in the medial prefrontal cortex (mPFC) of mice was significantly upregulated after extinction training of remote cued fear memory. Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory. In addition, CX-4945 significantly upregulated the expression of p-ERK1/2 and p-CREB in the mPFC. Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD.

Dorsal hippocampal astrocytes mediate the development of heroin withdrawal-enhanced fear learning.

There is a significant co-occurrence of opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) in clinical populations. However, the neurobiological mechanisms linking chronic opioid use, withdrawal, and the development of PTSD are poorly understood. Our previous research has shown that proinflammatory cytokines, expressed primarily by astrocytes in the dorsal hippocampus (DH), play a role in the development of heroin withdrawal-enhanced fear learning (HW-EFL), an animal model of PTSD-OUD comorbidity. Given the role of astrocytes in memory, fear learning, and opioid use, our experiments aimed to investigate their involvement in HW-EFL. Experiment 1 examined the effect of withdrawal from chronic heroin administration on GFAP surface area and volume, and identified increased surface area and volume of GFAP immunoreactivity in the dentate gyrus (DG) following 24-hour heroin withdrawal. Experiment 2 examined astrocyte morphology and synaptic interactions at the 24-hour withdrawal timepoint using an astroglial membrane-bound GFP (AAV5-GfaABC1D-lck-GFP). Although we did not detect significant changes in surface area and volume of GfaABC1D-Lck-GFP labelled astrocytes, we did observe a significant increase in the colocalization of astrocyte membranes with PSD-95 (postsynaptic density protein 95) in the DG. Experiment 3 tested if stimulating astroglial Gi signaling in the DH alters HW-EFL, and our results demonstrate this manipulation attenuates HW-EFL. Collectively, these findings contribute to our current understanding of the effects of heroin withdrawal on astrocytes and support the involvement of astrocytes in the comorbid relationship between opioid use and anxiety disorders.

The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Hippocampal Trauma Memory Processing Conveying Susceptibility to Traumatic Stress.

While the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted-Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma-related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled. One week later, mice were behaviorally phenotyped to identify mice resilient and susceptible to developing PTSD-like symptomatology. Three weeks post-learning, mice were re-exposed to the conditioning context to induce remote fear memory recall, and associated hippocampal neuronal activity was assessed. While no differences in the size of the hippocampal neuronal ensemble activated during fear learning were observed between groups, susceptible mice displayed a smaller ensemble activated upon remote fear memory recall in the ventral CA1, higher regional hippocampal parvalbuminneuronal density and a relatively lower activity of parvalbumininterneurons upon recall. Investigation of potential epigenetic regulators of the engram revealed rather generic (rather than engram-specific) differences between groups, with susceptible mice displaying lower hippocampal histone deacetylase 2 expression, and higher methylation and hydroxymethylation levels. These finding implicate variation in epigenetic regulation within the hippocampus, as well as reduced regional hippocampal activity during remote fear memory recall in interindividual differences in susceptibility to traumatic stress.

Cilostazol pretreatment prevents PTSD-related anxiety behavior through reduction of hippocampal neuroinflammation.

Current pharmacological treatments against post-traumatic stress disorder (PTSD) lack adequate efficacy. As a result, intense research has focused on identifying other molecular pathways mediating the pathogenesis of this condition. One such pathway is neuroinflammation, which has demonstrated a role in PTSD pathogenesis by causing synaptic dysfunction, neuronal death, and functional impairment in the hippocampus. Phosphodiesterase (PDE) inhibitors (PDEIs) have emerged as promising therapeutic agents against neuroinflammation in other neurological conditions. Furthermore, PDEIs have shown some promise in animal models of PTSD. However, the current model of PTSD pathogenesis, which is based on dysregulated fear learning, implies that PDE inhibition in neurons should enhance the acquisition of fear memory from the traumatic event. As a result, we hypothesized that PDEIs may improve PTSD symptoms through inhibiting neuroinflammation rather than long-term potentiation-related mechanisms. To this end, we tested the therapeutic efficacy of cilostazol, a selective inhibitor of PDE3, on PTSD-related anxiety symptoms in the underwater trauma model of PTSD. PDE3 is expressed much more richly in microglia and astrocytes compared to neurons in the murine brain. Furthermore, we used hippocampal indolamine 2,3-dioxygenase 1 (IDO) expression and interleukin 1 beta (IL-1ß) concentration as indicators of neuroinflammation. We observed that cilostazol pretreatment prevented the development of anxiety symptoms and the increase in hippocampal IDO and IL-1ß following PTSD induction. As a result, PDE3 inhibition ameliorated the neuroinflammatory processes involved in the development of PTSD symptoms. Therefore, cilostazol and other PDEIs may be promising candidates for further investigation as pharmacological therapies against PTSD.

Ketamine alleviates fear memory and spatial cognition deficits in a PTSD rat model via the BDNF signaling pathway of the hippocampus and amygdala.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with traumatic stress experiences. This condition can be accompanied by learning and cognitive deficits. Studies have demonstrated that ketamine can rapidly and significantly alleviate symptoms in patients with chronic PTSD. Nonetheless, the effects of ketamine on neurocognitive impairment and its mechanism of action in PTSD remain unclear. METHODS: In this study, different concentrations of ketamine (5, 10, 15, and 20 mg/kg, i.p.) were evaluated in rat models of single prolonged stress and electrophonic shock (SPS&S). Expression levels of brain-derived neurotrophic factor (BDNF) and post-synaptic density-95 (PSD-95) in the hippocampus (HIP) and amygdala (AMG) were determined by Western blot analysis and immunohistochemistry. RESULTS: The data showed that rats subjected to SPS&S exhibited significant PTSD-like cognitive impairment. The effect of ketamine on SPS&S-induced neurocognitive function showed a U-shaped dose effect in rats. A single administration of ketamine at a dosage of 10-15 mg/kg resulted in significant changes in behavioral outcomes. These manifestations of improvement in cognitive function and molecular changes were reversed at high doses (15-20 mg/kg). CONCLUSION: Overall, ketamine reversed SPS&S-induced fear and spatial memory impairment and the down-regulation of BDNF and BDNF-related PSD-95 signaling in the HIP and AMG. A dose equal to 15 mg/kg rapidly reversed the behavioral and molecular changes and promoted the amelioration of cognitive dysfunction. The enhanced association of BDNF signaling with PSD-95 effects could be involved in the therapeutic efficiency of ketamine for PTSD.

Association between microbiome and the development of adverse posttraumatic neuropsychiatric sequelae after traumatic stress exposure.

Patients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biological mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition after trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether the gut microbiomes of trauma-exposed emergency department patients who develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. We performed metagenomic analysis on stool samples (n = 51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA) study. Two-, eight- and twelve-week post-trauma outcomes for post-traumatic stress disorder (PTSD) (PTSD checklist for DSM-5), normalized depression scores (PROMIS Depression Short Form 8b) and somatic symptom counts were collected. Generalized linear models were created for each outcome using microbial abundances and relevant demographics. Mixed-effect random forest machine learning models were used to identify associations between APNS outcomes and microbial features and encoded metabolic pathways from stool metagenomics. Microbial species, including Flavonifractor plautii, Ruminococcus gnavus and, Bifidobacterium species, which are prevalent commensal gut microbes, were found to be important in predicting worse APNS outcomes from microbial abundance data. Notably, through APNS outcome modeling using microbial metabolic pathways, worse APNS outcomes were highly predicted by decreased L-arginine related pathway genes and increased citrulline and ornithine pathways. Common commensal microbial species are enriched in individuals who develop APNS. More notably, we identified a biological mechanism through which the gut microbiome reduces global arginine bioavailability, a metabolic change that has also been demonstrated in the plasma of patients with PTSD.

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.

A glutamatergic pathway between the medial habenula and the rostral ventrolateral medulla may regulate cardiovascular function in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a serious psychiatric disorder, and there is an association between it and the development of cardiovascular disease. The aim of this study was to explore whether there is a glutamatergic pathway connecting the medial habenula (MHb) with the rostral ventrolateral medulla (RVLM) that is involved in the regulation of cardiovascular function in a rat model of PTSD. Vesicular glutamate transporter 2 (VGLUT2)-positive neurons in the MHb region were retrogradely labeled with FluoroGold (FG) by the double-labeling technique of VGLUT2 immunofluorescence and FG retrograde tracing. Rats belonging to the PTSD model group were microinjected with artificial cerebrospinal fluid (ACSF) or kynurenic acid (KYN; a nonselective glutamate receptor blocker) into their RVLM. Subsequently, with electrical stimulation of MHb, the discharge frequency of the RVLM neurons, heart rate, and blood pressure were found to be significantly increased after microinjection of ACSF using an in vivo multichannel synchronous recording technology; however, this effect was inhibited by injection of KYN. The expression of N-methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits was significantly increased in RVLM of PTSD model rats analyzed by the Western blotting technique. These findings suggest that there may be a glutamatergic pathway connection between MHb and RVLM and that this pathway may be involved in the regulation of cardiovascular function in the PTSD model rats, by acting on NMDA and AMPA receptors in the RVLM.

Decreased mononuclear cell NR3C1 SKA2 and FKPB5 expression levels among adult survivors of suicide bombing terror attacks in childhood are associated with the development of PTSD.

Life threatening trauma and the development of PTSD during childhood, may each associate with transcriptional perturbation of immune cell glucocorticoid reactivity, yet their separable longer term contributions are less clear. The current study compared resting mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, its trans-activator spindle and kinetochore-associated protein 2 (SKA2), and its co-chaperon FKBP prolyl isomerase 5 (FKBP5), between a cohort of young adults first seen at the Hadassah Emergency Department (ED) after surviving a suicide bombing terror attack during childhood, and followed longitudinally over the years, and matched healthy controls not exposed to life threatening trauma. While significant reductions in mononuclear cell gene expression levels were observed among young adults for all three transcripts following early trauma exposure, the development of subsequent PTSD beyond trauma exposure, accounted for a small but significant portion of the variance in each of the three transcripts. Long-term perturbation in the expression of immune cell glucocorticoid response transcripts persists among young adults who develop PTSD following life threatening trauma exposure in childhood, denoting chronic dysregulation of immune stress reactivity.

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-1ß) 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.

The emerging role of the gut microbiome in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) occurs in some people following exposure to a terrifying or catastrophic event involving actual/threatened death, serious injury, or sexual violence. PTSD is a common and debilitating mental disorder that imposes a significant burden on individuals, their families, health services, and society. Moreover, PTSD is a risk factor for chronic diseases such as coronary heart disease, stroke, diabetes, as well as premature mortality. Furthermore, PTSD is associated with dysregulated immune function. Despite the high prevalence of PTSD, the mechanisms underlying its etiology and manifestations remain poorly understood. Compelling evidence indicates that the human gut microbiome, a complex community of microorganisms living in the gastrointestinal tract, plays a crucial role in the development and function of the host nervous system, complex behaviors, and brain circuits. The gut microbiome may contribute to PTSD by influencing inflammation, stress responses, and neurotransmitter signaling, while bidirectional communication between the gut and brain involves mechanisms such as microbial metabolites, immune system activation, and the vagus nerve. In this literature review, we summarize recent findings on the role of the gut microbiome in PTSD in both human and animal studies. We discuss the methodological limitations of existing studies and suggest future research directions to further understand the role of the gut microbiome in PTSD.

Sounds of danger and post-traumatic stress responses in wild rodents: ecological validity of a translational model of post-traumatic stress disorder.

In the wild, animals face a highly variable world full of predators. Most predator attacks are unsuccessful, and the prey survives. According to the conventional perspective, the fear responses elicited by predators are acute and transient in nature. However, the long-term, non-lethal effects of predator exposure on prey behavioral stress sequelae, such as anxiety and post-traumatic symptoms, remain poorly understood. Most experiments on animal models of anxiety-related behavior or post-traumatic stress disorder have been carried out using commercial strains of rats and mice. A fundamental question is whether laboratory rodents appropriately express the behavioral responses of wild species in their natural environment; in other words, whether behavioral responses to stress observed in the laboratory can be generalized to natural behavior. To further elucidate the relative contributions of the natural selection pressures influences, this study investigated the bio-behavioral and morphological effects of auditory predator cues (owl territorial calls) in males and females of three wild rodent species in a laboratory set-up: Acomys cahirinus; Gerbillus henleyi; and Gerbillus gerbillus. Our results indicate that owl territorial calls elicited not only "fight or flight" behavioral responses but caused PTSD-like behavioral responses in wild rodents that have never encountered owls in nature and could cause, in some individuals, enduring physiological and morphological responses that parallel those seen in laboratory rodents or traumatized people. In all rodent species, the PTSD phenotype was characterized by a blunting of fecal cortisol metabolite response early after exposure and by a lower hypothalamic orexin-A level and lower total dendritic length and number in the dentate gyrus granule cells eight days after predator exposure. Phenotypically, this refers to a significant functional impairment that could affect reproduction and survival and thus fitness and population dynamics.

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.

The potential role of GSK-3ß signaling pathway for amelioration actions of ketamine on the PTSD rodent model.

RATIONALE: Post-traumatic stress disorder (PTSD) is a complex, chronic psychiatric disorder typically triggered by life-threatening events and, as yet, lacks a specialized pharmacological treatment. The potential therapeutic role of ketamine, an N-methyl-D-aspartate receptor antagonist, in mitigating PTSD has been the subject of investigation. OBJECTIVE: The aim of this study was to elucidate alterations in the glycogen synthase kinase-3ß (GSK-3ß) signaling pathway in response to ketamine intervention, using the single prolonged stress (SPS) model of PTSD at a molecular level. METHODS: PTSD-like symptoms were simulated using the SPS model. Ketamine (10 mg/kg) and GSK-3ß antagonist SB216763 (5 mg/kg) were then administered intraperitoneally. Stress-related behavior was evaluated through the open field test (OFT) and the elevated plus maze test (EMPT). Additionally, brain activity was analyzed using quantitative electroencephalography (qEEG). Changes in protein and mRNA expressions of glucocorticoid receptor (GR), brain-derived neurotrophic factor (BDNF), GSK-3ß, phosphorylated ser-9 GSK-3ß (p-GSK-3ß), FK506 binding protein 5 (FKBP5), and corticotropin-releasing hormone (CRH) were assessed in the hypothalamus via western blot and qPCR. RESULTS: SPS-exposed rats exhibited reduced distance and time spent in the center of the open arms, a pattern divergent from control rats. qEEG readings revealed SPS-induced increases in alpha power, low gamma and high gamma power. Furthermore, SPS triggered an upregulation in the protein and gene expression of GSK-3ß, GR, BDNF, p-GSK-3ß, and FKBP5, and downregulated CRH expression in the hypothalamus. Ketamine administration following the SPS procedure counteracted these changes by increasing the time spent in the center of the OFT, the distance traversed in the open arms of the EMPT, and mitigating SPS-induced alterations in cerebral cortex oscillations. Moreover, ketamine reduced the protein levels of GSK-3ß, GR, p-GSK-3ß, and altered the ratio of p-GSK-3ß to GSK-3ß. Gene expression of GSK-3ß, GR, BDNF, and FKBP5 decreased in the SPS-Ket group compared to the SPS-Sal group. CONCLUSIONS: Ketamine appeared to remediate the abnormal GSK-3ß signaling pathway induced by SPS. These findings collectively suggest that ketamine could be a promising therapeutic agent for PTSD symptoms, working through the modulation of the GSK-3ß signaling pathway.