Mouse Model Of Posttraumatic Stress Disorder Research Articles

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.

PTSD-like mice display negative cardiac characteristics post-inescapable foot shock

Post-traumatic stress disorder (PTSD) is a risk factor for cardiovascular disease, however the mechanism behind this correlation is unknown. We hypothesized that PTSD alters cardiac homeostasis by increasing macrophage numbers and initiating cardiac fibrosis. To induce experimental PTSD, male and female C57BL/6 mice (4-weeks: n=16-17/sex, males=4.7±0.4 months old; females=4.8±0.3 months old; 8-weeks: n=13-16/sex, males=6.0±0.3 months old; females=6.3±0.5 months old) were exposed to 5 separate foot-shock incidences (IFS; 1.0 mA, 1 sec duration) in 6 min. Control mice (n=8-9/sex) were placed in the same chambers but experienced no foot shocks. Behavioral tests (16 parameters based on the DSM-5 clinical standards) were performed to characterize mice that do not demonstrate PTSD-like behavioral characteristics (NR) and PTSD-like mice. Doppler echocardiography measurements were collected serially up to 8-weeks post-IFS. Histological and gene assessments were collected 4- and 8-weeks post-IFS to measure markers of adverse cardiac remodeling that resulted in later functional changes. Over time PTSD-like mice demonstrated a decline in cardiac function becoming significantly impaired by 8-weeks as shown by an increase in E/e’ ratio along with left atrial diameter compared to controls, indicative of impaired LV filling pressure and diastolic dysfunction (p<0.05 for all). Beginning at 4-weeks post-IFS, PTSD-like mice had increased picrosirius red staining (PSR) compared to control mice (p<0.05) that remained elevated at 8-weeks. PTSD-like mice had increased macrophage numbers (Mac3) at 4-weeks post-IFS compared to control mice (p<0.05) and showed an increased trend when compared to controls 8-weeks post-IFS (p=0.09). To determine potential signaling mechanisms, Ccl2, Ccl5, and discoidin domain receptor tyrosine kinase 2 (DDR2) mRNA levels were assessed. Gene expression of Ccl2 demonstrated a decreased trend in PTSD-like mice (p=0.13), while Ccl5 (p=0.08) and DDR2 (p=0.06) mRNA demonstrated an increased trend in PTSD-like mice when compared to controls. Our data indicates that in a mouse model of PTSD, animals that demonstrate PTSD-like behaviors show signs of increased cardiac inflammation stimulating cardiac remodeling and cardiac dysfunction. This work was supported by the National Institutes of Health T32GM123055; the American Heart Association Innovator Project IPA35260039, GM113278; the Biomedical Laboratory Research and Development Service of the Veterans Affairs Offce of Research and Development Award IK2BX003922, I01BX00584; and South Carolina Translational Research Center UL1TR001450. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

D-Pinitol mitigates post-traumatic stress disorder-like behaviors induced by single prolonged stress in mice through mineralocorticoid receptor antagonism

Post-traumatic stress disorder (PTSD) is a mental illness that can occur in individuals who have experienced trauma. Current treatments for PTSD, typically serotonin reuptake inhibitors, have limited effectiveness for patients and often cause serious adverse effects. Therefore, a novel class of treatment with better pharmacological profile is necessary. D-Pinitol has been reported to be effective for depression and anxiety disorders, but there are no reports associated with PTSD. In the present study, we investigated the effects of D-pinitol in a mouse model of PTSD induced by a single prolonged stress (SPS) protocol. We examined the therapeutic effects of D-pinitol on emotional and cognitive impairments in the SPS mouse model. We also investigated the effects of D-pinitol on fear memory formation. Mineralocorticoid receptor transactivation assay, Western blot, and quantitative PCR were employed to investigate how D-pinitol exerts its pharmacological activities. D-Pinitol ameliorated PTSD-like behaviors in a SPS mouse model. D-Pinitol also normalized the increased mRNA expression levels and protein levels of the mineralocorticoid receptor in the amygdala. A mineralocorticoid receptor agonist reversed the effects of D-pinitol on fear extinction and recall, and the antagonistic property of D-pinitol against the mineralocorticoid receptor was confirmed in vitro. Our findings suggest that D-pinitol could serve as a potential therapeutic agent for PTSD due to its antagonistic effect on the mineralocorticoid receptor.

A computational model for learning from repeated traumatic experiences under uncertainty.

Traumatic events can lead to lifelong, inflexible adaptations in threat perception and behavior, which characterize posttraumatic stress disorder (PTSD). This process involves associations between sensory cues and internal states of threat and then generalization of the threat responses to previously neutral cues. However, most formulations neglect adaptations to threat that are not specific to those associations. To incorporate nonassociative responses to threat, we propose a computational theory of PTSD based on adaptation to the frequency of traumatic events by using a reinforcement learning momentum model. Recent threat prediction errors generate momentum that influences subsequent threat perception in novel contexts. This model fits primary data acquired from a mouse model of PTSD, in which unpredictable footshocks in one context accelerate threat learning in a novel context. The theory is consistent with epidemiological data that show that PTSD incidence increases with the number of traumatic events, as well as the disproportionate impact of early life trauma. Because the theory proposes that PTSD relates to the average of recent threat prediction errors rather than the strength of a specific association, it makes novel predictions for the treatment of PTSD.

Neuropeptide Y potentiates T-Lymphocyte inflammation after psychological trauma

Post-traumatic stress disorder (PTSD) is a psychiatric disorder characterized by severe behavioral alterations, but also demonstrates elevated levels of systemic inflammation, sympathoexcitation, and a potentiated risk for autoimmune and cardiovascular diseases. These physiological changes suggest perturbations to the immune system, however, the signaling mechanisms linking psychological trauma to the immune system are not well understood. Utilizing a pre-clinical mouse model of PTSD known as repeated social defeat stress (RSDS), we previously demonstrated that psychological trauma causes robust T-lymphocyte-driven inflammation in the spleen as evidenced by increased pro-inflammatory cytokine production (primarily interleukin 17A, IL-17A), inflammatory polarization, and enhanced mitochondrial reactive oxygen species. Moreover, targeted denervation of the spleen was able to completely ablate this T-lymphocyte inflammatory response after psychological trauma, suggesting the signal was autonomic and neural in nature. Given that the splenic nerve possesses only sympathetic neurons (no direct parasympathetic innervation), we hypothesized that psychological trauma mediates splenic T-lymphocyte inflammation via enhanced release of sympathetic neurotransmitters. To test this, we first exposed naïve primary T-lymphocytes to various sympathetic catecholamines, including dopamine, norepinephrine, and epinephrine. Contrary to our original hypothesis, we observed no significant changes in IL-17A expression or mitochondria reactive oxygen species. Next, we assessed the physiological response of naïve T-lymphocytes exposed to neuropeptide Y (NPY) given its role in both sympathoexcitation as well as in PTSD. Interestingly, naïve T-lymphocytes treated with NPY also demonstrated no effect, but when NPY was given in combination of norepinephrine, we observed both an increase in IL-17A gene expression (~2 fold) and intracellular redox (~2 fold). To further investigate this effect, we examined NPY levels in our RSDS mouse model over-time. Circulating NPY levels spiked immediately after only one day of RSDS (~4.5 fold, p=0.0317) but steadily declined over the remaining 10 day psychological trauma induction. Intriguingly, NPY levels were strongly correlated with both circulating IL-17A and T-lymphocyte mitochondrial reactive oxygen species levels after RSDS, supporting our in vitro observations. Overall, these data suggest NPY may be playing a critical role in shaping the inflammatory milieu after psychological trauma, which may enhance the likelihood of inflammatory comorbidities. NIH R01HL158521 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Investigations on Rho/ROCK signaling in post-traumatic stress disorder-like behavior in mice

Post-Traumatic Stress Disorder (PTSD) is a chronic condition that occurs in response to a traumatic event, and consequently, enhances the threat sensitivity. Rho/ROCK signaling has been implicated in the consolidation of fear memory, stress, depression, anxiety, and traumatic brain injury. However, its role in post-traumatic stress disorder remains elusive. Therefore, the present study was designed to explore the role of fasudil, a Rho/ROCK inhibitor, a mouse model of PTSD. Mice were subjected to underwater trauma stress followed by three situational reminders. Underwater trauma (UWT) significantly increased the freezing behavior, a marker of the formation of aversive memory, in response to situational reminders on the 3rd, 7th, and 14th days, suggesting the significant development of PTSD. Trauma and situational reminders were also associated with significant changes in behavioral parameters in open field, social interaction and actophotometer tests, along with a reduction in serum corticosterone levels. Fasudil (10 and 15 mg/kg) and sertraline (15 mg/kg), a standard drug for PTSD, significantly decreased the freezing behaviour in response to situational reminders, suggesting the inhibition of the formation of aversive fear memory. However, fasudil and sertraline did not modulate normal memory functions, as assessed on elevated plus maze test, before subjecting mice to traumatic stress. Treatment with fasudil and sertraline significantly restored the behavioral changes and normalized the corticosterone levels. Fasudil-mediated blockade of the Rho/ROCK pathway may be responsible for blocking the formation of aversive memory during the traumatic event, which may be manifested in form of decreased contextual fear response during situational reminders.

Reversal of hyperactive higher-order thalamus attenuates defensiveness in a mouse model of PTSD.

Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating psychiatric disease often accompanied by severe defensive behaviors, preventing individuals from integrating into society. However, the neural mechanisms of defensiveness in PTSD remain largely unknown. Here, we identified that the higher-order thalamus, the posteromedial complex of the thalamus (PoM), was overactivated in a mouse model of PTSD, and suppressing PoM activity alleviated excessive defensive behaviors. Moreover, we found that diminished thalamic inhibition derived from the thalamic reticular nucleus was the major cause of thalamic hyperactivity in PTSD mice. Overloaded thalamic innervation to the downstream cortical area, frontal association cortex, drove abnormal defensiveness. Overall, our study revealed that the malfunction of the higher-order thalamus mediates defensive behaviors and highlighted the thalamocortical circuit as a potential target for treating PTSD-related overreactivity symptoms.

Oxytocin Reduces Sensitized Stress–Induced Alcohol Relapse in a Model of Posttraumatic Stress Disorder and Alcohol Use Disorder Comorbidity

BackgroundThere is high comorbidity of posttraumatic stress disorder (PTSD) and alcohol use disorder with few effective treatment options. Animal models of PTSD have shown increases in alcohol drinking, but effects of stress history on subsequent vulnerability to alcohol relapse have not been examined. Here we present a mouse model of PTSD involving chronic multimodal stress exposure that resulted in long-lasting sensitization to stress-induced alcohol relapse, and this sensitized stress response was blocked by oxytocin (OT) administration. MethodsMale and female mice trained to self-administer alcohol were exposed to predator odor (TMT) + yohimbine over 5 consecutive days or left undisturbed. After reestablishing stable alcohol responding/intake, mice were tested under extinction conditions, and then all mice were exposed to TMT or context cues previously associated with TMT before a reinstatement test session. Separate studies examined messenger RNA expression of Oxt and Oxtr in hypothalamus following chronic stress exposure. A final study examined the effects of systemic administration of OT on stress-induced alcohol relapse in mice with and without a history of chronic stress experience. ResultsChronic stress exposure produced long-lasting sensitization to subsequent stress-induced alcohol relapse that also generalized to stress-related context cues and transcriptional changes in hypothalamic OT system. OT injected before the reinstatement test session completely blocked the sensitized stress–induced alcohol relapse effect. ConclusionsCollectively, these results provide support for the therapeutic potential of OT, along with highlighting the value of utilizing this model in evaluating other pharmacological interventions for treatment of PTSD/alcohol use disorder comorbidity.

Valeriana jatamansi Jones ex Roxb. Against Post-Traumatic Stress Disorder, Network Pharmacological Analysis, and In Vivo Evaluation.

Zhi zhu xiang (ZZX) is the root and rhizome of Valeriana jatamansi Jones ex Roxb. Recent studies have shown that ZZX can exert antianxiety, antidepressant, and sedative effects. Because post-traumatic stress disorder (PTSD) is similar to depression and anxiety in terms of its etiology, pathogenesis, and clinical manifestations, it is possible that ZZX may also be useful for the prevention and treatment of PTSD. In this study, a mouse model of PTSD was established and used to study the pharmacological action of a 95% ethanol extract of ZZX on PTSD via a series of classic behavioral tests. We found that a 95% ethanol extract of ZZX was indeed effective for relieving the symptoms of PTSD in mice. Moreover, network pharmacology analysis was used to predict the potential active ingredients, targets, and possible pathways of ZZX in the treatment of PTSD. The neurotransmitter system, the hypothalamic–pituitary–adrenal (HPA) axis, and the endocannabinoid (eCB) system were identified to be the most likely pathways for anti-PTSD action in ZZX. Due to the lack of a falsification mechanism in network pharmacology, in vivo tests were carried out in mice, and the expression levels of neurotransmitters, hormones, and genes of key targets were detected by enzyme-linked immunosorbent assay and real-time PCR to further verify this inference. Analysis showed that the levels of norepinephrine, 5-hydroxytryptamine, and glutamic acid were increased in the hippocampus, prefrontal cortex, and amygdala of PTSD mice, while the levels of dopamine and γ-aminobutyric acid were decreased in these brain regions; furthermore, ZZX could restore the expression of these factors, at least to a certain extent. The levels of adrenocorticotropic hormone, corticosterone, and corticotropin-releasing hormone were increased in these different brain regions and the serum of PTSD mice; these effects could be reversed by ZZX to a certain extent. The expression levels of cannabinoid receptor 1 and diacylglycerol lipase α mRNA were decreased in PTSD mice, while the levels of fatty acid amide hydrolase and monoacylglycerol lipase mRNA were increased; these effects were restored by ZZX to a certain extent. In conclusion, our findings suggest that ZZX may provide new therapeutic pathways for treating PTSD by the regulation of neurotransmitters, the HPA, and expression levels of eCB-related genes in the brain.

Sex, Pramipexole and Tiagabine Affect Behavioral and Hormonal Response to Traumatic Stress in a Mouse Model of PTSD.

Posttraumatic stress disorder (PTSD) has been associated with abnormal regulation of the hypothalamic-pituitary-adrenal gland axis (HPA). Women demonstrate a more robust HPA response and are twice as likely to develop PTSD than men. The role of sex hormones in PTSD remains unclear. We investigated whether post-trauma chronic treatment with the GABA-ergic agent tiagabine and dopamine-mimetic pramipexole affected the behavioral outcome and plasma levels of corticosterone, testosterone, or 17β-estradiol in female and male mice. These medications were investigated due to their potential capacity to restore GABA-ergic and dopaminergic deficits in PTSD. Animals were exposed to a single prolonged stress procedure (mSPS). Following 13 days treatment with tiagabine (10 mg/kg) or pramipexole (1 mg/kg) once daily, the PTSD-like phenotype was examined in the fear conditioning paradigm. Plasma hormones were measured almost immediately following the conditioned fear assessment. We report that the exposure to mSPS equally enhanced conditioned fear in both sexes. However, while males demonstrated decreased plasma corticosterone, its increase was observed in females. Trauma elevated plasma testosterone in both sexes, but it had no significant effects on 17β-estradiol. Behavioral manifestation of trauma was reduced by pramipexole in both sexes and by tiagabine in females only. While neither compound affected corticosterone in stressed animals, testosterone levels were further enhanced by tiagabine in females. This study shows sex-dependent efficacy of tiagabine but not pramipexole in a mouse model of PTSD-like symptoms and a failure of steroid hormones’ levels to predict PTSD treatment efficacy.

MMP9 mRNA is a potential diagnostic and treatment monitoring marker for PTSD: Evidence from mice and humans

Although matrix metalloproteinase 9 (MMP9) has been found associated with various psychiatric disorders and with threat memories in humans, its role in post-traumatic stress disorder (PTSD) and related animal models is understudied. Thus, we analyzed MMP9 mRNA expression kinetics during two different stress experiments, i.e., the Trier Social Stress Test and the dexamethasone suppression test (DST), in whole blood of two independent cohorts of PTSD patients vs. non-traumatized healthy controls (HC) and, moreover, in a mouse model of PTSD and in dexamethasone-treated mice. Besides MMP9, we quantified mRNA levels of four of its regulators, i.e., interleukin (IL)-1 receptor 1 and 2 (IL1R1, IL1R2), IL-6 receptor and tumor necrosis factor receptor 1 (TNFR1) in 10 patients exposed to the DST before vs. after successful PTSD psychotherapy vs. 13 HC and, except from Il6r, also in different brain regions of the PTSD mouse model. We are the first to show that blood MMP9 mRNA concentrations were elevated after acute dexamethasone in PTSD patients, improved upon partial remission of PTSD and were, furthermore, also elevated, together with its regulator Tnfr1, in the prefrontal cortex of PTSD-like mice. In contrast, blood TNFR1 and IL1R2 were markedly underexpressed in PTSD patients. In conclusion, we found translational evidence supporting that, I, TNFR1 and MMP9 mRNA expression might be involved in PTSD pathobiology, II, might constitute potential diagnostic blood biomarkers for PTSD and, importantly, III, post-dexamethasone blood MMP9 hyperexpression, which speculatively results from post-dexamethasone underexpression of IL1R2, might serve also as potential treatment monitoring biomarker for PTSD.

Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice.

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder occurring in susceptible individuals following a traumatic event. Understanding the mechanisms subserving trauma susceptibility/resilience is essential to develop new effective treatments. Increasing evidence suggests that non-coding RNAs, such as microRNAs (miRNAs), may play a prominent role in mediating trauma susceptibility/resilience. In this study, we evaluated the transcriptional expression of two key PTSD-related genes (FKBP5 and BDNF) and the relative targeting miRNAs (miR-15a-5p, miR-497a-5p, miR-511-5p, let-7d-5p) in brain areas of PTSD-related susceptible and resilient mice identified through our recently developed mouse model of PTSD (arousal-based individual screening (AIS) model). We observed lower transcript levels of miR-15a-5p, miR-497a-5p, and miR-511a-5p in the hippocampus and hypothalamus of susceptible mice compared to resilient mice, suggesting that the expression of these miRNAs could discriminate the two different phenotypes of stress-exposed mice. These miRNA variations could contribute, individually or synergically, to the inversely correlated transcript levels of FKBP5 and BDNF. Conversely, in the medial prefrontal cortex, downregulation of miR-15a-5p, miR-511-5p, and let-7d-5p was observed both in susceptible and resilient mice, and not accompanied by changes in their mRNA targets. Furthermore, miRNA expression in the different brain areas correlated to stress-induced behavioral scores (arousal score, avoidance-like score, social memory score and PTSD-like score), suggesting a linear connection between miRNA-based epigenetic modulation and stress-induced phenotypes. Pathway analysis of a miRNA network showed a statistically significant enrichment of molecular processes related to PTSD and stress. In conclusion, our results indicate that PTSD susceptibility/resilience might be shaped by brain-area-dependent modulation of miRNAs targeting FKBP5, BDNF, and other stress-related genes.

Anti-PTSD Effects of Hypidone Hydrochloride (YL-0919): A Novel Combined Selective 5-HT Reuptake Inhibitor/5-HT1A Receptor Partial Agonist/5-HT6 Receptor Full Agonist.

Posttraumatic stress disorder (PTSD) is a debilitating trauma and stressor-related disorder that has become a major neuropsychiatric problem, leading to substantial disruptions in individual health and societal costs. Our previous studies have demonstrated that hypidone hydrochloride (YL-0919), a novel combined selective 5-HT reuptake inhibitor/5-HT1A receptor partial agonist/5-HT6 receptor full agonist, exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 exerts anti-PTSD effects and its underlying mechanisms are still unclear. In the present study, we showed that repeated treatment with YL-0919 caused significant suppression of contextual fear, enhanced anxiety and cognitive dysfunction induced by the time-dependent sensitization (TDS) procedure in rats and by inescapable electric foot-shock in a mouse model of PTSD. Furthermore, we found that repeated treatment with YL-0919 significantly reversed the accompanying decreased expression of the brain-derived neurotrophic factor (BDNF) and the synaptic proteins (synapsin1 and GluA1), and ameliorated the neuroplasticity disruption in the prefrontal cortex (PFC), including the dendritic complexity and spine density of pyramidal neurons. Taken together, the current study indicated that YL-0919 exerts clear anti-PTSD effects, which might be partially mediated by ameliorating the structural neuroplasticity by increasing the expression of BDNF and the formation of synaptic proteins in the PFC.

Neuroimmune Contributions to T‐lymphocyte‐Driven Inflammation in a Preclinical Model of Post‐traumatic Stress Disorder (PTSD)

Post‐traumatic stress disorder (PTSD) is a devastating psychological disorder with an idiopathic etiology. Interestingly, patients with PTSD have a >3 fold risk of developing comorbid autoimmune diseases compared to matched controls, yet, the exact mechanisms underlying this risk remain unclear. A hallmark of PTSD is increased sympathetic tone, and previous work from our lab has shown that immune cells, primarily T‐lymphocytes, display an autoreactive phenotype when exposed to elevated levels of norepinephrine (NE). Therefore, we hypothesized that the sympathoexcitation observed in PTSD may be causally linked to T‐lymphocyte‐driven inflammation and the predisposition to autoimmune diseases. To test this hypothesis, we adapted a preclinical mouse model of PTSD known as social defeat stress. After validating the PTSD‐like behavioral phenotype of our trauma‐exposed mice, we investigated the neuroimmune interactions of T‐lymphocytes in the spleen that may govern the increased predilection for inflammatory diseases in PTSD patients. The spleen is a primary site of adaptive immune system activation, and is innervated exclusively by the sympathetic efferent splenic nerve. Trauma‐exposed animals exhibited a 2.5 fold increase in splenic catecholamines and 4.1 fold increase in splenic tyrosine hydroxylase (TH) content (p<0.05) compared to controls. Additionally, purified splenic T‐lymphocytes from socially‐defeated mice showed elevations in the pro‐inflammatory cytokines interleukin 6 (IL‐6, 1.84 fold increase, p<0.0001) and interleukin 17A (IL‐17A, 5.5 fold increase, p=0.0032). Importantly, TH content was tightly correlated with T‐lymphocyte IL‐6 and IL‐17A expression (R=0.43, p=0.0001 and R=0.87, p<0.0001, respectively), suggesting a neuroimmune mechanism of pro‐inflammation. To test this, we performed targeted splenic denervation to deduce the contribution of the splenic nerve to T‐lymphocyte‐driven inflammation after psychological trauma. Denervation reduced splenic NE content by 80% (p<0.0001), and persisted to at least 30 days after denervation. While splenic denervation did not alter the PTSD‐like behavioral changes after social defeat, denervation ameliorated the characteristic increase in gene expression of splenic T‐lymphocyte IL‐6 and IL‐17A after social defeat stress. Overall, our data suggest that psychological trauma results in altered inflammation through sympathetic modulation of splenic T‐lymphocytes. Further elucidation of this neuroimmune interaction will provide possible new biomarkers or therapeutic strategies to reduce the inflammatory‐driven morbidity and mortality of PTSD patients.Support or Funding InformationNIH R00HL123471, T32NS105594

Efficacy of rTMS in a mouse model of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is associated with brain changes that commonly involve the fear network including the prefrontal cortex (PFC), hippocampus and amygdala. Neurostimulation can been recommended as an adjunct to psychotherapy in order to facilitate extinction of fear in PTSD. Repetitive transcranial magnetic stimulation (rTMS) can thus target the PFC to provide promising treatment responses. However, preclinical rodent-based studies need to be performed to enhance the comprehension and empirical-driven efficacy of rTMS. We used a focal 40-mm coil to apply a high frequency/intensity rTMS pattern (5 daily sessions) to the ventromedial PFC (vmPFC) in a mouse model of PTSD. This procedure was assessed against fluoxetine (SSRI treatment). Through spatially precise stereotaxic framing, one session of rTMS (750 pulses) was able to focally increase c-Fos functional maps in the vmPFC immediately after stimulation. When used as a chronic treatment (5 daily sessions for 3750 pulses) in a foot-shock PTSD model, rTMS counteracted PTSD-related behavioural deficit in the object recognition task 6 days after the last treatment session and enhanced extinction dynamics in a reexposure task (4 days afterward) compared to sham treatment. Reexposure-associated c-Fos activity was found increased in the infralimbic cortex, the basolateral amygdala and the CA1 of ventral hippocampus of mice exposed to the trauma and treated with rTMS. In conclusion, chronic rTMS treatment reversed PTSD-induced impairments by acting on distributed networks of fear neurocircuitry that self-sustained 10 days post-treatment in the infralimbic cortex, the basolateral amygdala and the ventral CA1.

Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD

Few animal models exist that successfully reproduce several core associative and non-associative behaviours relevant to post-traumatic stress disorder (PTSD), such as long-lasting fear reactions, hyperarousal, and subtle attentional and cognitive dysfunction. As such, these models may lack the face validity required to adequately model pathophysiological features of PTSD such as CNS grey matter loss and neuroinflammation. Here we aimed to investigate in a mouse model of PTSD whether contextual fear conditioning associated with a relatively high intensity footshock exposure induces loss of neuronal dendritic spines in various corticolimbic brain regions, as their regression may help explain grey matter reductions in PTSD patients. Further, we aimed to observe whether these changes were accompanied by alterations in microglial cell number and morphology, and increased expression of complement factors implicated in the mediation of microglial cell-mediated engulfment of dendritic spines. Adult male C57Bl6J mice were exposed to a single electric footshock and subsequently underwent phenotyping of various PTSD-relevant behaviours in the short (day 2–4) and longer-term (day 29–31). 32 days post-exposure the brains of these animals were subjected to Golgi staining of dendritic spines, microglial cell Iba-1 immunohistochemistry and immunofluorescent staining of the complement factors C1q and C4. Shock exposure promoted a lasting contextual fear response, decreased locomotor activity, exaggerated acoustic startle responses indicative of hyperarousal, and a short-term facilitation of sensorimotor gating function. The shock triggered loss of dendritic spines on pyramidal neurons was accompanied by increased microglial cell number and complexity in the medial prefrontal cortex and dorsal hippocampus, but not in the amygdala. Shock also increased expression of C1q in the pyramidal layer of the CA1 region of the hippocampus but not in other brain regions. The present study further elaborates on the face and construct validity of a mouse model of PTSD and provides a good foundation to explore potential molecular interactions between microglia and dendritic spines.

Dopamine D2/D3 receptor agonists attenuate PTSD-like symptoms in mice exposed to single prolonged stress

Medications that enhance dopaminergic neurotransmission can be useful in the pharmacotherapy of posttraumatic stress disorder (PTSD), which manifests as fearful memory retrieval, anxiety and depression. We examined the effects of subchronic (15 days) treatment with select dopaminergic medications, including bromocriptine, modafinil, dihydrexidine, rotigotine and pramipexole, in a mouse model of PTSD induced by single prolonged stress (mSPS). The potential antidepressant-like and anxiolytic effects of the medications were measured by the forced swim test (FST) and the elevated plus maze (EPM) test, respectively. In addition, we studied the effects of these medications on memory retrieval in an auditory fear conditioning (FC) test, on ultrasonic vocalizations (USVs) induced by restraint stress, and on spontaneous locomotor activity (SLA). We report that a single exposure to a severe and complex set of stressors several days before testing increased immobility time in the FST and freezing in the FC paradigm and reduced the time spent in the open arms of the EPM. The stressed mice also displayed increased USVs, especially the short type. While none of the tested dopamine-mimetics exhibited anxiolytic-like effects, rotigotine produced antidepressant-like activity specifically in the mSPS-exposed animals. Moreover, both rotigotine and pramipexole shortened the duration of freezing in the fear conditioning test, but only in the mSPS-exposed mice. This study supports the hypothesis that the activation of dopaminergic D2/D3 receptors may be a promising pharmacotherapy for PTSD.

Comparing Perika St. John’s Wort and Sertraline for Treatment of Posttraumatic Stress Disorder in Mice

Posttraumatic stress disorder (PTSD) is a serious mental health condition that affects some individuals who have witnessed or experienced a life-threatening or traumatic event. An enhanced or exaggerated acoustic startle response (ASR), reflecting heightened sensitivity to unexpected, loud sound, is a hallmark symptom of PTSD. Antidepressant medications, such as sertraline, are first-line pharmacotherapeutic agents in the treatment of PTSD, but concerns about potential side effects or taking synthetic drugs prompt discovery of naturalistic therapeutic agents. This study examined the relative effectiveness of a compound containing St. John’s Wort (SJW), an herb widely prescribed for depression in Europe and sold as a dietary supplement in the United States, compared to sertraline (Zoloft) in a mouse model of PTSD. Thirty-six mice were tested for baseline ASR, then they were exposed to rats in a predator exposure paradigm known to induce PTSD-like symptoms. Mice were randomly divided into three groups for treatment (control, sertraline, SJW), and ASR was retested one week later. One-way ANOVAs found no significant group differences in ASR amplitude at baseline but a significant effect of Treatment Group after predator exposure, F(2, 33) = 5.645, p = .008, n2 = .225, when SJW-treated mice had ASR amplitudes that were significantly lower than sertraline-treated mice (by 27%) and controls (by 26%). Fecal boli counts showed a similar pattern, with lowest counts in SJW-treated mice. These results suggest SJW could be considered for studies of PTSD treatment in humans as well.

The 18 kDa Translocator Protein (TSPO) Overexpression in Hippocampal Dentate Gyrus Elicits Anxiolytic-Like Effects in a Mouse Model of Post-traumatic Stress Disorder.

The translocator protein (18 kDa) (TSPO) recently attracted increasing attention in the pathogenesis of post-traumatic stress disorder (PTSD). This study is testing the hypothesis that the overexpression of TSPO in hippocampus dentate gyrus (DG) could alleviate the anxiogenic-like response in the mice model of PTSD induced by foot-shock. In this study, hippocampal DG overexpression of TSPO significantly reversed the increase of the contextual freezing response, the decrease of the percentage of both entries into and time spent in the open arms in elevated plus maze test and the decrease of the account of crossings from the dark to light compartments in light–dark transition test induced by electric foot-shocks procedure. It was further showed that the behavioral effects of TSPO overexpression were blocked by PK11195, a selective TSPO antagonist. In addition, the expression of TSPO and level of allopregnanolone (Allo) decreased in the mouse model of PTSD, which was blocked by overexpression of TSPO in hippocampal dentate gyrus. The difference of neurogenesis among groups was consistent with the changes of TSPO and Allo, as evidenced by bromodeoxyuridine (BrdU)- positive cells in the hippocampal dentate gyrus. These results firstly suggested that TSPO in hippocampal dentate gyrus could exert a great effect on the occurrence and recovery of PTSD in this animal model, and the anti-PTSD-like effect of hippocampal TSPO over-expression could be at least partially mediated by up-regulation of Allo and subsequent stimulation of the adult hippocampal neurogenesis.

Inhibition of iNOS ameliorates traumatic stress-induced deficits in synaptic plasticity and memory

Post-traumatic stress disorder (PTSD) is characterized by cognitive deficits including impaired explicit memory. Nitric oxide (NO), which is generated by nitric oxide synthase (NOS), has been considered to modulate learning and memory. In current study, we evaluated the role of NOS in the mouse model of PTSD. We established the immobilization (IMO) mouse model of PTSD and analyzed mice behavior, NOS expression and hippocampal excitatory synaptic transmission after immobilization. We inhibited iNOS by applying of iNOS inhibitor 1400 W and monitored the effect of iNOS inhibition by 1400 W in IMO mice. IMO induced iNOS expression and resulted in abnormal behavior and deficits in synaptic plasticity and memory in mice. Inhibition of iNOS rescued abnormal hippocampal long-term potentiation and abnormal behavior in IMO mice. Inhibition of iNOS ameliorates traumatic stress-induced deficits in synaptic plasticity and memory.