Animal Model Of Post-traumatic Stress Disorder Research Articles

The Psychoactive Agent Crocin Can Regulate Hypothalamic-Pituitary-Adrenal Axis Activity.

Post-traumatic stress disorder (PTSD) occurs following life-threatening events. The activity of the hypothalamic-pituitary-adrenal (HPA) axis, which serves as the first line of defense against stress, is dysfunctional in this disorder. The current study aimed to investigate the role of Crocin in normalizing HPA function in an animal model of PTSD induced by electric foot shock. Rats were treated with Crocin 5 min prior to stress induction. The stimulus was re-introduced after 21 days, and we measured individual behaviors such as sniffing, rearing, grooming, and freezing. Enzyme-linked immunosorbent assays were performed to measure plasma levels of Corticosterone. On day 28, after rats were weighed and sacrificed, the adrenal and thymus glands were removed and subjected to real-time polymerase chain reaction to quantify the gene expression of corticotrophin-releasing hormone (CRH), glucocorticoid receptor (GluR), and arginine vasopressin (AVP). Our results demonstrate that rats re-exposed to a stressor developed characteristic symptoms of PTSD, but these were attenuated by Crocin. Treated rats showed significant changes in CRH expression in the hypothalamus, GluR expression in the pituitary, plasma Corticosterone levels, and freezing behavior. Together, these findings suggest that Crocin can regulate HPA axis activity in PTSD. It may serve an appropriate treatment for subjects who experience a traumatic event.

A Systematic Review of Tumor Necrosis Factor-α in Post-Traumatic Stress Disorder: Evidence from Human and Animal Studies.

Growing evidence suggests a pathophysiological role of cytokines in post-traumatic stress disorder (PTSD). Tumor necrosis factor (TNF)-α is a key cytokine. Therefore, we performed a systematic review to examine the findings regarding TNF-α derived from both animal and human studies of PTSD. Using PRISMA guidelines, we reviewed relevant articles in PubMed from inception until 11th April 2017. Human studies that reported group comparisons and/or longitudinal investigations of TNF-α production/concentration were included. Research reporting on TNF-α levels in animal models of PTSD were also included. Twenty-seven articles were identified. Data from human cross-sectional studies suggests that plasma/serum levels of TNF-α are elevated in those with PTSD, as compared to healthy controls. Longitudinal assessments of TNF-α are limited and data are mixed. Limited data from animal studies suggest an increased TNF-α production in the hippocampus of rats following stress, which can be reversed by immunomodulatory drugs. Our findings suggest TNF-α may be a potential biomarker and treatment target for PTSD. Findings need to be considered in light of heterogeneous methods for measurement and analysis of TNF-α concentration. Longitudinal research is needed to understand the role of TNF-α in the development and/or maintenance of PTSD.

Posttraumatic Stress Disorder: An Immunological Disorder?

Patients with posttraumatic stress disorder (PTSD) exhibit an increased state of inflammation. Various animal models for PTSD have shown some of the same immune imbalances as have been shown in human subjects with PTSD, and some of these studies are discussed in this review. However, animal studies can only indirectly implicate immune involvement in PTSD in humans. This review of mainly studies with human subjects focuses on dissecting the immunological role in the pathogenesis of PTSD following initial trauma exposure. It addresses both the inflammatory state associated with PTSD and the immune imbalance between stimulatory and inhibitory immune mediators, as well as variables that can lead to discrepancies between analyses. The concept of immunological treatment approaches is proposed for PTSD, as new treatments are needed for this devastating disorder that is affecting unprecedented numbers of Veterans from the long-standing wars in the Middle East and which affects civilians following severe trauma.

Effects of systemic glutamatergic manipulations on conditioned eyeblink responses and hyperarousal in a rabbit model of post-traumatic stress disorder.

Glutamatergic dysfunction is implicated in many neuropsychiatric conditions, including post-traumatic stress disorder (PTSD). Glutamate antagonists have shown some utility in treating PTSD symptoms, whereas glutamate agonists may facilitate cognitive behavioral therapy outcomes. We have developed an animal model of PTSD, based on conditioning of the rabbit's eyeblink response, that addresses two key features: conditioned responses (CRs) to cues associated with an aversive event and a form of conditioned hyperarousal referred to as conditioning-specific reflex modification (CRM). The optimal treatment to reduce both CRs and CRM is unpaired extinction. The goals of the study were to examine whether treatment with the N-methyl-D-aspartate glutamate receptor antagonist ketamine could reduce CRs and CRM, and whether the N-methyl-D-aspartate agonist D-cycloserine combined with unpaired extinction treatment could enhance the extinction of both. Administration of a single dose of subanesthetic ketamine had no significant immediate or delayed effect on CRs or CRM. Combining D-cycloserine with a single day of unpaired extinction facilitated extinction of CRs in the short term while having no impact on CRM. These results caution that treatments may improve one aspect of the PTSD symptomology while having no significant effects on other symptoms, stressing the importance of a multiple-treatment approach to PTSD and of animal models that address multiple symptoms.

Effect of oleuropein on cognitive deficits and changes in hippocampal brain-derived neurotrophic factor and cytokine expression in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. This psychopathological response to traumatic stressors induces learning and memory deficits in rats. Oleuropein (OLE), a major compound in olive leaves, has been reported to possess several pharmacological properties, including anti-cancer, anti-diabetic, anti-atherosclerotic and neuroprotective activities. However, the cognitive effects of OLE and its mechanism of action have remained unclear in PTSD. In this study, we examined whether OLE improved spatial cognitive impairment induced in rats following single prolonged stress (SPS), an animal model of PTSD. Male rats were treated intraperitoneally (i.p.) with vehicle or various doses of OLE for 14 consecutive days after the SPS procedure. The SPS procedure resulted in cognitive impairment in the object recognition task and the Morris water maze test, which was reversed by OLE (100mg/kg, i.p). Additionally, as assessed by immunohistochemistry and reverse transcription-polymerase chain reaction analysis, the administration of OLE significantly alleviated memory-associated decreases in the levels of brain-derived neurotrophic factor and cAMP response element-binding protein and mRNA in the hippocampus. Together, these findings suggest that OLE attenuated SPS-induced cognitive impairment significantly by inhibiting the expression of pro-inflammatory mediators in the rat brain. Thus, OLE reversed several behavioral impairments triggered by the traumatic stress of SPS and might be a potential useful therapeutic intervention for PTSD.

Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats

Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD.

The role of microRNAs in the therapeutic action of D-cycloserine in a post-traumatic stress disorder animal model: an exploratory study.

Post-traumatic stress disorder is characterized by impaired fear extinction and excessive anxiety. D-Cycloserine (DCS) has previously been shown to facilitate fear extinction and decrease anxiety in animal and human studies. This study utilized a contextual fear-conditioning animal model to investigate the involvement of microRNAs (miRNAs) in fear extinction and the reduction of anxiety, as mediated by the co-administration of DCS and behavioural fear extinction. Fear conditioning consisted of an electric foot shock; fear extinction consisted of behavioural fear extinction co-administered with either DCS or saline. The light/dark avoidance test was used to evaluate anxiety-related behaviour subsequent to fear conditioning and was used to evaluate anxiety-related behaviour following fear conditioning and to subsequently group animals into well-adapted and maladapted subgroups. These subgroups also showed significant differences in terms of fear extinction. Small RNAs extracted from the left dorsal hippocampus were sequenced using next-generation sequencing to identify differentially expressed miRNAs associated with DCS-induced fear extinction and reduction of anxiety. In-silico prediction analyses identified mRNA targets (from data of the same animals) of the differentially expressed miRNAs. Two of the predicted mRNA-miRNA interactions were functionally investigated. Overall, 32 miRNAs were differentially expressed between rats that were fear conditioned, received DCS and were well adapted and rats that were fear conditioned, received saline and were maladapted. Nineteen of these miRNAs were predicted to target and regulate the expression of 63 genes differentially expressed between fear-conditioned, DCS-administered, well-adapted and fear-conditioned, saline-administered, and maladapted groups (several of which are associated with neuronal inflammation, learning and memory). Functional luciferase assays indicated that rno-mir-31a-5p may have regulated the expression of interleukin 1 receptor antagonist (Il1rn) and metallothionein 1a (Mt1a). These differentially expressed miRNAs may be mediators of gene expression changes that facilitated decreased neuronal inflammation, optimum learning and memory and contributed towards effective fear extinction and reduction of anxiety following the co-administration of DCS and behavioural fear extinction.

A perspective on the contribution of animal models to the pharmacological treatment of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a prevalent, chronic, disabling disorder that may develop following exposure to a traumatic event. This review summarizes currently used animal models of PTSD and their potential role in the development of better therapeutics. Heterogeneity is one of the main characteristics of PTSD with the consequence that many pharmacological approaches are used to relieve symptoms of PTSD. To address the translational properties of the animal models, we discuss the types of stressors used, the rodent correlates of human PTSD (DSM-5) symptoms, and the efficacy of approved, recommended and off-label drugs used to treat PTSD in 'PTSD-animals'. Currently available animal models reproduce most PTSD symptoms and are validated by existing therapeutics. However, novel therapeutics are needed for this disorder as not one drug alleviates all symptoms and many have side effects that lead to non-compliance among PTSD patients. The true translational power of animal models of PTSD will only be demonstrated when new therapeutics acting through novel mechanisms become available for clinical practice.

Single-Prolonged-Stress-Induced Changes in Autophagy-Related Proteins Beclin-1, LC3, and p62 in the Medial Prefrontal Cortex of Rats with Post-traumatic Stress Disorder

Autophagy, or type II programmed cell death, plays a crucial role in many nervous system diseases. However, few studies have examined the role of autophagy in post-traumatic stress disorder (PTSD), and the mechanisms underlying PTSD are poorly understood. The objective of this research was to explore the expression of three important autophagy-related proteins, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), and p62/SQSTM1 (p62), in the medial prefrontal cortex (mPFC) of an animal model of PTSD to identify changes in autophagic activity during PTSD pathogenesis. PTSD was induced in rats by exposure to a single-prolonged stress (SPS). The Morris water maze was used to assess cognitive changes in rats from the SPS and control groups. Transmission electron microscopy (TEM) was employed to observe mPFC morphological changes. Immunohistochemistry, immunofluorescence, and Western blotting techniques were used to detect expression of Beclin-1, LC3, and p62 in the mPFC. The Morris water maze test results showed that the escape latency time was increased and that the percent time in the target quadrant was decreased in the SPS group compared with that in the control group. Numerous visible autolysosomes in mPFC neurons were observed using TEM after SPS stimulation. Compared with that in the control group, the expression of Beclin-1 and the LC3-II/I ratio significantly decreased at 1day, then increased and peaked at 7days, and slightly decreased at 14days after SPS stimulation, whereas the converse was found for p62 expression. In conclusion, dysregulation of autophagic activity in the mPFC may play a crucial role in PTSD pathogenesis.

Animal Models of PTSD: A Critical Review.

The goals of animal research in post-traumatic stress disorder (PTSD) include better understanding the neurophysiological etiology of PTSD, identifying potential targets for novel pharmacotherapies, and screening drugs for their potential use as PTSD treatment in humans. Diagnosis of PTSD relies on a patient interview and, as evidenced by changes to the diagnostic criteria in the DSM-5, an adequate description of this disorder in humans is a moving target. Therefore, it may seem insurmountable to model the construct of PTSD in animals such as rodents. Fortunately, the neural circuitry involved in fear and anxiety, thought to be essential to the etiology of PTSD in humans, is highly conserved throughout evolution. Furthermore, many symptoms can be modeled using behavioral tests that have face, construct, and predictive validity. Because PTSD is precipitated by a definite traumatic experience, animal models can simulate the induction of PTSD, and test causal factors with longitudinal designs. Accordingly, several animal models of physical and psychological trauma have been established. This review discusses the widely used animal models of PTSD in rodents, and overviews their strengths and weaknesses in terms of face, construct, and predictive validity.

Stimulation of Anxiety-Like Behavior via ERK Pathway by Competitive Serotonin Receptors 2A and 1A in Post-Traumatic Stress Disordered Mice

Background/Aims: Serotonin 5HT2A and 5HT1A receptors (5HT2AR, 5HT1AR) have the closest connection to anxiety-like behavior in post-traumatic stress disorder (PTSD). However, the underlying mechanism remains unclear. In this study, we explored the connection between 5HT2A and 5HT1A receptors and anxiety-like behavior. Methods: In the PTSD animal model, mice were exposed to conditioned fear stress coupled with single-prolonged stress (CF+SPS). Post stress infliction and behavioral tests, of which include open field, freezing behavior and elevated plus maze tests were carried out to examine establishment of the proposed model. Both Western blot analysis and immunofluorescence labeling were used to evaluate protein expressions of 5HT2AR, 5HT1AR, ERK1, ERK2 and c-Myc in the hippocampi of the mice and RT Q-PCR was employed for evaluation of the relative mRNA expressions. Results: Based on the model established utilizing the CF+SPS procedure, we found 5HT2AR to play a positive role on anxiety-like behavior by inhibiting the expression of 5HT1AR. In addition, the ERK-c-Myc pathway elicited the effect of 5HT2AR and 5HT1AR on anxiety-like behavior in PTSD, 5-HT enhanced the anxiety-like behavior through both 5HT2AR and 5HT1AR. Conclusion: These findings suggest competive interaction between 5HT2AR and 5HT1AR actively affects anxiety-like behavior in the hippocampi of PTSD mice via the ERK pathway.

Distinctive hippocampal zinc distribution patterns following stress exposure in an animal model of PTSD.

Emerging evidence suggests that zinc (Zn) deficiency is associated with depression and anxiety in both human and animal studies. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of Zn distribution. The work has focused on one case study, the association between an animal model of posttraumatic stress disorder (PTSD) and the Zn distribution in the rat hippocampus. Behaviors were assessed with the elevated plus-maze and acoustic startle response tests 7 days later. Preset cut-off criteria classified exposed animals according to their individual behavioral responses. To further characterize the distribution of Zn that occurs in the hippocampus 8 days after the exposure, laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging was used. It has been found that Zn distribution in the dentate gyrus (DG) sub-region in the hippocampus is clearly more widely spread for rats that belong to the extreme behavioral response (EBR) group as compared to the control group. Comparison of the Zn concentration changes in the cornu ammonis 1 (CA1) and the DG sub-regions of the hippocampus shows that the concentration changes are statistically significantly higher in the EBR rats compared to the rats in the control and minimal behavioral response (MBR) groups. In order to understand the mechanism of stress-induced hippocampal Zn dyshomeostasis, relative quantitative analyses of metallothionein (MT), B-cell lymphoma 2 (Bcl-2) and caspase 3 immunoreactivity were performed. Significant differences in the number of caspase-ir and Bcl-2 cells were found in the hippocampal DG sub-region between the EBR group and the control and MBR groups. The results of this study demonstrate a statistically significant association between the degree of behavioral disruption resulting from stress exposure and the patterns of Zn distribution and concentration changes in the various hippocampal regions. Taken together, these findings indicate that Zn distribution patterns play an active role in the neurobiological response to predator scent stress.

The wake-promoting drug modafinil stimulates specific hypothalamic circuits to promote adaptive stress responses in an animal model of PTSD.

Pharmacotherapeutic intervention during traumatic memory consolidation has been suggested to alleviate or even prevent the development of posttraumatic stress disorder (PTSD). We recently reported that, in a controlled, prospective animal model, depriving rats of sleep following stress exposure prevents the development of a PTSD-like phenotype. Here, we report that administering the wake-promoting drug modafinil to rats in the aftermath of a stressogenic experience has a similar prophylactic effect, as it significantly reduces the prevalence of PTSD-like phenotype. Moreover, we show that the therapeutic value of modafinil appears to stem from its ability to stimulate a specific circuit within the hypothalamus, which ties together the neuropeptide Y, the orexin system and the HPA axis, to promote adaptive stress responses. The study not only confirms the value of sleep prevention and identifies the mechanism of action of a potential prophylactic treatment after traumatic exposure, but also contributes to understanding mechanisms underlying the shift towards adaptive behavioral response.

Exploring a post-traumatic stress disorder paradigm in Flinders sensitive line rats to model treatment-resistant depression I: bio-behavioural validation and response to imipramine.

Co-morbid depression with post-traumatic stress disorder (PTSD) is often treatment resistant. In developing a preclinical model of treatment-resistant depression (TRD), we combined animal models of depression and PTSD to produce an animal with more severe as well as treatment-resistant depressive-like behaviours. Male Flinders sensitive line (FSL) rats, a genetic animal model of depression, were exposed to a stress re-stress model of PTSD [time-dependent sensitisation (TDS)] and compared with stress-naive controls. Seven days after TDS stress, depressive-like and coping behaviours as well as hippocampal and cortical noradrenaline (NA) and 5-hydroxyindoleacetic acid (5HIAA) levels were analysed. Response to sub-chronic imipramine treatment (IMI; 10 mg/kg s.c.×7 days) was subsequently studied. FSL rats demonstrated bio-behavioural characteristics of depression. Exposure to TDS stress in FSL rats correlated negatively with weight gain, while demonstrating reduced swimming behaviour and increased immobility versus unstressed FSL rats. IMI significantly reversed depressive-like (immobility) behaviour and enhanced active coping behaviour (swimming and climbing) in FSL rats. The latter was significantly attenuated in FSL rats exposed to TDS versus unstressed FSL rats. IMI reversed reduced 5HIAA levels in unstressed FSL rats, whereas exposure to TDS negated this effect. Lowered NA levels in FSL rats were sustained after TDS with IMI significantly reversing this in the hippocampus. Combining a gene-X-environment model of depression with a PTSD paradigm produces exaggerated depressive-like symptoms that display an attenuated response to antidepressant treatment. This work confirms combining FSL rats with TDS exposure as a putative animal model of TRD.

Sensitivity to trauma-associated cues is restricted to vulnerable traumatized rats and reinstated after extinction by yohimbine

While post-traumatic stress disorder (PTSD) symptom is mainly characterized by re-experiencing the traumatic event, the reactivity to trauma-associated cues in resilient and vulnerable subjects has not been extensively studied. Using an animal model of PTSD induced by a single prolonged stress (SPS), the responses of traumatized Vulnerable and Resilient rats to PTSD-like symptom tests and to trauma-associated cues were investigated. In addition, the implication of the noradrenergic system in “re-experiencing” was explored. Rats received either a SPS, combining a 2h restraint stress, a 20min forced-swim followed by a 15min rest, and a loss of consciousness produced by inhaling CO2 emissions, delivered in the presence of particular cues (tone and odor), or a control procedure. PTSD-like symptoms and reactivity to various trauma-associated cues (specific, contextual, or predictive) were tested from D15 to D60 after the SPS. Rats were then divided into Resilient and Vulnerable on the basis of three main symptom tests, including the elevated plus maze, the light-dark and the acoustic startle response tests. Although Resilient rats behaved like Controls rats, Vulnerable rats developed long-term PTSD-like symptoms on the main symptoms tests (anxiety and alteration of arousal), as well as other PTSD-like outcomes (such as anhedonia and avoidance to trauma-associated cues). These Vulnerable rats were also the only ones to demonstrate strong reactivity to trauma-associated cues. In addition, the alpha-2 adrenergic receptor antagonist, Yohimbine (i.p., 1.5mg/kg/ml), was able to reinstate fear responses to an extinguished trauma-associated odor. Our results established clear relationships between Vulnerability to trauma and reactivity to trauma-associated cues and further suggest an involvement of the noradrenergic system.

PTSD, a Disorder with an Immunological Component.

Post-traumatic stress disorder (PTSD) has been associated with an inflammatory state. However, few studies have addressed the mechanisms underlying this immune imbalance that favors inflammation or how this imbalance contributes to PTSD. Whether the immune imbalance influences responsiveness or unresponsiveness of patients to PTSD treatments is currently not known. This review brings forward an immune emphasis to a mental health disorder that is unprecedented in its prevalence among combat Veterans of the ongoing conflicts in Iraq and Afghanistan and which also afflicts civilians who have undergone extreme traumatic experiences, such as following natural disasters, serious accidents, or assaults. Included is an overview of the correlative associations in human subjects between PTSD and inflammation and studies in animal models of PTSD, demonstrating causal contributions of inflammation and immune dysregulation to PTSD-like behavior following stress exposure.

Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats

Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.

Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of PTSD

Increased activity of the noradrenergic system in the amygdala has been suggested to contribute to the hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two studies have examined the content of noradrenaline or its metabolites in the amygdala of rats previously exposed to traumatic stress showing inconsistent results. The aim of this study was to investigate the effects of an inescapable foot shock (IFS) procedure (1) on reactivity to novelty in an open-field (as an index of hyperarousal), and (2) on noradrenaline release in the amygdala during an acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of microinjections of propranolol, a β-adrenoreceptor antagonist, and clenbuterol, a β-adrenoreceptor agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA levels of β-adrenoreceptors (β1 and β2) in the amygdala, the hippocampus and the prefrontal cortex. Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After recovering from surgery, animals were exposed to IFS (10 shocks, 0.86mA, and 6s per shock) and seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed to IFS showed a reduced locomotion compared to non-shocked animals during the first 5min in the open-field. In the amygdala, IFS animals showed an enhanced increase of noradrenaline induced by stress compared to control animals. Bilateral microinjections of propranolol (0.5μg) into the amygdala one hour before testing in the open-field normalized the decreased locomotion observed in IFS animals. On the other hand, bilateral microinjections of clenbuterol (30ng) into the amygdala of control animals did not change the exploratory activity induced by novelty in the open field. IFS modified the mRNA expression of β1 and β2 adrenoreceptors in the prefrontal cortex and the hippocampus. These results suggest that an increased noradrenergic activity in the amygdala contributes to the expression of hyperarousal in an animal model of PTSD.

Administration of the TrkB receptor agonist 7,8-dihydroxyflavone prevents traumatic stress-induced spatial memory deficits and changes in synaptic plasticity

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc.

Distinctive cardiac autonomic dysfunction following stress exposure in both sexes in an animal model of PTSD

It is unclear whether the poor autonomic flexibility or dysregulation observed in patients with posttraumatic stress disorder (PTSD) represents a pre-trauma vulnerability factor or results from exposure to trauma. We used an animal model of PTSD to assess the association between the behavioral response to predator scent stress (PSS) and the cardiac autonomic modulation in male and female rats.The rats were surgically implanted with radiotelemetry devices to measure their electrocardiograms and locomotor activity (LMA). Following baseline telemetric monitoring, the animals were exposed to PSS or sham-PSS. Continuous telemetric monitoring (24h/day sampling) was performed over the course of 7days. The electrocardiographic recordings were analyzed using the time- and frequency-domain indexes of heart rate variability (HRV). The behavioral response patterns were assessed using the elevated plus maze and acoustic startle response paradigms for the retrospective classification of individuals according to the PTSD-related cut-off behavioral criteria.During resting conditions, the male rats had significantly higher heart rates (HR) and lower HRV parameters than the female rats during both the active and inactive phases of the daily cycle. Immediately after PSS exposure, both the female and male rats demonstrated a robust increase in HR and a marked drop in HRV parameters, with a shift of sympathovagal balance towards sympathetic predominance. In both sexes, autonomic system habituation and recovery were selectively inhibited in the rats whose behavior was extremely disrupted after exposure to PSS. However, in the female rats, exposure to the PSS produced fewer EBR rats, with a more rapid recovery curve than that of the male rats. PSS did not induce changes to the circadian rhythm of the LMA.According to our results, PTSD can be conceptualized as a disorder that is related to failure-of-recovery mechanisms that impede the restitution of physiological homeostasis.