Animal Model Of Post-traumatic Stress Disorder Research Articles

Dissociation in Effective Treatment and Behavioral Phenotype Between Stress-Enhanced Fear Learning and Learned Helplessness.

Post-traumatic stress disorder (PTSD) is a debilitating disease with relatively high lifetime prevalence. It is marked by a high diversity of symptoms and comorbidity with other psychiatric disease. Furthermore, PTSD has a high level of origin and symptom heterogeneity within the population. These characteristics taken together make it one of the most challenging diseases to effectively model in animals. However, with relatively little headway made in developing effective disease interventions, PTSD remains as a high priority target for animal model study. Learned Helplessness (LH) is a procedure classically used to model depression, but has in recent years transitioned to use as a model of PTSD. Animals in this procedure receive 100 inescapable and unpredictable tailshocks or simple restraint without shock. The following day, the animals are tested in a shuttle box, where inescapably-shocked subjects exhibit exaggerated fear and profound deficit in escape performance. Stress-enhanced fear learning (SEFL) also uses an acute (single session) stressor for modeling PTSD in rodents. The SEFL procedure begins with exposure to 15 footshocks or simple context exposure without shock. Animals that initially received the 15 footshocks exhibit future enhanced fear learning. In this review, we will compare the behavior, physiology, and interventions of these two animal models of PTSD. Despite considerable similarity (a single session containing inescapable and uncontrollable shock) the two procedures produce a very divergent set of behavioral consequences.

The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats.

Post-traumatic stress disorder (PTSD) currently has no FDA-approved treatments that reduce symptoms in the majority of patients. The ability to extinguish fear memory associations is impaired in PTSD individuals. As such, the development of extinction-enhancing pharmacological agents to be used in combination with exposure therapies may benefit the treatment of PTSD. Both mGlu5 and CB1 receptors have been implicated in contextual fear extinction. Thus, here we tested the ability of the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and cannabidiol (CBD) to reduce both conditioned and unconditioned fear. We used a predator-threat animal model of PTSD which we and others have previously shown to capture the heterogeneity of anxiety responses observed in humans exposed to trauma. Here, 1 week following a 10-min exposure to predator scent stress, rats were classified into stress-Susceptible and stress-Resilient phenotypes using behavioral criteria for elevated plus maze and acoustic startle response performance. Two weeks after classification, rats underwent 3 days of contextual fear extinction and were treated with vehicle, CDPPB or CBD prior to each session. Finally, the light-dark box test was employed to assess phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety. CDPBB but not CBD, reduced freezing in Susceptible rats relative to vehicle. In the light-dark box test for unconditioned anxiety, CBD, but not CDPPB, reduced anxiety in Susceptible rats. Resilient rats displayed reduced anxiety in the light-dark box relative to Susceptible rats. Taken together, the present data indicate that enhancement of mGlu5 receptor signaling in populations vulnerable to stress may serve to offset a resistance to fear memory extinction without producing anxiogenic effects. Furthermore, in a susceptible population, CBD attenuates unconditioned but not conditioned fear. Taken together, these findings support the use of predator-threat stress exposure in combination with stress-susceptibility phenotype classification as a model for examining the unique drug response profiles and altered neuronal function that emerge as a consequence of the heterogeneity of psychophysiological response to stress.

Animal models of post-traumatic stress disorder and novel treatment targets.

Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABAA receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.

Edaravone prevents memory impairment in an animal model of post-traumatic distress.

Post-traumatic stress disorder (PTSD) is a mental health problem that develops in a proportion of individuals after experiencing a potential life-threatening traumatic stress event. Edaravone is a free radical scavenger, with a neuroprotective effect against cognitive impairment in several animal models. In the present study, the protective effect of edaravone on PTSD-induced memory impairment was investigated. Single prolonged stress was used as an animal model of PTSD, comprising 2 h of restrain, 20-min forced swimming, 15-min rest, and 1-2-min diethyl ether exposure. Concurrently, edaravone was given at a dose of 6 mg/kg/day, intraperitoneally, for 21 days. The radial arm water maze was used to assess learning and memory. Antioxidant biomarkers were measured in hippocampus tissues. Chronic administration of edaravone prevented impairment of short-term and long-term memory. Edaravone also prevented the stress-induced decrease in the ratio of reduced glutathione/oxidized glutathione and the activities of glutathione peroxidase and catalase enzymes in the hippocampus, as well as increases in the levels of oxidized glutathione and thiobarbituric acid reactive substances. In conclusion, edaravone ameliorated oxidative stress and cognitive impairment associated with a PTSD model, probably by supporting antioxidant mechanism in the hippocampus.

Single Prolonged Stress as a Prospective Model for Posttraumatic Stress Disorder in Females

BackgroundSex plays an important role in susceptibility to stress triggered disorders. Posttraumatic Stress disorder (PTSD), a debilitating psychiatric disorder developed after exposure to a traumatic event, is two times more prevalent in women than men. However, the vast majority of animal models of PTSD, including single prolonged stress (SPS), were performed mostly with males.Objectives(1) Evaluate SPS as an appropriate model for PTSD in female rodents in terms of anxiety, depressive symptoms and changes of gene expression in the locus coeruleus; (2) Asses sex differences in SPS‐triggered changes in these measures; (3) Examine intranasal NPY as a potential early intervention for females.MethodsFemale rats were subjected to SPS and given either intranasal NPY or vehicle. Twelve and seven days later they were compared to unstressed controls on forced swim test (FST) and elevated plus maze (EPM) respectively. Changes in gene expression in the locus coeruleus (LC) were determined by quantitative RT‐PCR.Results and InterpretationSPS led to increased anxiety‐like behavior on EPM, and tended to raise depressive‐like behavior on FST. Following FST rats displayed elevated TH, CRHR1 and Y1R mRNA levels in the LC, consistent with increased activation of the noradrenergic system.The expression level of these mRNAs were unchanged following EPM. Intranasal NPY at the doses shown to be effective in males, did not prevent development of depressive or anxiety‐like behavior or molecular changes in the LC. SPS may be milder for females when compared to males, as they did not show despair or immobility as readily as males on the forced swim component of the SPS protocols. In addition, after SPS stressors females exhibited less immobility on FST than males, however there were little overall sex differences in anxiety‐like behavior on EPM.ConclusionsThe results indicate that while SPS could be an appropriate PTSD model for females, there are important sex differences, such as response to NPY, that need to be taken into account.Support or Funding InformationThis work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the DOD Department of Defense Broad Agency Announcement for Extramural Medical Research under Award No W81XWH‐16‐1‐0016 and by funds from the NYMC/Touro Bridge Funding Program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Single Prolonged Stress as a Prospective Model for Posttraumatic Stress Disorder in Females.

Sex plays an important role in susceptibility to stress triggered disorders. Posttraumatic Stress disorder (PTSD), a debilitating psychiatric disorder developed after exposure to a traumatic event, is two times more prevalent in women than men. However, the vast majority of animal models of PTSD, including single prolonged stress (SPS), were performed mostly with males. Here, we evaluated SPS as an appropriate PTSD model for females in terms of anxiety, depressive symptoms and changes in gene expression in the noradrenergic system in the brain. In addition, we examined intranasal neuropeptide Y (NPY) as a possible treatment in females. Female rats were subjected to SPS and given either intranasal NPY or vehicle in two separate experiments. In the first experiment, stressed females were compared to unstressed controls on forced swim test (FST) and for levels of expression of several genes in the locus coeruleus (LC) 12 days after SPS exposure. Using a separate cohort of animals, experiment two examined stressed females and unstressed controls on the elevated plus maze (EPM) and LC gene expression 7 days after SPS stressors. SPS led to increased anxiety-like behavior on EPM and depressive-like behavior on FST. Following FST, the rats displayed elevated tyrosine hydroxylase (TH), CRHR1 and Y1R mRNA levels in the LC, consistent with increased activation of the noradrenergic system. The expression level of these mRNAs was unchanged following EPM, except Y1R. Intranasal NPY at the doses shown to be effective in males, did not prevent development of depressive or anxiety-like behavior or molecular changes in the LC. The results indicate that while SPS could be an appropriate PTSD model for females, sex differences, such as response to NPY, are important to consider.

Sex Differences in Nociceptin/Orphanin FQ Peptide Receptor-Mediated Pain and Anxiety Symptoms in a Preclinical Model of Post-traumatic Stress Disorder.

Nociceptin/Orphanin FQ (N/OFQ) is a neuropeptide that modulates pain transmission, learning/memory, stress, anxiety, and fear responses via activation of the N/OFQ peptide (NOP or ORL1) receptor. Post-traumatic stress disorder (PTSD) is an anxiety disorder that may arise after exposure to a traumatic or fearful event, and often is co-morbid with chronic pain. Using an established animal model of PTSD, single-prolonged stress (SPS), we were the first to report that NOP receptor antagonist treatment reversed traumatic stress-induced allodynia, thermal hyperalgesia, and anxiety-like behaviors in male Sprague-Dawley rats. NOP antagonist treatment also reversed SPS-induced serum and CSF N/OFQ increase and circulating corticosterone decrease. The objective of this study was to examine the role of the NOP receptor in male and female rats subjected to traumatic stress using Wistar wild type (WT) and NOP receptor knockout (KO) rats. The severity of co-morbid allodynia was assessed as change in paw withdrawal threshold (PWT) to von Frey and paw withdrawal latency (PWL) to radiant heat stimuli, respectively. PWT and PWL decreased in male and female WT rats within 7 days after SPS, and remained decreased through day 28. Baseline sensitivity did not differ between genotypes. However, while male NOP receptor KO rats were protected from SPS-induced allodynia and thermal hypersensitivity, female NOP receptor KO rats exhibited tactile allodynia and thermal hypersensitivity to the same extent as WT rats. Male NOP receptor KO rats had a lower anxiety index (AI) than WT, but SPS did not increase AI in WT males. In contrast, SPS significantly increased AI in WT and NOP receptor KO female rats. SPS increased circulating N/OFQ levels in male WT, but not in male NOP receptor KO, or WT or KO female rats. These results indicate that the absence of the NOP receptor protects males from traumatic-stress-induced allodynia and hyperalgesia, consistent with our previous findings utilizing a NOP receptor antagonist. However, female NOP receptor KO rats experience allodynia, hyperalgesia and anxiety-like symptoms to the same extent as WT females following SPS. This suggests that endogenous N/OFQ-NOP receptor signaling plays an important, but distinct, role in males and females following exposure to traumatic stress.

Updates in PTSD Animal Models Characterization.

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental disorder afflicting more than 7% of the US population and 12% of military service members. Since the Afghanistan and Iraq wars, thousands of US service members have returned home with PTSD. Despite recent progress, the molecular mechanisms underlying the pathology of PTSD are poorly understood. To promote research on PTSD (especially its molecular mechanisms) and to set a molecular basis for discovering novel medications for this disorder, well-validated animal models are needed. However, to develop PTSD animal models is a challenging process, due to predisposing factors such as physiological, behavioral, emotional, and cognitive changes that emerge after trauma. Currently, there is no well-validated animal model of PTSD, although several stress paradigms mimic the behavioral symptoms and neurological alterations seen in PTSD. In this chapter, we will provide an overview of animal models of PTSD including learned helplessness, footshock, restraint stress, inescapable tail shock, single-prolonged stress, underwater trauma, social isolation, social defeat, early-life stress, and predator-based stress. We emphasize rodent models because they reproduce some of the behavioral and biotical phenotypes seen in PTSD. We will also present data showing that homologous biological measures are increasingly incorporated in studies to assess markers of risk and therapeutic response in these models. Therefore, PTSD animal models may be refined in hopes of capitalizing on the understanding of the molecular mechanisms and delivering tools in order to develop new and more efficacious treatments for PTSD.

Research Progress on Post-Traumatic Stress Disorder and Its Animal Model

Posttraumatic stress disorder (PTSD) is to a persistently severe mental disorder which is caused by individual exposure to some unusual threatening or catastrophic stressful events. Its essential clinical manifestations refer to repeated playback of traumatic experience, durative avoidance of related clues, mental numbness or affection paralysis, and persistent increase of vigilance level. At present, the pathogenesis of PTSD has not been fully elucidated, and the clinical therapeutic effect has not been ideal. Generally, the classical animal model of PTSD is mouse; the domestic and international researches in the animal model of PTSD in recent years remain active, which are summarized as follows.

Effect of acupuncture on blood oxygen concentration in brain of rats with post-traumatic stress disorder based on functional near-infrared spectroscopy

To observe the effect of acupuncture on blood oxygen concentration in the brain of rats with post-traumatic stress disorder (PTSD) based on functional near-infrared spectroscopy (fNIRS), thus to reveal the mechanisms of acupuncture in intervening the brain function of PTSD rats. Sixty Sprague-Dawley (SD) rats were randomly divided into a blank group, a model group, a grasping group, a paroxetine group and an acupuncture group, with 12 rats in each group. Except the blank group, rats in the other groups all received incarceration plus electric shock for 7 d to prepare the PTSD animal model. One hour before the stress model was established, rats in each group received the designated intervention: rats in the blank group and the model group did not receive any intervention; rats in the grasping group received grasping and fixation; rats in the paroxetine group received paroxetine hydrochloride solution by intragastric administration; and rats in the acupuncture group received acupuncture. Six-day treatment was a course, with 2 courses of treatment conducted for a total of 12 d. After the modeling, rats in each treatment group received intervention for 5 d, and the fNIRS system was used to collect and record the changes in the concentrations of oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (d-Hb) and total hemoglobin (t-Hb) of the involved rat’s brain regions, and also to assess the brain function. Compared with the blank group, the concentration of HbO2 was significantly increased, the concentration of d-Hb was significantly decreased, and the concentration of t-Hb was significantly increased in the model group and the grasping group after the intervention, and the differences were statistically significant (all P 0.05). Compared with the grasping group, the concentration of HbO2 was significantly decreased, the concentration of d-Hb was significantly increased, and the concentration of t-Hb was significantly decreased in the paroxetine group and the acupuncture group, and the differences were statistically significant (all P 0.05). Acupuncture can regulate the blood oxygen concentration in the brain of PTSD model rats, which may be an important mechanism of acupuncture in intervening the brain function in PTSD rats.

The anxiolytic-like effects of ginsenoside Rg2 on an animal model of PTSD

Post traumatic stress disorder (PTSD) is one of the mental illness. The antidepressant-like properties of ginsenoside Rg2 (GRg2) have been shown, while little is known about its anti-PTSD-like effects. In the present study, the PTSD-associated behavioral deficits in rats were induced following exposure to single prolonged stress (SPS). The results showed that the decreased time and entries in the open arms in elevated plus maze test (EPMT) and increased freezing duration in contextual fear paradigm (CFP) were reversed by GRg2 (10 and 20 mg/kg) without affecting the locomotor activity. In addition, GRg2 (10 and 20 mg/kg) could block the decreased levels of progesterone, allopregnanolone, serotonin (5-HT), 5-Hydroxyindoleacetic acid (5-HIAA), corticotropin releasing hormone (CRH), corticosterone (Cort) and adrenocorticotropic hormone (ACTH) in the brain or serum. In summary, GRg2 alleviated the PTSD-associated behavioral deficits with biosynthesis of neurosteroids, normalization of serotonergic system and HPA axis dysfunction.

Effects of Oxytocin on Fear Memory and Neuroinflammation in a Rodent Model of Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterized by fear extinction abnormalities, which involve biological dysfunctions among fear circuit areas in the brain. Oxytocin (OXT) is a neuropeptide that regulates sexual reproduction and social interaction and has recently earned specific attention due to its role in adjusting neurobiological and behavioral correlates of PTSD; however, the mechanism by which this is achieved remains unclear. The present study aimed to examine whether the effects of OXT on traumatic stress-induced abnormalities of fear extinction (specifically induced by single prolonged stress (SPS), an animal model of PTSD) are associated with pro-inflammatory cytokines. Seven days after SPS, rats received intranasal OXT 40 min before a cue-dependent Pavlovian fear conditioning-extinction test in which rats’ freezing degree was used to reflect the outcome of fear extinction. We also measured mRNA expression of IL-1β, IFN-γ, and TNF-α in the medial prefrontal cortex (mPFC), hippocampus, and amygdala at the end of the study, together with plasma oxytocin, corticosterone, IL-1β, IFN-γ, and TNF-α, to reflect the central and peripheral changes of stress-related hormones and cytokines after SPS. Our results suggested that intranasal OXT effectively amends the SPS-impaired behavior of fear extinction retrieval. Moreover, it neurochemically reverses the SPS increase in pro-inflammatory cytokines; thus, IL-1β and IFN-γ can be further blocked by the OXT antagonist atosiban (ASB) in the hippocampus. Peripheral profiles revealed a similar response pattern to SPS of OXT and corticosterone (CORT), and the SPS-induced increase in plasma levels of IL-1β and TNF-α could be reduced by OXT. The present study suggests potential therapeutic effects of OXT in both behavioral and neuroinflammatory profiles of PTSD.

Effects of Trauma in Adulthood and Adolescence on Fear Extinction and Extinction Retention: Advancing Animal Models of Posttraumatic Stress Disorder.

Evidence for and against adolescent vulnerability to posttraumatic stress disorder (PTSD) is mounting, but this evidence is largely qualitative, retrospective, or complicated by variation in prior stress exposure and trauma context. Here, we examine the effects of development on trauma vulnerability using adult post-natal (PN) day 61, early adolescent (PN23) and mid adolescence (PN34) rats and two types of trauma: an established animal model of PTSD, single prolonged stress (SPS), and a novel composite model—SPS predation (SPSp) version. We demonstrate that early and mid adolescent rats are capable of fear conditioning and fear extinction, as well as extinction retention. Our results also demonstrate that both types of trauma induced a deficit in the retention of fear extinction in adulthood, a hallmark of PTSD, but not after early or mid adolescence trauma, suggesting that adolescence might convey resilience to SPS and SPSp traumas. Across all three life stages, the effects of SPS exposure and a novel predation trauma model, SPSp, had similar effects on behavior suggesting that trauma type did not affect the likelihood of developing PTSD-like symptoms, and that SPSp is a predation-based trauma model worth exploring.

The anxiolytic-like effects of estazolam on a PTSD animal model

Post-traumatic stress disorder (PTSD) is a serious psychiatric disorder. Estazolam has been shown to produce anxiolytic-, hypnotic-, amnestic-, and sedative-like effects. However, few studies are concerned about its anti-PTSD-like effects. The anti-PTSD-like effects of estazolam were evaluated by single prolonged stress animal model. After exposure to single prolonged stress, rats (Sprague-Dawley, male, 8 weeks) were administered by estazolam (0.5, 1 and 2 mg/kg, i.p.) from day 2 to 13 once daily. The behavioral assessments were performed during treatment with drugs. After the behavioral evaluation, the role of allopregnanolone in the anti-PTSD-like effects of estazolam was also evaluated via astrocyte cells and brain tissues (e.g. prefrontal cortex, hippocampus, and amygdala). The PTSD-like behavioral deficits were significantly blocked by estazolam (1 and 2 mg/kg, i.p.) without affecting locomotor activity. Consistently, the levels on allopregnanolone were increased by estazolam (1 and 2 mg/kg, i.p.) in prefrontal cortex, hippocampus, and amygdala. The levels of allopregnanolone were increased by sertraline (1 µmoL/L) and estazolam (4 µmoL/L), while the effects were antagonized by trilostane (1 µmoL/L) and finasteride (1 µmoL/L) in astrocyte cells, respectively. Collectively, the anxiety-like behavior deficits were ameliorated by estazolam in the single prolonged stress animal model that was associated with biosynthesis of allopregnanolone.

Traumatic Stress Produces Distinct Activations of GABAergic and Glutamatergic Neurons in Amygdala.

Posttraumatic stress disorder (PTSD) is an anxiety disorder characterized by intrusive recollections of a severe traumatic event and hyperarousal following exposure to the event. Human and animal studies have shown that the change of amygdala activity after traumatic stress may contribute to occurrences of some symptoms or behaviors of the patients or animals with PTSD. However, it is still unknown how the neuronal activation of different sub-regions in amygdala changes during the development of PTSD. In the present study, we used single prolonged stress (SPS) procedure to obtain the animal model of PTSD, and found that 1 day after SPS, there were normal anxiety behavior and extinction of fear memory in rats which were accompanied by a reduced proportion of activated glutamatergic neurons and increased proportion of activated GABAergic neurons in basolateral amygdala (BLA). About 10 days after SPS, we observed enhanced anxiety and impaired extinction of fear memory with increased activated both glutamatergic and GABAergic neurons in BLA and increased activated GABAergic neurons in central amygdala (CeA). These results indicate that during early and late phase after traumatic stress, distinct patterns of activation of glutamatergic neurons and GABAergic neurons are displayed in amygdala, which may be implicated in the development of PTSD.

Hyperbaric oxygen therapy restored traumatic stress-induced dysregulation of fear memory and related neurochemical abnormalities

Individuals with posttraumatic stress disorder (PTSD) are characterized by fear memory problems and hypocortisolemia of which traumatic stress-induced monoaminergic disruption over infralimbic (IL) cortex is considered the key mechanism. Hyperbaric oxygen therapy (HBOT) has recently proven its utility in treating several mental disorders but remains unexplored for PTSD. The present study aimed to examine the effects of 5-day HBO paradigm on traumatic stress (single prolonged stress, SPS, an animal model of PTSD)-induced dysregulation of fear memory/anxiety profiles and related abnormalities in IL monoamines and plasma corticosterone. Rats were randomly assigned to four groups (CON-sham, CON-HBOT, SPS-sham, and SPS-HBOT) and received Pavlovian fear conditioning test or elevated-T maze (ETM). The extracellular and tissue levels of monoamines over the IL cortex and the activity of the hypothalamus–pituitary–adrenal axis (i.e., the plasma corticosterone level and expression of the glucocorticoid receptor (GR) in the IL, hippocampus, amygdala, and hypothalamus) were measured. The results demonstrated that HBOT restored behaviorally the SPS-impaired fear extinction retrieval ability and SPS-induced conditioned anxiety, and neurochemically the SPS-reduced IL monoamines efflux level, and the corticosterone profiles. The present study shows some positive effects of HBOT in both behavioral and neurochemical profiles of PTSD outcomes.

Sex differences in a rabbit eyeblink conditioning model of PTSD.

We have developed a rabbit model of posttraumatic stress disorder (PTSD) which recapitulates several core features of PTSD, particularly hyperarousal and conditioned responding to trauma-associated cues. The work conducted with this model has all been done in male rabbits and, given sex differences in PTSD prevalence, it is important to expand our animal model of PTSD to include female rabbits to determine if they develop core features of PTSD, and if those core features can be treated. This is particularly important because, contrary to human studies, nearly all animal studies have found that males are consistently more vulnerable to various forms of acute and chronic stress than females. Using eyeblink conditioning in which we paired tone with a brief periorbital shock, we found that although both male and female rabbits acquired identical levels of conditioning, females showed more hyperarousal after conditioning but seemed to respond somewhat better to treatment.

Propranolol produces short-term facilitation of extinction in a rabbit model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a learning-based anxiety disorder with significant public health challenges due to difficulties in treating the complex, multiple symptomology. We have developed an animal model of PTSD, based on Pavlovian eyeblink conditioning in rabbits, 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). We have found previously that unpaired extinction is ideal for reducing both CRs and CRM simultaneously and shows sensitivity to systemic serotonergic and glutamatergic manipulations. The following study aimed to extend our work to examine the role of the noradrenergic system, dysregulation of which is strongly implicated as part of the neurobiology of PTSD and which may also play a role in the balance shift from fear reconsolidation to extinction during treatment. The goal of the following two studies was to examine whether the β-adrenergic receptor antagonist propranolol combined with either a full or brief course of unpaired extinction treatment could enhance extinction of CRs and/or CRM. Results showed a within-session facilitation of propranolol on extinction of CRs, particularly during the first extinction session, and a short-term enhancement of extinction of CRM when extinction treatment was brief. However, neither benefit translated to long-term extinction retention for the majority of subjects. Findings suggest that propranolol may provide the most therapeutic benefit in situations of high arousal early in treatment, which may be more important for future patient compliance rather than long-term treatment outcomes.

P.2.040 - Cognitive functioning in post-traumatic stress disorder: a meta-analysis of evidence from animal models and clinical studies

In the aftermath of a traumatic experience, some people develop post-traumatic stress disorder (PTSD). Cognitive processes play a crucial role in current clinical diagnosis and treatment of PTSD. Three core symptom clusters of PTSD are cognitive in nature (i.e. re-experiencing, avoidance and negative alterations in cognitions) [1] and cognitive processes form a major component in evidence-based therapies for PTSD (e.g. EMDR, cognitive behavioural therapy) [2]. To improve the prevention and treatment of PTSD in the future, (fundamental) research needs to elaborate on underlying mechanisms and identify opportunities for (new) treatment strategies. However, research efforts need to align with clinical reality since only translational findings will foster clinical progress. In the case of PTSD, this implies research attention for the cognitive domain (including learning & memory). The aim of the current meta-analysis was firstly to review and integrate the existing knowledge on learning, memory and fear conditioning in PTSD patients compared to healthy controls. Subsequently, data from animal models of PTSD was analysed and compared to patient-data, to investigate if preclinical data follows the same patterns as clinical data, and identify possible explanations for potential discrepancies. The database search was conducted in PubMed and only original research articles were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and guidelines were used to conduct the searches, to guide data extraction, to summarize evidence and to report the results [3]. 184 articles were included in this study (60,9% preclinical data). In 53,8% of the studies fear-conditioning experiments were performed, the other studies assessed learning and memory of more neutral information. The results indicate that PTSD patients are better in learning and memory of emotional or fearful information, but perform worse than healthy controls in learning and memory of neutral information. Importantly, preclinical data showed comparable results, with even stronger associations between PTSD and parameters of learning and memory. The stronger effect found in animal models, could be due to the more controlled nature of preclinical research, which is for example reflected in subject background (e.g. laboratory animals vs. patients with variations in comorbidity and medication use) and experimental environment. Differences in learning and memory of trauma-related, visual, verbal and spatial memory are discussed. Analysis revealed that included papers varied in timing between encoding and retrieval, as well as between trauma and cognitive testing. In addition, preclinical studies predominantly used fear conditioning approaches, whereas learning and memory of emotional or neutral information was mainly assessed in clinical studies. Insight in the discrepancies mentioned above could inspire future experimental designs of (pre)clinical studies to adopt a more translational, thereby more valuable, set-up. Overall, the results underline the importance of the learning and memory deficits in PTSD and suggest that animal models can be used to model the cognitive domain of PTSD.

P.2.020 - Blunted basal corticosterone pulsatility predicts post-exposure susceptibility to post-traumatic stress disorder phenotype in rats

Introduction Glucocorticoid (GC) hormones play a major role in orchestrating the physiological and behavioral reactions essential for homeostasis. As such, these hormones enable the organism to prepare for, respond to, and cope with the acute demands of physical and emotional stressors [1]. The secretion of GC hormones is a dynamic process which displays, in addition to a circadian pattern of release, an ultradian rhythmicity in the blood and in target tissues [2] Inadequate GC release following stress not only delays recovery but can also interfere with the processing or interpretation of stressful information, resulting in long-term disruptions of memory integration processes [3]. An example of such an impaired process is post-traumatic stress disorder (PTSD) [4]. In the rat, corticosterone ultradian pulses have a near-hourly frequency and changes in the amplitude of these pulses throughout the 24 h cycle determine the circadian variation in hormone secretion [2]. Aims We used an animal model of PTSD [5] in order to assess whether stress-induced impairment of behavioral responses is mediated by an aberrant secretion of corticosterone. Methods Serial blood samples were collected manually via the jugular vein cannula during the inactive phase in conscious male rats at 20-min intervals for a period of 5 h before and 6.5 h after exposure to predator scent stress (PSS). The outcome measures included behavior in an elevated plus-maze and acoustic startle response 7 days after exposure. Individual animals were retrospectively classified as having extreme, partial, and minimal behavioral responses according to pre-set cut-off criteria for behavioral response patterns [5] and blood samples were analyzed retrospectively for corticosterone secretion patterns. For the behavioral results and for serum corticosterone levels, the statistical analyses were performed using one-way analysis of variance (ANOVA), bonferroni tests were used to examine differences between individual groups. To gain additional understanding about the relationship between behavioral measures and corticosterone pulsatility parameters, two sets of regression analysis were conducted: Pearson's correlation analysis was used to describe the relationship between each behavioral variable and corticosterone pulsatility parameters across the entire sample. The contribution of each variable that exhibited a significant correlation (or trend) was then evaluated using a multiple stepwise-regression analysis. Results Under basal conditions, the amplitude of ultradian oscillations of corticosterone levels, rather than the mean corticosterone level or the frequency of corticosterone pulsatility, was significantly reduced in individuals who displayed PTSD-phenotype 8 days later. In addition, extreme disruption of behavior on day 8 post-exposure was also characterized by a blunting of corticosterone response to the stressor. Animals with behavior that was only partially affected or unaffected displayed none of the above changes. Conclusions Blunted basal corticosterone pulse amplitude is a pre-existing susceptibility or risk factor for PTSD, which originates from prior (life) experiences and may therefore predict post-exposure PTSD-phenotype in rats. Further studies confirming these findings in animals and in human subjects are required to ascertain whether dysregulation in pulsatility indeed predisposes individuals to, or in fact underlies, faults in the HPA-axis response to stress and renders them vulnerable to PTSD.