Extinction and reinstatement sex-dependently affect freezing behavior, pain perception, locomotion, and rearing behavior in a rat model of posttraumatic stress disorder (PTSD).

Enhanced fear learning occurs subsequent to traumatic or stressful events and is a persistent challenge to the treatment of post-traumatic stress disorder (PTSD). Facilitation of learning produced by prior stress can elicit an exaggerated fear response to a minimally aversive event or stimulus. Stress-enhanced fear learning (SEFL) is a rat model of PTSD; rats previously exposed to the SEFL 15 electrical shocks procedure exhibit several behavioral responses similar to those seen in patients with PTSD. However, past reports found that SEFL is not mitigated by extinction (a model of exposure therapy) when the spaced extinction began 24 h after stress. Recent studies found that extinction from 10 min to 1 h subsequent to fear conditioning “erased” learning, whereas later extinction, occurring from 24 to 72 h after conditioning did not. Other studies indicate that massed extinction is more effective than spaced procedures. Therefore, we examined the time-dependent nature of extinction on the stress-induced enhancement of fear learning using a massed trial's procedure. Experimental rats received 15 foot shocks and were given either no extinction or massed extinction 10 min or 72 h later. Our present data indicate that SEFL, following traumatic stress, is resistant to immediate massed extinction. Experimental rats showed exaggerated new fear learning regardless of when extinction training occurred. Thus, post-traumatic reactivity such as SEFL does not seem responsive to extinction treatments.

Sex differences in the effect of chronic REM sleep deprivation and extinction learning on freezing behavior and BDNF and GSK-3β expression levels in a rat model of fear conditioning.

Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD

Posttraumatic stress disorder (PTSD) is a known risk factor for the development of chronic pain conditions, and almost 1 in 5 individuals with chronic pain fulfills the criteria for PTSD. However, the relationship between PTSD and pain is poorly understood and studies on pain perception in patients with PTSD show inconsistent results suggesting that different sensory profiles exist among individuals with PTSD. Here, we (1) systematically summarize the current literature on experimentally evoked pain perception in patients with PTSD compared to subjects without PTSD, and (2) assess whether the nature of the traumatic event is associated with different patterns in pain perception. The main outcome measures were pain threshold, pain tolerance, and pain intensity ratings as well as measures of temporal summation of pain and conditioned pain modulation. A systematic search of MEDLINE, EMBASE, Web of Science, PsycINFO, and CINAHL identified 21 studies for the meta-analysis, including 422 individuals with PTSD and 496 PTSD-free controls. No main effect of PTSD on any outcome measure was found. However, stratification according to the nature of trauma revealed significant differences of small to medium effect sizes. Combat-related PTSD was associated with increased pain thresholds, whereas accident-related PTSD was associated with decreased pain thresholds. No clear relationship between PTSD and experimentally evoked pain perception exists. The type of trauma may affect pain thresholds differently indicating the presence of different subgroups with qualitative differences in pain processing.

Pharmacological Resistance of Stress Enhanced Fear Learning in an Animal Model of Post-Traumatic Stress Disorder Virginia Long, Wendy Fujioka, Dorsa Amir and Michael Fanselow University of California, Los Angeles USA 1. Introduction In anxiety disorders such as PTSD, normal fear responding and learning, which is adaptive and helps us survive, is altered in such way that fear becomes maladaptive, interfering with an organism’s ability to alter and adapt behavior in situationally appropriate ways. Maladaptive fear learning is thought to underlie the behavioral symptoms of anxiety disorders such as PTSD (Charney, 2004; Rosen & Schulkin, 1998) when fear and fear responses dominate behavior even in benign circumstances. The fear learning circuit normally participates in adaptive learning and response to danger, however after trauma some individuals show symptoms of PTSD such as: abnormal response to milder stressors, increased vigilance and startle response (American Psychiatric Association., 2000). Stress enhanced fear learning (SEFL) models some specific aspects of PTSD. Using this model we can examine the consequences of trauma--how acute stress or a traumatic event permanently alters the way fear is learned and how these permanent changes in the fear learning circuitry produce maladaptive responses and maladaptive fear learning. Post-traumatic stress disorder (PTSD) is an anxiety disorder that is debilitating and profoundly affects the lives of men and women worldwide. The Diagnostic and Statistical Manual of Mental Disorders (DSM) criterion for a diagnosis of PTSD requires exposure or experience of a traumatic or life-threatening event (American Psychiatric Association., 2000). Trauma may be caused by combat, violence (such as assault, rape, robbery), severe accidents, disasters (natural or man-made). Any one of these traumatic events will be experienced by one-third of the population (Brunello et al., 2001). While the majority of people will not develop PTSD, it is estimated that 10 to 20% of people who experience an acute traumatic event will develop the disorder (Brunello et al., 2001). Symptoms of PTSD include re-experiencing of the trauma, avoidance, and hyper-arousal. Re-experiencing of the trauma can manifest as vivid and emotionally intense memories of the event in flashbacks, nightmares, or ruminations that give the patient a feeling of re-living the trauma. Avoidance of situations, people, or places that remind patients of the trauma is another aspect of the disorder. Increased physiological and psychological arousal, including enhanced startle response and hyper-vigilance also contribute and are indicative of the maladaptive fear learning associated with PTSD. PTSD is thought to be much more prevalent than the estimated 7.8%. Furthermore, many cases of PTSD may be unreported and thus undiagnosed (Brunello et al., 2001). www.intechopen.com

Chemogenetic activation of the mPFC alleviates impaired fear memory extinction in an animal model of PTSD

Emotional Reactivity in Posttraumatic Stress Disorder:Behavioural and Neurobiological Correlates of Underlying Mechanisms and the Role of Emotional Memory Modification

BackgroundCombat post-traumatic stress disorder (PTSD) involves significant suffering, impairments in social and occupational functioning, substance use and medical comorbidity, and increased mortality from suicide and other causes. Many veterans continue to suffer despite current treatments. Deep brain stimulation (DBS) has shown promise in refractory movement disorders, depression and obsessive-compulsive disorder, with deep brain targets chosen by integration of clinical and neuroimaging literature. The basolateral amygdala (BLn) is an optimal target for high-frequency DBS in PTSD based on neurocircuitry findings from a variety of perspectives. DBS of the BLn was validated in a rat model of PTSD by our group, and limited data from humans support the potential safety and effectiveness of BLn DBS.Methods/DesignWe describe the protocol design for a first-ever Phase I pilot study of bilateral BLn high-frequency DBS for six severely ill, functionally impaired combat veterans with PTSD refractory to conventional treatments. After implantation, patients are monitored for a month with stimulators off. An electroencephalographic (EEG) telemetry session will test safety of stimulation before randomization to staggered-onset, double-blind sham versus active stimulation for two months. Thereafter, patients will undergo an open-label stimulation for a total of 24 months. Primary efficacy outcome is a 30% decrease in the Clinician Administered PTSD Scale (CAPS) total score. Safety outcomes include extensive assessments of psychiatric and neurologic symptoms, psychosocial function, amygdala-specific and general neuropsychological functions, and EEG changes. The protocol requires the veteran to have a cohabiting significant other who is willing to assist in monitoring safety and effect on social functioning. At baseline and after approximately one year of stimulation, trauma script-provoked 18FDG PET metabolic changes in limbic circuitry will also be evaluated.DiscussionWhile the rationale for studying DBS for PTSD is ethically and scientifically justified, the importance of the amygdaloid complex and its connections for a myriad of emotional, perceptual, behavioral, and vegetative functions requires a complex trial design in terms of outcome measures. Knowledge generated from this pilot trial can be used to design future studies to determine the potential of DBS to benefit both veterans and nonveterans suffering from treatment-refractory PTSD.Trial registrationPCC121657, 19 March 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/1745-6215-15-356) contains supplementary material, which is available to authorized users.

ABSTRACTBackground: Women have a two to three times higher risk of developing post-traumatic stress disorder (PTSD) compared to men. Several factors are involved explaining this difference (Christiansen & Hansen, 2015). Both psychosocial and biological explanations (e.g. oxytocin related) have been suggested and will be reviewed in this paper. To date, we are still behind in gender- and sex-sensitive research and reporting.Prevalence and type of trauma: The lifetime prevalence of PTSD is about 10–12% in women and 5–6% in men. There are similar differences between the sexes for (comorbid) disorders such as major depression and anxiety disorders. PTSD subcluster scores have been found to be increased in women, e.g. for re-experiencing and anxious arousal (Charak et al., 2014). Men and women experience different types of trauma, both in private life and at work (e.g. police officers, Van der Meer et al., 2017), with women being exposed to more high-impact trauma (e.g. sexual trauma) than men, and at a younger age. Trauma early in life has more impact, especially when it involves type II trauma interfering with neurobiological development and personality. Traumatic stress affects different areas of the brains of boys and girls at different ages.Acute phase, stress-coping and psychotherapy: In the acute phase, women generally score higher than men on acute subjective responses, e.g. threat perception, peritraumatic dissociation and known predictors of PTSD. Women handle stressful situations differently and have evolved differentially to support these different behaviours. For instance, women in stressful situations may use a tend-and-befriend response rather than the fight-or-flight response that is often assumed. Emotion-focused, defensive and palliative coping are more prevalent in women, while problem-focused coping is higher in men. Women seek more social support, the lack of it being the most consistent predictor of negative outcome of trauma. Women have been shown to benefit more from psychotherapy then men in the reduction of PTSD symptoms.Psychobiological reactions and effects of oxytocin: Although only 2% of psychobiological research has been conducted in females (mainly rats), sex differences have been shown. Women appear to have a more sensitized hypothalamus–pituitary–axis than men, while men appear to have a sensitized physiological hyperarousal system. PTSD has consistently been associated with amygdala hyperactivity, ventromedial prefrontal cortex (vmPFC) hypoactivity and reduced communication (functional connectivity) between the vmPFC and amygdala, with the lower PFC control over the amygdala providing an explanation for the excessive fear response in PTSD. We hypothesized that the oxytocin system, which is associated with social support, fear and stress responses, was likely to play a sex-specific role in the stress response. In recently traumatized patients, we found that the effects of administration of oxytocin on amygdala reactivity to emotional stimuli depend on stimulus valence and sex (Frijling, 2017). In PTSD patients, we showed sex-specific routes for the effects of single oxytocin administration on the potential to diminish anxiety (fear learning) and fear expression by the amygdala: increased inhibitory control of the vmPFC over the centromedial nucleus in men and fewer excitatory dorsal anterior cingulate cortex projections to the basolateral nucleus in women. So, while our findings add to accumulating evidence that oxytocin administration could potentially enhance treatment response in PTSD, the routes in men and women differ (Frijling, 2017).Gender policy: In summary, all of these sex and gender differences in brain and behaviour together may explain why PTSD is more prevalent in women than in men. Clearly, we should not simplify. There are no male or female stereotypes, but some features are more common in women and others in men. To fully understand the differences, we need more gender- and sex-sensitive research as well as reporting (e.g. see the gender policy of the European Association of Science Editors). In 2016, the European Journal of Psychotraumatology was the first to implement a gender policy (Olff, 2016), i.e. authors are asked to: report the sex of research subjects, justify single-sex studies, discriminate between sex and gender (mostly for human research), analyse how sex or gender impact the results, and discuss sex and gender issues when relevant. This should not only apply to the field of psychotrauma, but deserves a much broader implementation. In doing so, we hope to obtain information that will improve sex- and gender-specific approaches to helping those affected by psychotrauma.

Post-traumatic stress disorder (PTSD) is a psychiatric disease that may occur after intense psychological trauma or physiological stress. Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) and the serine/threonine kinase (Akt)/glycogen synthase kinase-3β (GSK-3β) signaling pathway are critically involved in brain plasticity, including hippocampal-dependent learning and memory, while sevoflurane impairs memory processing. Thus, we hypothesized that sevoflurane can suppress fear learning by regulating the expression of BDNF and the Akt/GSK-3β signaling pathway in a rat model of PTSD. Rats were exposed to sevoflurane during or after a 15 foot-shock stressor. Thereafter, rats were subjected to a single foot-shock in a totally different environment. The fear response was recorded in response to the 15 foot-shock and the single foot-shock environments. In another set of experiments, the brain tissue was harvested and subjected to biochemistry studies. Our data suggested that increasing sevoflurane concentrations decreased stress-enhanced fear learning (SEFL) when given during but not after the stressor. Furthermore, administration of lithium chloride (100 mg/kg, intraperitoneally) 30 min before the contextual fear conditioning reversed the inhibitory effect of 0.8 % sevoflurane on SEFL as well as phosphorylated (p)-Akt, p-GSK-3β and BDNF expressions. Our data suggested that increasing sevoflurane administration during but not after the stressor can impair SEFL in a rat model of PTSD, which may be due, at least in part, to the regulation of hippocampal BDNF expression and the Akt/GSK-3β signaling pathway.

Evidence has shown a wide range of changes in pain perception in posttraumatic stress disorder (PTSD). The present study aimed to explore changes in thermal pain threshold in both sexes of rats exposed to electrical footshocks in different periods after fear conditioning. Fear conditioning (PTSD-like model) was induced by three footshocks (0.8mA, 3s) paired with sounds (75 dB, 3s). Extinction was performed using twenty sounds (75 dB, 3s) with no footshocks, 1h after footshocks. Freezing and pain threshold were measured 2h, 2 days, 7 days, or 30 days after PTSD or extinction (there was not any recall session). The results showed freezing behavior showed a downward trend over time in males, while an upward trend over time in females. Extinction slightly decreased freezing behavior in males, while significantly decreased it in females. Pain threshold was increased in male PTSD rats, while after 30days, there was no change in pain perception. In females, pain threshold was restored in both PTSD-7d and - 30d groups. Extinction decreased pain threshold in males, with stronger effect in females. BDNF was decreased and GSK-3beta was increased in male PTSD rats, except PTSD-30d only for BDNF. In females, BDNF level was restored in both PTSD-7d and - 30d, and also, increased in PTSD-2d group, while GSK-3beta was increased. In conclusion, significant sex differences were observed in freezing behavior, pain threshold, and BDNF. Notably, it seems that GSK-3beta may be involved in freezing and pain perception changes only in females exposed to extinction session.

Abstracts from the NIH Office of Research on Women's Health 2018 Annual BIRCWH Meeting – Building Interdisciplinary Research Careers in Women's Health November 28, 2018

Post-traumatic stress disorder (PTSD) is a trauma and stressor-related disorder that results in a prolonged stress response. It is associated with increased oxidative stress and inflammation in the prefrontal cortex (PFC) and hippocampus (HC). The only approved therapy for PTSD is selective serotonin re-uptake inhibitors (SSRIs), but their efficacy is marginal. Recently, we demonstrated that over-production of norepinephrine (NE) as the possible reason for the lack of efficacy of SSRIs. Hence, there is a need for novel therapeutic approaches for the treatment of PTSD. In this study, we investigated the anti-inflammatory role of blueberries in modulating inflammatory markers and neurotransmitter levels in PTSD. Rats were fed either a blueberry enriched (2%) or a control diet. Rats were exposed to cats for one hour on days 1 and 11 of a 31-day schedule to simulate traumatic conditions. The rats were also subjected to psychosocial stress via daily cage cohort changes. At the end of the study, the rats were euthanized and the PFC and HC were isolated. Monoamines were measured by high-performance liquid chromatography. Reactive oxygen species (ROS), gene and protein expression levels of inflammatory cytokines were also measured. In our PTSD model, NE levels were increased and 5-HT levels were decreased when compared to control. In contrast, a blueberry enriched diet increased 5-HT without affecting NE levels. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also studied and they confirmed our findings. The enhanced levels free radicals, gene and protein expression of inflammatory cytokines seen in the PTSD group were normalized with a blueberry enriched diet. Decreased anxiety in this group was shown by improved performance on the elevated plus-maze. These findings indicate blueberries can attenuate oxidative stress and inflammation and restore neurotransmitter imbalances in a rat model of PTSD.

The endurance of memories of emotionally arousing events serves the adaptive role of minimizing future exposure to danger and reinforcing rewarding behaviors. However, following a traumatic event, a subset of individuals suffers from persistent pathological symptoms such as those seen in posttraumatic stress disorder (PTSD). Despite the availability of pharmacological treatments and evidence-based cognitive behavioral therapy, a considerable number of PTSD patients do not respond to the treatment, or show partial remission and relapse of the symptoms. In controlled laboratory studies, PTSD patients show deficient ability to extinguish conditioned fear. Failure to extinguish learned fear could be responsible for the persistence of PTSD symptoms such as elevated anxiety, arousal, and avoidance. It may also explain the high non-response and dropout rates seen during treatment. Animal models are useful for understanding the pathophysiology of the disorder and the development of new treatments. This review examines studies in a rodent model of PTSD with the goal of identifying behavioral and physiological factors that predispose individuals to PTSD symptoms. Single prolonged stress (SPS) is a frequently used rat model of PTSD that involves exposure to several successive stressors. SPS rats show PTSD-like symptoms, including impaired extinction of conditioned fear. Since its development by the Liberzon lab in 1997, the SPS model has been referred to by more than 200 published papers. Here we consider the findings of these studies and unresolved questions that may be investigated using the model.

Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis – related proteins in a rat model of post-traumatic stress disorder