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

In the wild, animals face a highly variable world full of predators. Most predator attacks are unsuccessful, and the prey survives. According to the conventional perspective, the fear responses elicited by predators are acute and transient in nature.

The potential beneficial effect of sleep deprivation following traumatic events to preventing PTSD: Review of current insight regarding sleep, memory, and trauma resonating with ancient rituals-Àìsùn Oku (African) and Tsuya (Japanese).

Sleep figures in numerous ancient texts, for example, Epic of Gilgamesh, and has been a focus for countless mystical and philosophical texts. Even in the present century, sleep remains one of the most complex behaviors whose function still remains to be further explored. Current hypotheses suggest that among other functions, sleep contributes to memory processes.

MDMA treatment paired with a trauma-cue promotes adaptive stress responses in a translational model of PTSD in rats.

MDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, combined with psychotherapy has demonstrated efficacy for the treatment of chronic posttraumatic stress disorder (PTSD) patients. This controlled prospective study aimed to assess the bio-behavioral underpinnings of MDMA in a translational model of PTSD. Rats exposed to predator-scent stress (PSS) were subjected to a trauma-cue at day 7 shortly after single-dose MDMA injection (5 mg/kg).

Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder.

Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity.

Role of Endogenous and Exogenous Corticosterone on Behavioral and Cognitive Responses to Low-Pressure Blast Wave Exposure.

The complex interactions and overlapping symptoms of comorbid post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) induced by an explosive blast wave have become a focus of attention in recent years, making clinical distinction and effective intervention difficult. Because dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to underlie trauma-related (psycho)pathology, we evaluated both the endogenous corticosterone response and the efficacy of exogenous hydrocortisone treatment provided shortly after blast exposure. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast wave produced by exploding a thin copper wire.

Blunted basal corticosterone pulsatility predicts post-exposure susceptibility to PTSD phenotype in rats.

The basal activity of the hypothalamic-pituitary-adrenal axis is highly dynamic and is characterized by both circadian and ultradian (pulsatile) patterns of hormone secretion. Pulsatility of glucocorticoids has been determined to be critical for optimal transcriptional, neuroendocrine, and behavioral responses. We used an animal model of post-traumatic stress disorder (PTSD) to assess whether stress-induced impairment of behavioral responses is correlated with aberrant secretion of corticosterone.

Use of Tumor Markers in Gastrointestinal Cancers: Surgeon Perceptions and Cost-Benefit Trade-Off Analysis.

Background: Gastrointestinal cancers constitute the third most common cancers worldwide. Tumor markers have long since been used in the postoperative surveillance of these malignancies; however, the true value in clinical practice remains undetermined.

Objective: This study aimed to evaluate the clinical utility of three tumor markers in colorectal and esophagogastric cancer.

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).

Predator-scent stress, ethanol consumption and the opioid system in an animal model of PTSD.

Emerging literature points to stress exposure as a potential contributor to the development of alcohol abuse, but animal models have yielded inconsistent results. Converging experimental data indicate that the endogenous opioid system modulates alcohol consumption and stress regulation. The aim of the present study is to examine the interplay between stress exposure, behavioral stress responses, ethanol (EtOH) consumption and the endogenous opioid system in an animal model of posttraumatic stress disorder.

Controlled Low-Pressure Blast-Wave Exposure Causes Distinct Behavioral and Morphological Responses Modelling Mild Traumatic Brain Injury, Post-Traumatic Stress Disorder, and Comorbid Mild Traumatic Brain Injury-Post-Traumatic Stress Disorder.

The intense focus in the clinical literature on the mental and neurocognitive sequelae of explosive blast-wave exposure, especially when comorbid with post-traumatic stress-related disorders (PTSD) is justified, and warrants the design of translationally valid animal studies to provide valid complementary basic data. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast-wave produced by exploding a thin copper wire. By combining cognitive-behavioral paradigms and ex vivo brain MRI to assess mild traumatic brain injury (mTBI) phenotype with a validated behavioral model for PTSD, complemented by morphological assessments, this study sought to examine our ability to evaluate the biobehavioral effects of low-intensity blast overpressure on rats, in a translationally valid manner.

Distinctive hippocampal and amygdalar cytoarchitectural changes underlie specific patterns of behavioral disruption following stress exposure in an animal model of PTSD.

Alterations in cytoarchitecture and molecular signaling have been observed in adaptive and maladaptive responses to stress and presumably underlie the physiological and behavioral changes observed. The relationship between behavioral responses to stress exposure and changes in cytoarchitecture of subregions of the hippocampus and amygdala was investigated in an animal model of PTSD. Behaviors in elevated plus-maze and acoustic startle response tests were assessed in rats 7 days after exposure to predator scent stress.

Diurnal fluctuations in HPA and neuropeptide Y-ergic systems underlie differences in vulnerability to traumatic stress responses at different zeitgeber times.

The hypothalamic-pituitary-adrenal (HPA) axis displays a characteristic circadian pattern of corticosterone release, with higher levels at the onset of the active phase and lower levels at the onset of the inactive phase. As corticosterone levels modify the response to stress and influence the susceptibility to and/or severity of stress-related sequelae, we examined the effects of an acute psychological trauma applied at different zeitgeber times (ZTs) on behavioral stress responses. Rats were exposed to stress either at the onset of the inactive-(light) phase (ZT=0) or at the onset of the active-(dark) phase (ZT=12).

Maintaining the clinical relevance of animal models in translational studies of post-traumatic stress disorder.

The diagnosis of Post-Traumatic Stress Disorder (PTSD) is conditional on directly experiencing or witnessing a significantly threatening event and the presence of a certain minimal number of symptoms from each of four symptom clusters (re-experiencing, avoidance, negative cognition and mood, and hyperarousal) at least one month after the event (DSM 5) (American Psychiatric Association 2013). Only a proportion of the population exposed develops symptoms fulfilling the criteria. The individual heterogeneity in responses of stress-exposed animals suggested that adapting clearly defined and reliably reproducible "diagnostic", i.

Blunting of the HPA-axis underlies the lack of preventive efficacy of early post-stressor single-dose Delta-9-tetrahydrocannabinol (THC).

The therapeutic value of Delta-9-tetrahydrocannabinol (Δ9-THC) in the aftermath of trauma has recently raised interest. A prospective animal model for posttraumatic stress disorder was employed to assess the behavioral effects of a single dose of Δ9-THC administered intraperitoneally following exposure to psychogenic stress. Animals were exposed to predator scent stress and treated 1h later with Δ9-THC (1, 5 and 10mg/kg) or vehicle.

Translationally relevant modeling of PTSD in rodents.

Post-traumatic stress disorder (PTSD) is clinically defined in DSM-4 by exposure to a significantly threatening and/or horrifying event and the presence of a certain number of symptoms from each of three symptom clusters at least one month after the event. Since humans clearly do not respond homogeneously to a potentially traumatic experience, the heterogeneity in animal responses might be regarded as confirming the validity of animal studies, rather than as representing a problem. A model of diagnostic criteria for psychiatric disorders could therefore be applied to animal responses to augment the validity of study data, providing that the criteria for classification are clearly defined, reliably reproducible and yield results that conform to findings in human subjects.

Animal models of post-traumatic stress disorder.

Animal behavioral studies have commonly regarded the entire group of animals subjected to the study conditions as homogeneous, disregarding individual differences in response patterns. The following discussion will focus on a method of analyzing data that aims to model clinical diagnostic criteria applied to individual patterns of response using data from behavioral measures, and employing cut-off scores to distinguish between extremes of response versus non-response and the sizeable proportion of study subjects in-between them. This protocol unit will present the concept of the model and its background, provide detailed protocols for each of its components, and present a selection of studies employing and examining the model, alongside the underlying translational rationale of each.

Post-exposure sleep deprivation facilitates correctly timed interactions between glucocorticoid and adrenergic systems, which attenuate traumatic stress responses.

Reliable evidence supports the role of sleep in learning and memory processes. In rodents, sleep deprivation (SD) negatively affects consolidation of hippocampus-dependent memories. As memory is integral to post-traumatic stress symptoms, the effects of post-exposure SD on various aspect of the response to stress in a controlled, prospective animal model of post-traumatic stress disorder (PTSD) were evaluated.

The long-term abnormalities in circadian expression of Period 1 and Period 2 genes in response to stress is normalized by agomelatine administered immediately after exposure.

In mammals, the circadian and stress systems are involved in adaptation to predictable and unpredictable stimuli, respectively. A series of experiments examined the relationship between stress-induced posttraumatic stress (PTSD)-like behavioral response patterns in rats and brain levels of genes related to circadian rhythms. The effects of agomelatine, administered immediately after exposure, on stress-related behavior and on local expression of Per1 and Per2 were assessed.

High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies.

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below.

The characteristic long-term upregulation of hippocampal NF-κB complex in PTSD-like behavioral stress response is normalized by high-dose corticosterone and pyrrolidine dithiocarbamate administered immediately after exposure.

Nuclear factor-κB (NF-κB) is a ubiquitously expressed transcription factor for genes involved in cell survival, differentiation, inflammation, and growth. This study examined the role of NF-κB pathway in stress-induced PTSD-like behavioral response patterns in rats. Immunohistochemical technique was used to detect the expression of the NF-κB p50 and p65 subunits, I-κBα, p38, and phospho-p38 in the hippocampal subregions at 7 days after exposure to predator scent stress.

Animal model for PTSD: from clinical concept to translational research.

In humans, the diagnosis of PTSD is made only if an individual exhibits a certain number of symptoms from each of three quite well defined symptom clusters over a certain period of time. Animal behavioral studies, however, have generally tended to overlook this aspect and have commonly regarded the entire group of animals subjected to certain study conditions as homogeneous. Thus, in an attempt to develop animal models of long-term chronic behavioral responses to stress (i.

Early post-stressor intervention with propranolol is ineffective in preventing posttraumatic stress responses in an animal model for PTSD.

The therapeutic value of β-adrenoceptor blockage, using propranolol, in the aftermath of traumatic experience is uncertain. A prospective, controlled animal model of posttraumatic stress disorder (PTSD) was employed to assess the effects of propranolol on long-term behavioral responses to stress. Animals exposed to predator scent stress received a single bolus of propranolol (10 or 15mg/kg) or vehicle 1h post-exposure.

Mapping the brain pathways of traumatic memory: inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory processes and attenuates traumatic stress responses in rats.

Background: Protein kinase M zeta (PKMzeta), a constitutively active isoform of protein kinase C, has been implicated in protein synthesis-dependent maintenance of long-term potentiation and memory storage in the brain. Recent studies reported that local application of ZIP, a membrane-permeant PKMzeta inhibitor, into the insular cortex (IC) of behaving rats abolished long-term memory of taste associations.

Method: This study assessed the long-term effects of local applications of ZIP microinjected immediately (1 h) or 10 days after predator scent stress exposure, in a controlled prospectively designed animal model for PTSD.

A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder.

Background: Activation of glucocorticoid receptors (GR) increases expression of the mitogen-activated protein kinase (MAPK) pathway leading to increased expression of Zif/268, an effector immediate early gene involved in cellular growth, intracellular signaling, and synaptic modification. Glucocorticoids induce expression of Zif/268 through two distinct mechanisms: a rapid-onset, MAPK-independent pathway and a slower-onset, MAPK-dependent mechanism.

Method: This study investigated both rapid and long-term expression of GR protein in the cytosolic extract, its translocation to the nucleus, and expression of mRNA for the Zif/268 gene in selected brain areas, associated with circulating levels of corticosterone, in an animal model of PTSD.