Rodent Model Of Post-traumatic Stress Disorder Research Articles

Effects of early social isolation and adolescent single prolonged stress on anxiety-like behaviors and voluntary ethanol consumption in female Long Evans rats.

Exposure to stress during childhood and adolescence is a risk factor for alcohol use disorder (AUD) and comorbid conditions, including posttraumatic stress disorder (PTSD). We previously established an adolescent social isolation (SI) model that leads to the emergence of a wide range of behavioral risk factors for AUD, including increased anxiety-like behavior, locomotor activity, and ethanol consumption in male and female rats. Here, we sought to test the hypothesis that SI may increase vulnerability to single prolonged stress (SPS), a rodent model of PTSD. Female Long Evans rats (n = 8/group) were either single-housed or group-housed (GH) (4/cage) on postnatal day 21. One week later, rats underwent testing in the open field test (OFT), elevated plus-maze (EPM), and successive alleys test (SAT). Following initial behavioral testing, a subset of SI/GH rats were exposed to SPS. All rats were then tested on the novelty-suppressed feeding test (NSFT) followed by fear conditioning and home cage two-bottle choice to assess ethanol consumption. SI significantly increased activity in the OFT and anxiety-like behavior on the SAT, but not the EPM. While SI and SPS alone had no effect on the NSFT, exposure to both stressors significantly increased approach latency. Complex effects of stress history were observed across a 3-day fear conditioning paradigm and no group differences were observed with home cage ethanol consumption, regardless of prior ethanol exposure. The results from this study provide novel evidence that SI interacts with SPS in female rats to influence behavior in assays of unconditioned anxiety-like behavior (NSFT) and conditioned fear. Surprisingly, stress exposure had no effect on home cage ethanol consumption. Ultimately, these models provide useful avenues to examine the interaction between stressful experiences, alcohol exposure, biological sex, and the neurobiological adaptations underlying potential risk factors for psychiatric conditions.

Brain Monoamine Dysfunction in Response to Predator Scent Stress Accompanies Stress-Susceptibility in Female Rats.

Post-traumatic stress disorder (PTSD) is prevalent in women; however, preclinical research on PTSD has predominantly been conducted in male animals. Using a predator scent stress (PSS) rodent model of PTSD, we sought to determine if stress-susceptible female rats show altered monoamine concentrations in brain regions associated with PTSD: the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and dorsal (dHIPP) and ventral (vHIPP) hippocampus. Female Sprague-Dawley rats were exposed to a single, 10-min PSS exposure and tested for persistent anhedonia, fear, and anxiety-like behavior over four weeks. Rats were phenotyped as stress-Susceptible based on sucrose consumption in the sucrose preference task and time spent in the open arms of the elevated plus maze. Brain tissue was collected, and norepinephrine, dopamine, serotonin, and their metabolites were quantified using high-performance liquid chromatography. Stress-susceptibility in female rats was associated with increased dopamine and serotonin turnover in the mPFC. Susceptibility was also associated with elevated dopamine turnover in the NAc and increased norepinephrine in the vHIPP. Our findings suggest that stress-susceptibility after a single stress exposure is associated with long-term effects on monoamine function in female rats. These data suggest interventions that decrease monoamine turnover, such as MAOIs, may be effective in the treatment of PTSD in women.

Protective effects of glucocorticoid receptor antagonist Mifepristone on fear memory extinction impairment in a rat model of PTSD

IntroductionCentral glucocorticoid receptor (GR) has been found to play an important role in the interpretation of cognitive abnormalities of posttraumatic stress disorder (PTSD), particularly focused on the extinction failure of fear memory. Potential of using GR antagonist as a pharmacological agent to prevent PTSD-related fear memory disruption is worth investigating.ObjectivesWe aimed to examine whether GR antagonist Mifepristone (RU486) administered before single prolonged stress (SPS) can prevent rats from fear memory extinction impairment.MethodsIn the present study, SPS was employed in rats to induce a rodent model of PTSD. 60 minutes before SPS, RU486 (20 mg/kg) was administered by intraperitoneal injection. Seven days after SPS, rats received a protocol of behavioral testing to measure their abilities of specific fear memory (by a cue-dependent fear conditioning paradigm) and nonspecific spatial memory (by T-maze). Neurochemically, we measured plasma corticosterone with or without dexamethasone suppression, activation ratio of GR and levels of norepinephrine, dopamine, and serotonin in amygdala, paraventricular nucleus, dorsal and ventral hippocampus.ResultsOur results found that RU486 exerted protective effects on SPS-induced fear extinction impairment. Corticosterone of SPS-RU486 rats was less suppressed by dexamethasone. GR became less activated in dorsal hippocampus of SPS-RU486 rats.ConclusionsThe findings supported the utility of GR antagonism in preventing the development of PTSD.DisclosureNo significant relationships.

Effects of RU486 in Treatment of Traumatic Stress-Induced Glucocorticoid Dysregulation and Fear-Related Abnormalities: Early versus Late Intervention.

Central glucocorticoid receptor (GR) activity is enhanced following traumatic events, playing a key role in the stress-related cognitive abnormalities of posttraumatic stress disorder (PTSD). GR antagonists are expected to have potential as pharmacological agents to treat PTSD-related symptoms such as anxiety and fear memory disruption. However, an incubation period is usually required and stress-induced abnormalities do not develop immediately following the trauma; thus, the optimal intervention timing should be considered. Single prolonged stress (SPS) was employed as a rodent PTSD model to examine the effects of early or late (1–7 versus 8–14 days after the SPS) sub-chronic RU486 (a GR antagonist) administration. Behaviorally, fear conditioning and anxiety behavior were assessed using the fear-conditioning test and elevated T-maze (ETM), respectively. Neurochemically, the expressions of GR, FK506-binding proteins 4 and 5 (FKBP4 and FKBP5), and early growth response-1 (Egr-1) were assessed in the hippocampus, medial prefrontal cortex (mPFC), amygdala, and hypothalamus, together with the level of plasma corticosterone. Early RU486 administration could inhibit SPS-induced behavioral abnormalities and glucocorticoid system dysregulation by reversing the SPS-induced fear extinction deficit, and preventing SPS-reduced plasma corticosterone levels and SPS-induced Egr-1 overexpression in the hippocampus. Early RU486 administration following SPS also increased the FKBP5 level in the hippocampus and hypothalamus. Finally, both early and late RU486 administration inhibited the elevated hippocampal FKBP4 level and hypothalamus GR level in the SPS rats. Early intervention with a GR antagonist aids in the correction of traumatic stress-induced fear and anxiety dysregulation.

Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice.

Humans with post-traumatic stress disorder (PTSD) exhibit sleep disturbances that include insomnia, nightmares, and enhanced daytime sleepiness. Sleep disturbances are considered a hallmark feature of PTSD; however, little is known about the cellular and molecular mechanisms regulating trauma-induced sleep disorders. Using a rodent model of PTSD called "Single Prolonged Stress" (SPS) we examined the requirement of the brain-type fatty acid binding protein Fabp7, an astrocyte expressed lipid-signaling molecule, in mediating trauma-induced sleep disturbances. We measured baseline sleep/wake parameters and then exposed Fabp7 knock-out (KO) and wild-type (WT) C57BL/6N genetic background control animals to SPS. Sleep and wake measurements were obtained immediately following the initial trauma exposure of SPS, and again 7 days later. We found that active-phase (dark period) wakefulness was similar in KO and WT at baseline and immediately following SPS; however, it was significantly increased after 7 days. These effects were opposite in the inactive-phase (light period), where KOs exhibited increased wake in baseline and following SPS, but returned to WT levels after 7 days. To examine the effects of Fabp7 on unconditioned anxiety following trauma, we exposed KO and WT mice to the light-dark box test before and after SPS. Prior to SPS, KO and WT mice spent similar amounts of time in the lit compartment. Following SPS, KO mice spent significantly more time in the lit compartment compared to WT mice. These results demonstrate that mutations in an astrocyte-expressed gene (Fabp7) influence changes in stress-dependent sleep disturbances and associated anxiety behavior.

Positive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fear

N-methyl-D-aspartate receptor (NMDAR) modulators have recently received increased attention as potential therapeutics for posttraumatic stress disorder (PTSD). Here, we tested a novel NMDAR-positive modulator, NYX-783, in the following two rodent models of PTSD: an auditory fear-conditioning model and a single-prolonged stress (SPS) model. We examined the ability of NYX-783 to reduce subsequent fear-based behaviors by measuring enhanced fear extinction and reduced spontaneous recovery (spontaneous return of fear) in male mice. NYX-783 administration significantly reduced spontaneous recovery in both PTSD models and enhanced fear extinction in the SPS model. Furthermore, NYX-783 increased the NMDA-induced inward currents of excitatory and inhibitory neurons in the infralimbic medial prefrontal cortex (IL mPFC) and that the GluN2B subunit of NMDARs on pyramidal neurons in the IL mPFC is required for its effect on spontaneous recovery. The downstream expression of brain-derived neurotrophic factor was required for NYX-783 to achieve its behavioral effect. These results elucidate the cellular targets of NYX-783 and the molecular mechanisms underlying the inhibition of spontaneous recovery. These preclinical findings support the hypothesis that NYX-783 may have therapeutic potential for PTSD treatment and may be particularly useful for inhibiting spontaneous recovery.

Peptide LCGA-17 Attenuates Behavioral and Neurochemical Deficits in Rodent Models of PTSD and Depression.

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant.

Single prolonged stress blocks sleep homeostasis and pre-trauma sleep deprivation does not exacerbate the severity of trauma-induced fear-associated memory impairments.

Sleep is intimately linked to cognitive performance and exposure to traumatic stress that leads to post-traumatic stress disorder (PTSD) impairs both sleep and cognitive function. However, the contribution of pre-trauma sleep loss to subsequent trauma-dependent fear-associated memory impairment remains unstudied. We hypothesized that sleep deprivation (SD) prior to trauma exposure may increase the severity of a PTSD-like phenotype in rats exposed to single prolonged stress (SPS), a rodent model of PTSD. Rats were exposed to SPS alone, SD alone, or a combination of SPS+SD and measures of fear-associated memory impairments and vigilance state changes were compared to a group of control animals not exposed to SPS or SD. We found that SPS, and SPS+SD animals showed impaired fear-associated memory processing and that the addition of SD to SPS did not further exaggerate the effect of SPS alone. Additionally, the combination of SPS with SD results in a unique homeostatic sleep duration phenotype when compared to SD, SPS, or control animals. SPS exposure following SD represses homeostatic rebound and eliminates sleep-deprivation-induced increases in NREM sleep delta power. This work identifies a unique time frame where trauma exposure and sleep interact and identifies this window of time as a potential therapeutic treatment window for staving off the negative consequences of trauma exposure.

Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model

Accumulating evidence suggests that elevated inflammation contributes to the pathophysiology of post-traumatic stress disorder (PTSD) and that anti-inflammatory drugs might be a new treatment strategy for PTSD. It has been reported that beta-hydroxybutyrate (BHB), one of the main ketone bodies produced, can have an anti-inflammatory and antidepressant effect. Here, we investigated the potential anti-anxiety and anti-inflammatory effects of BHB using a rodent PTSD model, induced by single prolonged stress (SPS). Male, Sprague–Dawley rats were employed in this study. Repeated administration of BHB attenuated SPS-induced anxiety-related behaviors evaluated by the elevated plus maze test. SPS increased the serum levels of TNF-α and IL-1β. In contrast, BHB administration partially attenuated the increase of serum TNF-α. These findings demonstrate that BHB exerts its anxiolytic effects, possibly by inhibiting systemic TNF-α. Hence, BHB may be a novel therapeutic candidate for the treatment of PTSD.

Increases in dendritic spine density in BLA without metabolic changes in a rodent model of PTSD.

Imaging studies have shown abnormal amygdala function in patients with posttraumatic stress disorder (PTSD). In addition, alterations in synaptic plasticity have been associated with psychiatric disorders and previous reports have indicated alterations in the amygdala morphology, especially in basolateral (BLA) neurons, are associated with stress-related disorders. Since, some individuals exposed to a traumatic event develop PTSD, the goals of this study were to evaluate the early effects of PTSD on amygdala glucose metabolism and analyze the possible BLA dendritic spine plasticity in animals with different levels of behavioral response. We employed the inescapable footshock protocol as an experimental model of PTSD and the animals were classified according to the duration of their freezing behavior into distinct groups: "extreme behavioral response" (EBR) and "minimal behavioral response". We evaluated the amygdala glucose metabolism at baseline (before the stress protocol) and immediately after the situational reminder using the microPET and the radiopharmaceutical 18F-FDG. The BLA dendritic spines were analyzed according to their number, density, shape and morphometric parameters. Our results show the EBR animals exhibited longer freezing behavior and increased proximal dendritic spines density in the BLA neurons. Neither the amygdaloid glucose metabolism, the types of dendritic spines nor their morphometric parameters showed statistically significant differences. The extreme behavior response induced by this PTSD protocol produces an early increase in BLA spine density, which is unassociated with either additional changes in the shape of spines or metabolic changes in the whole amygdala of Wistar rats.

Preclinical findings on the potential of intranasal neuropeptide Y for treating hyperarousal features of PTSD.

Acoustic startle response (ASR) assesses hyperarousal, a core symptom of posttraumatic stress disorder (PTSD). Intranasal neuropeptide Y (NPY) administration was shown to prevent hyperarousal in single prolonged stress (SPS) rodent PTSD model. However, it is unclear how ASR itself alters responses to stress. Rats (A-S-A) were exposed to acoustic startle (AS) 1 day before SPS (ASR1) and 2 weeks afterward (ASR2). Other groups were exposed in parallel to either AS (A-A) or SPS or neither. SPS enhanced ASR2. In relevant brain areas, mRNA levels were determined by qRT-PCR. In mediobasal hypothalamus, AS or SPS each increased CRH mRNA levels without an additive effect. Exposure to AS appeared to dampen some responses to SPS. The SPS-triggered reduction of GR and FKBP5 gene expression was not observed in A-S-A group. In locus coeruleus, SPS increased CRHR1 and reduced Y2R mRNAs, but not in A-S-A group. In both regions, AS altered NPY receptor gene expression, which may mediate dampening responses to SPS. In second experiment, intranasal NPY administered 2 weeks after SPS reversed hyperarousal symptoms for at least 7 days. This study reveals important effects of AS on the NPY system and demonstrates that intranasal NPY elicits long-lasting reversal of traumatic stress-triggered hyperarousal.

Pair-housing rats does not protect from behavioral consequences of an acute traumatic experience.

Posttraumatic stress disorder (PTSD) is an extremely debilitating disease with a broad array of associated symptoms, making the disorder difficult to diagnose and treat. In humans, patients seem to benefit from group therapy or other means of promoting social behavior. To test these effects on our rodent model of PTSD, adult, male rats were housed in either single or pair conditions prior to and during an acute stressor to induce PTSD-like behaviors in these rats. Subsequently, rats were assessed for PTSD-like symptoms to determine the effect of social housing on stress-induced phenotypes. Posttrauma phenotypes, including enhanced fear conditioning and anxiety-related behavior, persisted regardless of the animal's housing condition. It is possible that any housing driven improvements to stress-induced phenotypes would require longer periods of pair housing than were used in these experiments. Although PTSD patients show improved health outcomes following social interaction or group therapy, the fear and anxiety phenotypes seen following an acute stressor in an animal model of the disease endured despite an animal's housing condition. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effects of pregabalin on neurobehavior in an adult male rat model of PTSD.

Posttraumatic stress disorder (PTSD) can be a very debilitating condition. Effective approaches to prevent and treat PTSD are important areas of basic science research. Pregabalin (PGB), a gabapentinoid derivative of γ-aminobutyric acid, possesses the potential to positively affect neurobehavioral changes associated with PTSD. Using a rodent model of PTSD, the aims of this study were to determine the effects of PGB as a possible prevention for the development of PTSD-like symptoms and its use as a possible treatment. A prospective, experimental, between groups design was used in conjunction with a three-day restraint/shock PTSD stress model. Sixty rats were randomly assigned between two groups, non-stressed and stressed (PTSD). Each of the main two groups was then randomly assigned into six experimental groups: control vehicle, control PGB, control naïve, PTSD vehicle, PTSD Pre-PGB (prophylactic), PTSD Post-PGB (non-prophylactic). The neurobehavioral components of PTSD were evaluated using the elevated plus maze (EPM), Morris water maze (MWM), and forced swim test (FST). Pregabalin administered 24 hours before the initial PTSD event or for 10 days following the last PTSD stress event did not statistically improve mean open arm exploration on the EPM, spatial memory, and learning in the MWM or behavioral despair measured by the FST (p > 0.05).

D-Cycloserine Facilitates Reversal in an Animal Model of Post-traumatic Stress Disorder

Many psychiatric disorders are associated with cognitive dysfunction that is ineffectively treated by existing pharmacotherapies and which may contribute to poor real-world functioning. D-cycloserine (DCS) is a partial N-methyl-D-aspartate (NMDA) agonist that has attracted attention because of its cognitive enhancing properties, including in people with post-traumatic stress disorder (PTSD). Here, we examined the effect of DCS on reversal learning - a type of cognitive flexibility – following exposure to single prolonged stress (SPS), a rodent model of PTSD. Male Sprague Dawley rats (n = 64) were trained to press levers in an operant chamber, matched for performance and assigned to SPS or control (unstressed) groups. Following SPS, rats received three additional lever press sessions, followed by a side bias test on day three. One day later they learned a response discrimination rule (press left or right lever, opposite to side bias) and on a subsequent day were trained (and tested) for reversal to the opposite lever. DCS (15 mg/kg) or vehicle was administered 30 minutes prior to the reversal session. No between-group differences were found in acquisition or retrieval of the initial rule, but a significant drug x stress interaction on response discrimination reversal indicated that DCS had a greater beneficial effect on SPS rats’ cognitive flexibility than it did on performance in controls. These findings add to a growing literature on the beneficial effects of DCS for treating a wide variety of deficits that develop following exposure to extreme stress and may have implications for the development of novel pharmacotherapies for PTSD.

Potential of Intranasal Neuropeptide Y (NPY) and/or Melanocortin 4 Receptor (MC4R) Antagonists for Preventing or Treating PTSD.

There is a great need for effective treatment options for post-traumatic stress disorder (PTSD). Neuropeptide Y (NPY) is associated with resilience to traumatic stress. MC4R antagonists, such as HS014, also reduce response to stress. Both regulate stress-responsive systems - the hypothalamic-pituitary-axis (HPA) and the noradrenergic nervous system and their associated behaviors. Therefore, we examined if their intranasal delivery to brain could attenuate development of PTSD-related symptoms in single prolonged stress (SPS) rodent PTSD model. Three regimens were used: (1) prophylactic treatment 30 min before SPS stressors, (2) early intervention right after SPS stressors, (3) therapeutic treatment when PTSD behaviors are manifested 1 wk or more after the traumatic stress. NPY delivered by regimen 1 or 2 prevented SPS-triggered elevation in anxiety, depressive-like behavior, and hyperarousal and reduced dysregulation of HPA axis. Hypothalamic CRH mRNA and GR in ventral hippocampus were significantly induced in vehicle- but not NPY-treated group. NPY also prevented hypersensitivity of LC/NE system to novel mild stressor and induction of CRH in amygdala. Some of these impairments were also reduced with HS014, alone or together with NPY. When given after symptoms were manifested (regiment 3), NPY attenuated anxiety and depressive behaviors. This demonstrates strong preclinical proof of concept for intranasal NPY, and perhaps MC4R antagonists, for non-invasive early pharmacological interventions for PTSD and comorbid disorders and possibly also as therapeutic strategy.

A Systematic Review of Interleukin-1β in Post-Traumatic Stress Disorder: Evidence from Human and Animal Studies

Pro-inflammatory cytokines, such as interleukin (IL)-1β, have been implicated as underlying pathophysiological mechanisms and potential biomarkers of post-traumatic stress disorder (PTSD). This systematic review examines data regarding IL-1β production/concentration in human and animal studies of PTSD. In accordance with PRISMA guidelines, relevant articles from PubMed were reviewed from inception until July 10, 2017. Nineteen studies were eligible for inclusion. Animal studies demonstrated increased hippocampal IL-1β in rodent models of PTSD. Several immunomodulatory drugs were shown to reduce elevated IL-1β levels and anxiety-like behaviors in animals. Human cross-sectional studies showed contradictory results; serum and plasma IL-1β concentrations in PTSD patients were either elevated or did not differ from control groups. In vitro IL-1β production by stimulated cells demonstrated no difference between PTSD and control participants, although spontaneous in vitro production of IL-1β was increased in the PTSD group. The findings from 2 longitudinal studies were inconsistent. Given the conflicting findings, it is premature to consider IL-1β as a biomarker of PTSD. Anti-inflammatory agents may reduce IL-1β, and be a potential basis for future therapeutic agents in PTSD treatment. More longitudinal research is needed to better understand the role of IL-1β in the development and/or maintenance of PTSD.

Using the Single Prolonged Stress Model to Examine the Pathophysiology 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.

The ventromedial prefrontal cortex in a model of traumatic stress: fear inhibition or contextual processing?

The ventromedial prefrontal cortex (vmPFC) has consistently appeared altered in post-traumatic stress disorder (PTSD). Although the vmPFC is thought to support the extinction of learned fear responses, several findings support a broader role for this structure in the regulation of fear. To further characterize the relationship between vmPFC dysfunction and responses to traumatic stress, we examined the effects of pretraining vmPFC lesions on trauma reactivity and enhanced fear learning in a rodent model of PTSD. In Experiment 1, lesions did not produce differences in shock reactivity during an acute traumatic episode, nor did they alter the strength of the traumatic memory. However, when lesioned animals were subsequently given a single mild aversive stimulus in a novel context, they showed a blunting of the enhanced fear response to this context seen in traumatized animals. In order to address this counterintuitive finding, Experiment 2 assessed whether lesions also attenuated fear responses to discrete tone cues. Enhanced fear for discrete cues following trauma was preserved in lesioned animals, indicating that the deficit observed in Experiment 1 is limited to contextual stimuli. These findings further support the notion that the vmPFC contributes to the regulation of fear through its influence on context learning and contrasts the prevailing view that the vmPFC directly inhibits fear.

Behavioral and cognitive impact of early life stress: Insights from an animal model

BackgroundChildren subjected to traumatic events during childhood are reported to exhibit behavioral and cognitive deficits later in life, often leading to post-traumatic stress disorder (PTSD) and major depression. Interestingly, some children continue to remain normal despite being exposed to the same risk factors. These trauma-related behavioral and cognitive profiles across different stages of life are not well understood. Animal studies can offer useful insights. ObjectiveThe goal of this study was to determine the impact of early life exposure to traumatic events on behavioral and cognitive profile in rats by tracking the behavior of each rat at different ages. MethodsWe utilized the single prolonged stress (SPS), a rodent model of PTSD, to study the effects of early life stress. Male Sprague-Dawley rats were exposed to SPS on post-natal day (PND) 25. Tests to assess anxiety- and depression-like behavior, as well as learning and memory function were performed at PND32, 60 and 90. ResultsRats exposed to SPS exhibited both anxiety- and depression-like behavior at PND32. And, short-term (STM) but not long-term memory (LTM) was impaired. Rats exposed to SPS at PND60 exhibited anxiety- but not depression-like behavior. STM but not LTM was impaired. Rats exposed to SPS at PND90 exhibited fearful (as indicated by elevated plus maze test) but not an overall anxiety-like behavior (in light and dark test). These rats also displayed significant depression-like behavior with no changes in STM or LTM. Interestingly, when data was further analyzed, two subsets of PND90 rats exposed to SPS were identified, “susceptible”: with depression-like behavior and “resilient”: without depression-like behavior. Importantly, while resilient group expressed early signs of anxiety- (at PND32 and PND60) and depression-like behavior (at PND32), these behavioral deficits were absent at PND90. On the other hand, susceptible PND90 rats exposed to SPS expressed later onset of anxiety-like behavior (at PND60), while depression-like phenotype was evident only later on at PND90. ConclusionsOur findings suggest that early life stress caused co-occurrence of anxiety and depression-like behavior at PND32 (mimics human early-adolescent period). This co-occurrence was lost at PND60 with demonstration of anxiety- but not depression-like behavior. Later, depression but not anxiety-like behavior was observed at PND90. It seems that behavioral adaptations occur at the critical PND60 stage (mimics human late-adolescent period), where behavioral and cognitive switching occurs, thereby, expressing susceptible and resilient phenotypes.

Change of Rin1 and Stathmin in the Animal Model of Traumatic Stresses.

The molecular mechanism of fear memory is poorly understood. Therefore, the pathogenesis of post-traumatic stress disorder (PTSD), whose symptom presentation can enhance fear memory, remains largely unclear. Recent studies with knockout animals have reported that Rin1 and stathmin regulate fear memory. Rin1 inhibits acquisition and promotes memory extinction, whereas stathmin regulates innate and basal fear. The aim of our study was to examine changes in the expression of Rin1 and stathmin in different animal models of stress, particluarly traumatic stress. We used three animal traumatic stresses: single prolonged stress (SPS, which is a rodent model of PTSD), an immobilization-stress (IM) and a Loud sound stress (LSS), to examine the change and uniqueness in Rin1/stathmin expression. Behavioral tests of SPS rats demonstrated increased anxiety and contextual fear-conditioning. They showed decreased long-term potentiation (LTP), as well as decreased stathmin and increased Rin1 expression in the hippocampus and the amygdala. Expression of the stathmin effector, tubulin, and downstream molecules Rin1, Rab5, and Abl, appeared to increase. Rin1 and EphA4 were endogenously coexpressed in primary neurons after SPS stimulation. IM rats exhibited increased anxiety behavior and enhanced fear-conditioning to contextual and auditory stimuli. Similar changes in expression of Rin1/stathmin were observed in IM rats whereas no changes were observed in rats exposed to a loud sound. These data suggest that changes in expression of the Rin1 and stathmin genes may be involved in rodents with SPS and IM stresses, which provide valuable insight into fear memories under abnormal conditions, particularly in PTSD.