Fear-potentiated Startle Paradigm Research Articles

HIV Interacts with Posttraumatic Stress Disorder to Impact Fear Psychophysiology in Trauma-Exposed Black Women.

The prevalence of posttraumatic stress disorder (PTSD) among people living with HIV (PLWH) is higher than in the general population and can impact health behaviors. The influence of HIV on PTSD psychophysiology requires further investigation due to implications for the treatment of PTSD in PLWH. Utilizing fear-potentiated startle (FPS), we aimed to interrogate the influence of PTSD and HIV on fear responses. Women (18-65 years of age) recruited from the Women's Interagency HIV Study in Atlanta, GA (n = 70, 26 without HIV and 44 with HIV), provided informed consent and completed a semistructured interview to assess trauma exposure and PTSD symptom severity. Participants also underwent an FPS paradigm to assess fear acquisition and extinction: Psychophysiological indices that measure how individuals learn new fear and then subsequently attempt to suppress this fear. Women with PTSD, who did not have HIV, exhibited a greater startle response compared to women without PTSD or HIV during late acquisition to both the danger cue, reinforced conditioned stimulus (CS+, p = 0.013)), and the safety cue, non-reinforced conditioned stimulus (CS-, p = 0.046)), whereas women living with HIV (WLH) and PTSD demonstrated blunted fear responses compared to women with PTSD only. During extinction, WLH comorbid with PTSD exhibited an increased fear response during the extinction period in comparison to all other groups (p = 0.023). Women without PTSD demonstrated a reduction in the fear response during extinction regardless of HIV status. Our findings indicate that HIV further modifies fear psychophysiology in WLH with comorbid PTSD, highlighting the importance of considering HIV status in conjunction with PTSD treatment.

Pre-Learning Stress That Is Temporally Removed from Acquisition Impairs Fear Learning.

Few studies have examined the time-dependent effects of stress on fear learning. Previously, we found that stress immediately before fear conditioning enhanced fear learning. Here, we aimed to extend these findings by assessing the effects of stress 30 min prior to fear conditioning on fear learning and fear generalization. Two hundred and twenty-one healthy adults underwent stress (socially evaluated cold pressor test) or a control manipulation 30 min before completing differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli. Stress impaired the acquisition of fear on Day 1 but had no significant impact on fear generalization. The stress-induced impairment of fear learning was particularly evident in participants who exhibited a robust cortisol response to the stressor. These findings are consistent with the notion that stress administered 30 min before learning impairs memory formation via corticosteroid-related mechanisms and may help us understand how fear memories are altered in stress-related psychological disorders.

The fear that remains: Associations between trauma, related psychopathology, and fear-potentiated startle in youth resettled as refugees.

Fear-potentiated startle (FPS) can be used to measure fear and safety learning-behaviors affected by trauma that may map onto posttraumatic stress disorder (PTSD). Therefore, FPS could be a candidate biomarker of trauma-related psychopathology and a potential identifier of trauma-exposed youth in need of focused treatment. We enrolled n=71 (35 females, Mage =12.7 years) Syrian youth exposed to civilian war trauma. Eyeblink electromyogram (EMG) data from a differential conditioning FPS paradigm were obtained 2.5 years after resettlement. Youth provided self-report of trauma exposure (Harvard Trauma Questionnaire) and PTSD symptoms (UCLA PTSD Reaction Index). While FPS during conditioning was not associated with symptoms, associations with psychopathology emerged in fear extinction. Probable PTSD was associated with FPS in the last block of extinction, such that FPS to threat cue was significantly greater in the PTSD+ group compared to the PTSD- group at the end of extinction (F=6.25, p=.015). As with adults, we observed a deficit in extinction learning but not fear conditioning in youth with PTSD. These results support the use of trauma-informed cognitive behavioral therapy based on the learning principles of extinction in youth with PTSD.

Protocol for a randomized controlled study examining the role of rapid eye movement sleep in fear-related mechanisms: rapid eye movement fragmentation and fear inhibition in adults with insomnia disorders before and after cognitive behavioral therapy for insomnia.

Insomnia confers a 2.5-to-3-fold risk of developing posttraumatic stress disorder (PTSD) after a traumatic event. The mechanism underlying this increased risk, however, remains unknown. We postulate insomnia may contribute to PTSD by disrupting rapid eye movement (REM) sleep, as REM sleep disruption has been shown to impair fear inhibitory processes, which are central to the natural recovery from trauma. To test this hypothesis, the following protocol aims to: (1) examine the relationship between REM sleep and fear inhibition in insomnia, and (2) examine whether reducing REM fragmentation by treating insomnia, in turn, improves fear inhibition. Ninety-two adults with Insomnia Disorder will be block randomized (1:1; stratified by sex) to an active treatment (7 weekly sessions of Cognitive Behavioral Therapy for Insomnia (CBT-I) via telehealth) or waitlist control condition. REM sleep (latent variable derived from REM %, REM efficiency, and REM latency) and fear inhibition (i.e. safety signal and extinction recall) will be assessed pre- and post-treatment in a 4 night/3 day testing protocol via at-home polysomnography and the fear-potentiated startle paradigm, respectively. Fear extinction recall will serve as the primary outcome, while safety signal recall will serve as the secondary outcome. In summary, this study aims to test an underlying mechanism potentially explaining why insomnia greatly increases PTSD risk, while demonstrating an existing clinical intervention (CBT-I) can be used to improve this mechanism. Findings will have potential clinical implications for novel approaches in the prevention, early intervention, and treatment of PTSD.

Childhood Maltreatment in Females Is Associated with Enhanced Fear Acquisition and an Overgeneralization of Fear.

Childhood maltreatment may alter fear neurocircuitry, which results in pathological anxiety and depression. One alteration of fear-related behaviors that has been observed in several psychiatric populations is an overgeneralization of fear. Thus, we examined the association between childhood maltreatment and fear generalization in a non-clinical sample of young adults. Two hundred and ninety-one participants underwent differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli (GS) without the presence of the US. Participants also completed questionnaires that assessed symptoms of childhood maltreatment, anxiety, depression, and post-traumatic stress disorder (PTSD). Participants reporting high childhood maltreatment (n = 71; 23 males, 48 females) exhibited significantly greater anxiety, depression, and symptoms of PTSD than participants reporting low childhood maltreatment (n = 220; 133 males, 87 females). Females reporting high childhood maltreatment demonstrated significantly enhanced fear learning and greater fear generalization, based on their fear-potentiated startle responses. Our findings suggest that childhood maltreatment may sex-dependently influence the development of fear neurocircuitry and result in greater fear generalization in maltreated females.

P127 Study protocol for examining the role of REM sleep in trauma-recovery mechanisms: REM fragmentation and fear inhibition in adults with insomnia disorder before and after cognitive behavioural therapy for insomnia (CBT-I)

Abstract Introduction Insomnia has been shown to increase by 2.5-3 fold the risk of developing posttraumatic stress disorder (PTSD) after a traumatic event. The mechanism underlying this increased risk, however, remains unknown. We postulate insomnia may be contributing to PTSD by disrupting rapid eye movement (REM) sleep in the same way it has been shown to impair fear inhibitory processes, which are central to the natural recovery from trauma. To test this, the following protocol aims to: (1) examine the relationship between REM sleep fragmentation and fear inhibition in insomnia; and (2) examine whether correcting REM fragmentation by treating the insomnia, in turn, improves fear inhibition. Methods Ninety-two adults with insomnia disorder will be randomly allocated to an active treatment or waitlist control condition. Active treatment involves 7 weekly sessions of cognitive behavioural therapy for insomnia (CBT-I) with a clinician via telehealth. REM fragmentation and fear inhibition (i.e., safety learning and extinction recall) will be assessed pre- and post-treatment in a 4night/3day testing protocol via at-home polysomnography and the fear-potentiated startle paradigm, respectively. Discussion This study aims to be the first to test an underlying mechanism potentially explaining why insomnia greatly increases PTSD risk, while demonstrating an existing clinical intervention (CBT-I) can be used to improve this mechanism. Findings will have potential clinical implications for novel approaches in the prevention, early intervention, and treatment of PTSD.

Anxiety, fear extinction, and threat-related amygdala reactivity in children exposed to urban trauma

Introduction Childhood trauma is strongly associated with fear-related psychopathology, like anxiety and posttraumatic stress disorder (PTSD). Atypical fear extinction and neural responses to social threat (i.e., negative emotional faces) may serve as intermediate phenotypes preceding the emergence of fear-related psychopathology during childhood and adolescence. However, few studies have examined associations among these phenotypes in trauma-exposed youth. Methods 29 9-year-old children with high rates of trauma exposure (Mdn = 4, min = 0, max= 14 total events) completed a fear-potentiated startle paradigm assessing fear conditioning and extinction and an emotional faces functional magnetic resonance imaging (fMRI) task assessing neural responses to fearful and neutral faces. Results Overall amygdala response was positively associated with anxiety (peak coordinates: x = −30, y = −6, z = −24; Z = 3.54; pFWEcorrected = 0.011; k = 24 voxels) and fear-potentiated startle during early extinction (peak coordinates x = 28, y = −6, z = −18; Z = 3.50; pFWEcorrected = 0.012; k = 19 voxels). Across the session, amygdala reactivity to fearful faces increased (F(1, 29) = 4.427, p = .044) and was positively associated with fear-potentiated startle during early extinction (r = .56, p = .002). Conclusions We found a positive association between increasing amygdala response to threatening faces and fear load, that is, heightened fear-potentiated startle during early extinction, in trauma-exposed children. These fear-based intermediate phenotypes may share underlying amygdala circuits, such that hyperactivity may represent an early marker of anxiety risk in trauma-exposed youth.

Predicting PTSD symptoms in firefighters using a fear-potentiated startle paradigm and machine learning

This study develops a fear-potentiated startle paradigm (FPS) and a machine learning approach to accurately predict PTSD symptoms using electrogram data. A three-phase fear-potentiated startle paradigm was designed to assess the conditioning, generalization, and extinction of fear. Electrooculogram and electrocardiogram signals were collected during the FPS. A total of 1107 Chinese firefighters participated in the study. The Chinese version PCL-C was administered to all subjects. A cutoff of 38 or higher is used to indicate PTSD symptoms. Electrogram features were extracted and selected to build a machine learning model to classify individuals. The machine learning model was 5-fold cross validated. The importance of the selected features was calculated. Classification performance metrics were evaluated for the machine learning model. The machine learning model can identify firefighters with a PCL-C score of 38 or above with sensitivity and specificity both above 0.85 when 5-fold cross validated on a 1107-person sample. The area under the receiver operating characteristic curve of the model is 0.93. Features related to fear generalization are found to be the most important. The proposed fear-potentiated startle paradigm and machine learning approach can accurately predict PTSD symptoms in Chinese firefighters, which can improve the screening and diagnosis of PTSD.

Distinctive impacts of sexual trauma versus non-sexual trauma on PTSD profiles in highly trauma-exposed, Black women

BackgroundPrior findings suggest that psychopathology following interpersonal trauma or assaultive violence may present differently from prototypical posttraumatic stress disorder (PTSD). However, whether this is true for sexual trauma (ST) in the context of other salient lifetime traumatic experiences is yet unknown. We predicted that ST exposure may result in higher avoidance and numbing symptoms and blunted fear responses, relative to non-sexual trauma (NST), particularly if ST occurred during childhood. MethodsParticipants were n = 5163 Black women recruited in an urban public hospital. We investigated effects of ST on PTSD symptoms, fear-potentiated startle (FPS) response (n = 285), and amygdala reactivity and habituation to social threat cues with fMRI (n = 95). ResultsST was associated with greater PTSD symptoms (p = 2.64 × 10−21), but this was observed across all symptom clusters. Women who experienced repeated ST in both childhood and adulthood showed greater PTSD (p = .0009) and numbing symptoms (p = .002). In the FPS paradigm, the ST group startled more on all blocks and stimulus types than the NST group (p = .004). Developmental timing of ST did not influence startle magnitude. ST was not associated with amygdala habituation or reactivity. LimitationsGeneralizability is limited to Black women with a high trauma burden. Associations are cross-sectional, limiting causal conclusions. ConclusionWhile survivors of ST may present with more severe PTSD symptoms, their profiles are not characteristically different from similar NST controls. Childhood sexual abuse exposure alone did not result in a unique symptom profile. ST represents a uniquely high-burden stressor with likelihood for more severe posttraumatic outcomes.

Uncertain in the face of change: Lack of contingency shift awareness during extinction is associated with higher fear-potentiated startle and PTSD symptoms in children

Intolerance of uncertainty is a transdiagnostic risk factor for fear-related disorders and is associated with higher levels of anxiety in children and adolescents. It is unclear how uncertainty relates to development of psychopathology in children who have experienced trauma in early life. The present study used a fear-potentiated startle paradigm in children to examine associations between uncertainty (assessed as unawareness of a change in reinforcement during fear extinction) and symptoms of anxiety and posttraumatic stress disorder (PTSD), as well as startle potentiation to threat and safety cues. Results showed that unaware children had strong positive associations between trauma exposure and PTSD symptoms, whereas aware children did not. Uncertainty interacted with anxiety in that children who were both unaware and had higher anxiety displayed higher fear-potentiated startle to safety cues and did not show discrimination between threat and safety during fear conditioning. These results suggest that anxious children who persist in associating a threat cue with an aversive event during extinction, after repeated presentations of the no longer reinforced conditioned stimulus, may express psychophysiological phenotypes related to PTSD.

Fear-potentiated startle predicts longitudinal change in transdiagnostic symptom dimensions of anxiety and depression

BackgroundElevated defensive responding, through startle reflex (SR) and skin conductance response (SCR), may contribute to onset and maintenance of depression and anxiety. Most work examining SR and SCR has predicted psychiatric diagnoses. There is a paucity of research examining links between SR or SCR and dimensional measures of psychopathology. MethodsWe used latent growth curve modeling to predict longitudinal change in three symptom factors (i.e., General Distress, Fears, Anhedonia-Apprehension) from SR and SCR measured during a fear-potentiated startle paradigm among adolescents oversampled for neuroticism (N = 129). ResultsElevated SCR in danger phases before and after an unpleasant muscle contraction predicted increasing Fears over time. Elevated SR in safe phases post-contraction also predicted increasing Fears over time. Attenuated SR in safe phases post-contraction predicted elevated General Distress longitudinally. Attenuated SCR pre-contraction in danger phases predicted elevated Anhedonia-Apprehension over time. LimitationsOur non-clinical sample may limit generalizability of results. Additionally, we did not assess change in SR and SCR over time. ConclusionsThe present study demonstrates that SR and SCR during a fear-potentiated startle paradigm predict longitudinal change in dimensional anxiety and depression symptom factors and relatedly, that SR and SCR may represent risk factors for the exacerbation of symptomatology.

Female Carriers of the Met Allele of the BDNF Val66Met Polymorphism Develop Weaker Fear Memories in a Fear-Potentiated Startle Paradigm

Female Carriers of the Met Allele of the BDNF Val66Met Polymorphism Develop Weaker Fear Memories in a Fear-Potentiated Startle Paradigm

Effects of oxytocin administration on fear-potentiated acoustic startle in co-occurring PTSD and alcohol use disorder: A randomized clinical trial

Co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common and particularly associated with elevation of hyperarousal compared to PTSD alone. Treatment options are limited. Oxytocin regulates physiological stress response. Intranasal oxytocin administration has demonstrated potential in reducing symptoms of both PTSD and AUD. This study addresses a gap in the literature by investigating effects of intranasal oxytocin on startle reactivity, an important potential marker of both PTSD and AUD symptomatology. This is a randomized, double-blind, placebo-controlled, within- and between-participant, crossover, dose-ranging study examining the effects of a single administration of oxytocin 20 IU versus 40 IU versus placebo on psychophysiological responses to a common laboratory fear-potentiated acoustic startle paradigm in participants with PTSD-AUD (n = 47) and controls (n = 37) under three different levels of threat. Contrary to our hypothesis, for the PTSD-AUD group, oxytocin 20 IU had no effect on startle reactivity, while oxytocin 40 IU increased measures of startle reactivity. Additionally, for PTSD-AUD only, ambiguous versus low threat was associated with an elevated skin conductance response. For controls only, oxytocin 20 IU versus placebo was associated with reduced startle reactivity.

Ventromedial and insular cortical volume moderates the relationship between BDNF Val66Met and threat sensitivity

While the BDNF Val66Met polymorphism has been linked to various trauma and anxiety – related psychiatric disorders, limited focus has been on the neural structures that might modulate its relationship with objective measures of threat sensitivity. Therefore, we assessed whether there was an interaction of Val66Met polymorphism with brain area volumes previously associated with anxiety and PTSD, such as the ventromedial prefrontal cortex (vmPFC), insular cortex (IC), and dorsal and ventral anterior cingulate cortices (dACC and vACC), in predicting fear-potentiated psychophysiological response in a clinical sample of Veterans. 110 participants engaged in a fear-potentiated acoustic startle paradigm and provided genetic and imaging data. Fear conditions included no, ambiguous, and high threat conditions (shock). Psychophysiological response measures included electromyogram (EMG), skin conductance response (SCR), and heart rate (HR). PTSD status, trauma history, and demographics were also assessed. There was an interaction of Met allele carrier status with vmPFC, IC, dACC, and vACC volumes for predicting SCR (p < 0.001 for all regions). However, only vmPFC and IC significantly moderated the relationship between Val66Met and psychophysiological response (SCR). The Val66met polymorphism may increase susceptibility to PTSD and anxiety disorders via an interaction with reduced vmPFC and IC volume. Future research should examine whether these relationships might be associated with a differential course of illness longitudinally or response to treatments.

An analysis of fear inhibition and fear extinction in a sample of veterans with obstructive sleep apnea (OSA): Implications for co-morbidity with post-traumatic stress disorder (PTSD)

Obstructive sleep apnea (OSA) is a respiratory condition characterized by interrupted sleep due to repeated, temporary collapse of the soft tissue of the upper airway that can lead to a cascade of physiological and psychological adverse health outcomes. The most common therapeutic interventions for OSA patients include the application of continuous positive airway pressure (CPAP) which acts to keep the airway open and, as such, provides less interrupted and more restorative sleep. Improved sleep has been linked to more efficacious treatments for psychiatric conditions most notably those that include cognitive-behavioral elements, new learning, and memory consolidation. In the current study, we investigated the acquisition, inhibition, and extinction of conditioned fear in OSA patients, before and after CPAP therapy, using an established fear-potentiated startle paradigm. Patients with OSA displayed an intact ability to acquire, inhibit, and extinguish fear prior to CPAP treatment and this ability was significantly enhanced following CPAP usage. In addition, those patients with more severe OSA, as measured by apnea-hypopnea index (AHI), were more likely to show improved fear inhibition and extinction. Lastly, we observed impairments in discrimination between reinforced and nonreinforced conditioned stimuli, in the inhibition of fear, and in fear extinction in a subset of patients with OSA and co-morbid posttraumatic stress disorder (PTSD). These data suggest that evolving treatment algorithms for PTSD should address disrupted sleep problems prior to initiation of inhibition/extinction-based exposure therapies.

Adolescent Vulnerability to Heightened Emotional Reactivity and Anxiety After Brief Exposure to an Obesogenic Diet.

BackgroundEmerging evidence demonstrates that diet-induced obesity disrupts corticolimbic circuits underlying emotional regulation. Studies directed at understanding how obesity alters brain and behavior are easily confounded by a myriad of complications related to obesity. This study investigated the early neurobiological stress response triggered by an obesogenic diet. Furthermore, this study directly determined the combined impact of a short-term obesogenic diet and adolescence on critical behavioral and molecular substrates implicated in emotion regulation and stress.MethodsAdolescent (postnatal day 31) or adult (postnatal day 81) Lewis rats were fed for 1 week with an experimental Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). We used the acoustic fear-potentiated startle (FPS) paradigm to determine the effects of the WD on cued fear conditioning and fear extinction. We used c-Fos mapping to determine the functional influence of the diet and stress on corticolimbic circuits.ResultsWe report that 1-week WD consumption was sufficient to induce fear extinction deficits in adolescent rats, but not in adult rats. We identify fear-induced alterations in corticolimbic neuronal activation and demonstrate increased prefrontal cortex CRHR1 messenger RNA (mRNA) levels in the rats that consumed the WD.ConclusionOur findings demonstrate that short-term consumption of an obesogenic diet during adolescence heightens behavioral and molecular vulnerabilities associated with risk for anxiety and stress-related disorders. Given that fear extinction promotes resilience and that fear extinction principles are the foundation of psychological treatments for posttraumatic stress disorder (PTSD), understanding how obesogenic environments interact with the adolescent period to affect the acquisition and expression of fear extinction memories is of tremendous clinical relevance.

Amygdalar corticotropin-releasing factor mediates stress-induced anxiety

The extended amygdala, including the Central nucleus of the Amygdala (CeA) and the Bed Nucleus of the Stria Terminalis (BNST), is a complex structure that plays a pivotal role in emotional behavior. The CeA and the BNST are highly interconnected, being the amygdala traditionally more associated with fear and the BNST with anxiety. Yet, studies using excitotoxic lesions also show the involvement of the CeA in the development of stress-induced anxiety. Likewise, others have also highlighted the role of corticotropin-releasing factor (CRF), a neuropeptide highly expressed in CeA, as an anxiogenic factor and, consequently, important for in anxiety disorders.Here, we used an inducible RNAi lentiviral system to assess the effects of reducing CRF expression in CeA in the development of anxiety-like behavior in a model of Chronic Unpredictable Stress. In addition, we evaluated CRF RNAi-mediated alterations in the stress-triggered molecular signature in the BNST.Knockdown of CRF in the CeA decreased stress-induced anxiety levels. No differences were found in a fear-potentiated startle paradigm. Additionally, we observed that stress-induced alterations in the expression of CRF receptors within the BNST are attenuated by CRF knockdown in the CeA.These results emphasize the importance of the role that amygdalar CRF plays in the modulation of anxiety-like behavior and in the molecular signature of stress in the BNST.

Gonadal hormone fluctuations do not affect the expression or extinction of fear-potentiated startle in female rats.

Prior studies suggest that levels of ovarian hormones may affect learning and memory in rats, including studies of fear conditioning and extinction. We previously showed that female rats show reduced retention of extinction compared to males when measuring fear-potentiated startle, but not when measuring freezing behavior. One commonly reported observation in studies of freezing behavior is that rats with increased levels of estradiol during extinction learning show better retention of extinction than rats given extinction training when levels of estradiol are low. Here, we tested the hypothesis that fear extinction retention in a fear-potentiated startle paradigm in females is influenced by levels gonadal hormones, which we had not accounted for in our original report. We used the fear-potentiated startle paradigm to test if extinction learning was affected by estrous phase, ovariectomy, or acute systemic injections of estradiol in ovariectomized rats. We report that neither the expression nor extinction of fear-potentiated startle differed in rats given extinction training in proestrus compared to those in metestrus. Removal of the ovaries had no effect on fear acquisition or extinction learning as assessed by fear-potentiated startle. Finally, systemic injections of estradiol given to ovariectomized rats before extinction training had no effect on the expression of fear or the retention of extinction. Our findings suggest that the effect of female gonadal hormones on fear conditioning and extinction may depend on the measure of fear employed or by the parameters used to study fear learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A novel method to trigger the reconsolidation of fear memory

The procedure of memory reconsolidation provides an opportunity to improve some mental disorders caused by maladaptive memories, such as Posttraumatic Stress Disorder. Prediction error was considered a necessary condition for triggering memory reconsolidation. However, it is difficult to create a satisfying prediction error to successfully open memory reconsolidation in a clinical context. The purpose of this study was to explore a more practicable method to trigger memory reconsolidation. We used a successive 4-day fear-potentiated startle paradigm to compare the effect of uncertainty with prediction error during retrieval on preventing the return of fear. Bayes factor, combined with p value and effect size, was used as the main indicator of statistical inference. The results indicated that spontaneous recovery and reinstatement of fear were not observed in the uncertainty group, whereas return of fear was observed for the prediction error group. However, the direct comparison between the two groups did not yield statistically significant results, potentially reflecting a lack of statistical power. Nonetheless, these results suggest that uncertainty retrieval could be a better means to trigger memory reconsolidation than prediction error, making uncertainty a worthwhile factor to consider in future research on memory reconsolidation.

Treatment with a heat-killed preparation of Mycobacterium vaccae after fear conditioning enhances fear extinction in the fear-potentiated startle paradigm

The hygiene hypothesis or “Old Friends” hypothesis proposes that inflammatory diseases are increasing in modern urban societies, due in part to reduced exposure to microorganisms that drive immunoregulatory circuits and a failure to terminate inappropriate inflammatory responses. Inappropriate inflammation is also emerging as a risk factor for anxiety disorders, affective disorders, and trauma-and stressor-related disorders, including posttraumatic stress disorder (PTSD), which is characterized as persistent re-experiencing of the trauma after a traumatic experience. Traumatic experiences can lead to long-lasting fear memories and fear potentiation of the acoustic startle reflex. The acoustic startle reflex is an ethologically relevant reflex and can be potentiated in both humans and rats through Pavlovian conditioning. Mycobacterium vaccae is a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has been demonstrated to enhance fear extinction in the fear-potentiated startle paradigm when given prior to fear conditioning. To determine if immunization with M. vaccae after fear conditioning also has protective effects, adult male Sprague Dawley rats underwent fear conditioning on days −37 and −36 followed by immunizations (3x), once per week beginning 24 h following fear conditioning, with a heat-killed preparation of M. vaccae NCTC 11659 (0.1 mg, s.c., in 100 µl borate-buffered saline) or vehicle, and, then, 3 weeks following the final immunization, were tested in the fear-potentiated startle paradigm (n = 12 per group). Rats underwent fear extinction training on days 1 through 6 followed by spontaneous recovery 14 days later (day 20). Rats were euthanized on day 21 and brain tissue was sectioned for analysis of Tph2, Htr1a, Slc6a4, Slc22a3, and Crhr2 mRNA expression throughout the brainstem dorsal and median raphe nuclei. Immunization with M. vaccae did not affect fear expression on day 1. However, M. vaccae-immunized rats showed enhanced enhanced within-session fear extinction on day 1 and enhanced between-session fear extinction beginning on day 2, relative to vehicle-immunized controls. Immunization with M. vaccae and fear-potentiated startle had minimal effects on serotonergic gene expression when assessed 42 days after the final immunization. Together with previous studies, these data are consistent with the hypothesis that immunoregulatory strategies, such as immunization with M. vaccae, have potential for both prevention and treatment of trauma- and stressor-related psychiatric disorders.