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Introduction: Anxiety and anxiety-influenced disorders are sexually dimorphic with women being disproportionately affected compared to men. Given the increased prevalence in women and the documented differences in anxiety and trauma behavior between male and female rats this paper sought to examine the link between stress, anxiety, and fear learning and extinction in female rats. We tested the hypothesis that a mild stressor will induce short-and long-term increases in anxiety and produce long term effects on subsequent fear learning and extinction behavior. Methods: We induced anxiety in female Sprague-Dawley rats with a short (3 min) exposure to a ball of cat hair infused with 150 µl of cat urine (mild stressor) that elicits innate fear but does not cause fear conditioning. The control group was exposed to fake cat hair. Anxiety was assessed in the Light-Dark Open Field (LDOF) or Elevated Plus Maze (EPM) before, immediately after and 4 days after stimulus exposure. Two weeks later, all animals were subject to Contextual Fear Conditioning (CFC) in the Shock Arm of a Y-maze, blocked off from the rest of the maze. Memory and fear extinction (learning of safety) was assessed in the following four days by placing each rat in one of the Safe Arms and measuring avoidance extinction (time spent and number of entries in the Shock Arm). Results: Cat hair exposure induced changes in anxiety-like behavior in the shortterm that appeared resolved 4 days later. However, the cat-hair exposed rats had long-term (2 weeks) phenotypic changes expressed as altered exploratory behavior in an emotionally neutral novel place. Fear learning and extinction were not impaired. Yet, using avoidance extinction, we demonstrated that the phenotypic difference induced by the mild stressor could be documented and dissociated from learning and memory. Discussion: These findings demonstrate that the history of stress, even mild stress, has subtle long-term effects on behavior even when short-term anxiety appears resolved. [ABSTRACT FROM AUTHOR]

Balanced fear supports human rational decision-making and useful behavioral responses. In contrast, overwhelming, persistent, and unbalanced fear can paralyze the individual and result in heightened anxiety, lack of cognitive flexibility, fear-based public compliance and serious mental health issues. Psychobiotics research has established that a healthy microbiome is required for balanced fear and mental health protection via control of fear extinction. The recent COVID-19 pandemic featured daily, persistent, fear-of-a-single-contagion conditioning on a global scale paired with various behavioral mandates (e.g., lockdowns of the healthy, required wearing of face masks in many locations including schools, isolation from environmental microbes and each other through the closure of beaches and parks, and restrictions on social gatherings including access to family members in hospitals and senior-assisted facilities). Such mandates degraded the human microbiome and isolated us from each other and useful environmental microbes. It also ignored the historic role of secondary bacterial pathogens in pandemic deaths. This narrative review examines how the institutional promotion of fear-of-a-single-contagion, lack of balanced risk communication, and appalling disregard of our fundamental nature (as majority-microbial human superorganisms) resulted in problems rather than solutions. This review illustrates that government-public health-media promotion of pervasive fear and microbiome-degrading behaviors: (1) increased public compliance, (2) reduced cognitive flexibility, and (3) increased risk of mental health conditions. However, a portion of the general public chose a healthier path through their increased consumption of microbiome- and immune-supportive supplements and fermented foods during and after the COVID-19 pandemic. For a healthier future, public health must follow the lead of this population to ensure that human freedom, rather than paralyzing fear, dominates our future. [ABSTRACT FROM AUTHOR]

Fear refers to an adaptive response in the face of danger, and the formed fear memory acts as a warning when the individual faces a dangerous situation again, which is of great significance to the survival of humans and animals. Excessive fear response caused by abnormal fear memory can lead to neuropsychiatric disorders. Fear memory has been studied for a long time, which is of a certain guiding effect on the treatment of fear-related disorders. With continuous technological innovations, the study of fear has gradually shifted from the level of brain regions to deeper neural (micro) circuits between brain regions and even within single brain regions, as well as molecular mechanisms. This article briefly outlines the basic knowledge of fear memory and reviews the neurobiological mechanisms of fear extinction and relapse, which aims to provide new insights for future basic research on fear emotions and new ideas for treating trauma and fear-related disorders. [ABSTRACT FROM AUTHOR]

Fear extinction is the basis of exposure therapies for posttraumatic stress disorder (PTSD), but half of patients do not improve. Predicting fear extinction in individuals with PTSD may inform personalized exposure therapy development. The participants were 125 trauma-exposed adults (96 female) with a range of PTSD symptoms. Electromyography, electrocardiogram, and skin conductance were recorded at baseline, during dark-enhanced startle, and during fear conditioning and extinction. Using a cross-validated, hold-out sample prediction approach, three penalized regressions and conventional ordinary least squares were trained to predict fear-potentiated startle during extinction using 50 predictor variables (5 clinical, 24 self-reported, and 21 physiological). The predictors, selected by penalized regression algorithms, were included in multivariable regression analyses, while univariate regressions assessed individual predictors. All the penalized regressions outperformed OLS in prediction accuracy and generalizability, as indexed by the lower mean squared error in the training and holdout subsamples. During early extinction, the consistent predictors across all the modeling approaches included dark-enhanced startle, the depersonalization and derealization subscale of the dissociative experiences scale, and the PTSD hyperarousal symptom score. These findings offer novel insights into the modeling approaches and patient characteristics that may reliably predict fear extinction in PTSD. Penalized regression shows promise for identifying symptom-related variables to enhance the predictive modeling accuracy in clinical research. [ABSTRACT FROM AUTHOR]

Fear extinction is pivotal for inhibiting fear responding to former threat‐predictive stimuli. In rodents, short intervals between fear acquisition and extinction impair extinction recall compared to long intervals. This is called Immediate Extinction Deficit (IED). Importantly, human studies of the IED are sparse and its neurophysiological correlates have not been examined in humans. We, therefore, investigated the IED by recording electroencephalography (EEG), skin conductance responses (SCRs), an electrocardiogram (ECG), and subjective ratings of valence and arousal. Forty male participants were randomly assigned to extinction learning either 10 min after fear acquisition (immediate extinction) or 24 h afterward (delayed extinction). Fear and extinction recall were assessed 24 h after extinction learning. We observed evidence for an IED in SCR responses, but not in the ECG, subjective ratings, or in any assessed neurophysiological marker of fear expression. Irrespective of extinction timing (immediate vs. delayed), fear conditioning caused a tilt of the non‐oscillatory background spectrum with decreased low‐frequency power (<30 Hz) for threat‐predictive stimuli. When controlling for this tilt, we observed a suppression of theta and alpha oscillations to threat‐predictive stimuli, especially pronounced during fear acquisition. In sum, our data show that delayed extinction might be partially advantageous over immediate extinction in reducing sympathetic arousal (as assessed via SCR) to former threat‐predictive stimuli. However, this effect was limited to SCR responses since all other fear measures were not affected by extinction timing. Additionally, we demonstrate that oscillatory and non‐oscillatory activity is sensitive to fear conditioning, which has important implications for fear conditioning studies examining neural oscillations. Our findings provide further knowledge about the neurophysiological foundations of fear and extinction learning and the critical role of timing between both learning phases. By disentangling oscillatory and non‐oscillatory brain activity we show that standard power estimates can be highly distorted due to fear‐induced non‐oscillatory brain dynamics. Moreover, while animal studies demonstrate that timing of extinction learning impacts long‐term fear suppression, we observed that a similar effect of extinction timing seems to be limited to only some domains of fear responding in humans. [ABSTRACT FROM AUTHOR]

The ventromedial prefrontal cortex has been viewed as a locus for storage and recall of extinction memory. However, the synaptic and cellular mechanisms underlying these processes remain elusive. We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the ventromedial prefrontal cortex in fear extinction retrieval. We found that both constitutive and conditional APPL1 knockout decreased NMDA receptor (NMDAR) function in the ventromedial prefrontal cortex and impaired fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduced NMDAR currents and disrupted extinction retrieval. We also identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolished NMDAR-dependent synaptic potentiation and disrupted extinction retrieval, while chemogenetic activation of this ensemble simultaneously rescued the impaired behaviors. Our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons in retrieving extinction memory by controlling NMDAR-dependent potentiation. [ABSTRACT FROM AUTHOR]

Background Posttraumatic stress disorder is characterized by deficits in cognitive flexibility related to dysfunction of the medial prefrontal cortex (mPFC). Exposure therapy can effectively reverse these deficits. Fear extinction in rodents bears similarity to exposure therapy. Extinction reverses chronic stress–induced deficits in cognitive flexibility on the attentional set-shifting test (AST), an mPFC-mediated process. This therapeutic effect requires activity of pyramidal neurons and brain derived neurotrophic factor (BDNF) signaling in infralimbic cortex (IL). However, the circuit mechanisms governing BDNF-mediated plasticity initiated by extinction in IL are unknown. The ventral hippocampus (vHipp) plays a role in regulating IL activity during extinction, and plasticity in vHipp is necessary for extinction memory consolidation. Therefore, we investigated the role of vHipp input to IL in the effects of extinction in reversing stress-induced cognitive deficits. Methods vHipp input to IL was silenced using a Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) via local infusion of clozapine-N-oxide (CNO) into IL before extinction. A day later, rats were tested on AST. In a separate experiment, we tested whether vHipp input to the IL induces BDNF signaling to exert therapeutic effects. We activated the vHipp using a Gq-DREADD, and injected an anti-BDNF neutralizing antibody into IL. Rats were tested on the AST 24 hours later. Results Silencing the vHipp input to IL prevented the beneficial effects of extinction in reversing stress-induced cognitive deficits. Activating vHipp input to IL in the absence of extinction was sufficient to reverse stress-induced deficits in set-shifting. The beneficial effects were blocked by local infusion of a neutralizing anti-BDNF antibody into IL. Conclusions vHipp-driven BDNF signaling in IL is critical for extinction to counteract the deleterious cognitive effects of chronic stress. [ABSTRACT FROM AUTHOR]

Emerging research in animal models and healthy women indicates that the sex hormone estradiol may moderate fear of extinction. There is limited research on estradiol in exposure-based therapy among clinically anxious women. The current pilot study aimed to address this gap by comparing exposure outcomes in women with panic disorder (PD) who had high (HE) vs. low estradiol (LE). Twenty-eight women (14 per group) with PD completed two interoceptive exposure sessions on consecutive days as well as self-report measures of panic severity. Electrodermal activity was assessed continuously throughout the exposure sessions. Results showed that although anxiety sensitivity and subjective distress improved from pre- to postexposure, suggesting that the intervention was effective in reducing panic-related anxiety, there were no differences in outcomes between the HE and LE groups. The findings suggest that estradiol may not moderate outcomes in exposure therapy in clinically anxious samples, although replication in larger samples will be needed. [ABSTRACT FROM AUTHOR]

The ability to store, retrieve, and extinguish memories of adverse experiences is an essential skill for animals' survival. The cellular and molecular factors that underlie such processes are only partially known. Using chondroitinase ABC treatment targeting chondroitin sulfate proteoglycans (CSPGs), previous studies showed that the maturation of the extracellular matrix makes fear memory resistant to deletion. Mice lacking the cartilage link protein Crtl1 (Crtl1-KO mice) display normal CSPG levels but impaired CSPG condensation in perineuronal nets (PNNs). Thus, we asked whether the presence of PNNs in the adult brain is responsible for the appearance of persistent fear memories by investigating fear extinction in Crtl1-KO mice. We found that mutant mice displayed fear memory erasure after an extinction protocol as revealed by analysis of freezing and pupil dynamics. Fear memory erasure did not depend on passive loss of retention; moreover, we demonstrated that, after extinction training, conditioned Crtl1-KO mice display no neural activation in the amygdala (Zif268 staining) in comparison to control animals. Taken together, our findings suggest that the aggregation of CSPGs into PNNs regulates the boundaries of the critical period for fear extinction. [ABSTRACT FROM AUTHOR]

We review findings and propose a model explaining why womens adaptation to traumatic stress might be different than mens, including the role of cycling hormones and sleep differences in the development of post-traumatic stress and other stress-related disorders. Women are diagnosed with stress-related mental health disorders at a higher frequency than men. Most mental health disorders involve sleep disturbances, which may contribute to these disorders. The mechanisms by which sleep contributes to the development of mental health disorders in women have not been addressed in basic research. Sleep features such as spindle density and rapid eye movement (REM) sleep theta power are important for the role of sleep in emotion and cognition. The effect of hormonal cycles on these and other critical sleep features is only beginning to be understood. We explore what sleep factors could confer resilience to mental health disorders and how they might be altered by hormonal cycles in women. We target a specific system at the nexus of arousal control, stress response, and memory consolidation processes that has not been explored at all in women or across the hormonal cycle in animal studies: the locus coeruleus noradrenergic (LC-NE) system.

Recent research indicates that there is mixed success in using exposure therapies on patients with post-traumatic stress disorder (PTSD). Our study argues that there are two major reasons for this: The first is that there are nonassociative aspects of PTSD, such as hyperactive amygdala activity, that cannot be attenuated using the exposure therapy; The second is that exposure therapy is conceptualized from the theoretical framework of Pavlovian fear extinction, which we know is heavily context dependent. Thus, reducing fear response in a therapist's office does not guarantee reduced response in other situations. This study also discusses work relating to the role of the hippocampus in context encoding, and how these findings can be beneficial for improving exposure therapies.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations. To better understand how fear learning and underlying neural systems might be altered after mTBI, we examined the acquisition of cued fear conditioning and its extinction along with brain morphology and dendritic plasticity in a mouse model of mTBI. To induce mTBI in adult male C57BL/6J mice, a lateral fluid percussive injury (LFP 1.7) was produced using a fluid pulse of 1.7 atmosphere force to the right parietal lobe. Behavior in LFP 1.7 mice was compared to behavior in mice from two separate control groups: mice subjected to craniotomy without LFP injury (Sham) and mice that did not undergo surgery (Unoperated). Following behavioral testing, neural endpoints (dendritic structural plasticity and neuronal volume) were assessed in the basolateral nucleus of the amygdala (BLA), which plays a critical sensory role in fear learning, and medial prefrontal cortex (mPFC), responsible for executive functions and inhibition of fear behaviors. No gross motor abnormalities or increased anxiety-like behaviors were observed in LFP or Sham mice after surgery compared to Unoperated mice. We found that all mice acquired fear behavior, assessed as conditioned freezing to auditory cue in a single session of 6 trials, and acquisition was similar across treatment groups. Using a linear mixed effects analysis, we showed that fear behavior decreased overall over 6 days of extinction training with no effect of treatment group across extinction days. However, a significant interaction was demonstrated between the treatment groups during within-session freezing behavior (5 trials per day) during extinction training. Specifically, freezing behavior increased across within-session extinction trials in LFP 1.7 mice, whereas freezing behavior in control groups did not change on extinction test days, reflecting a dissociation between within-trial and between-trial fear extinction. Additionally, LFP mice demonstrated bilateral increases in dendritic spine density in the BLA and decreases in dendritic complexity in the PFC. The translational implications are that individuals with TBI undergoing fear extinction therapy may demonstrate within-session aberrant learning that could be targeted for more effective treatment interventions. • TBI mouse model showed normal between-session fear extinction (FE) vs. controls. • However, within-session freezing for TBI mice was increased during FE vs. controls. • The TBI group had reduced dendritic arborizations in prefrontal cortex (PFC). • The TBI group showed greater basolateral amygdalar (BLA) spine density vs. controls. • TBI produced aberrant FE with reciprocal changes in dendrites in PFC and BLA. [ABSTRACT FROM AUTHOR]

The relationship between structural characteristics and extinction-induced brain activations in anxiety disorders (ANX) remains a space for greater exploration. In this study, we assessed gray matter volume (GMV) and its associated functional activations during fear extinction memory recall in an ANX cohort. We performed voxel-based morphometry analysis to examine GMVs from ANX (n = 92) and controls (n = 73). We further examined the correlation between GMVs and extinction-induced neural activations during recall across groups. In the patients' group, we observed decreased GMV in the anterior hippocampus and increased GMV in the dorsolateral prefrontal cortex (dlPFC). Hippocampal volume was positively correlated with ventromedial prefrontal cortex activation in healthy controls, while it was negatively correlated with dorsal anterior cingulate cortex (dACC) activation in ANX. The dlPFC volume was positively correlated with activations of dACC, pre- and post-central gyrus, and supramarginal gyrus only in healthy controls. Therefore, the link between structural and functional imbalance within the hippocampus and dlPFC might contribute to the pathophysiology of ANX. In the controls, the relationship between structural variance in the hippocampus and dlPFC and extinction-induced neural activations is consistent with a greater ability to regulate fear responding; associations that were absent in the ANX cohort. Furthermore, our findings of structure-function abnormalities within key nodes of emotional homeostasis in ANX point to dlPFC as a potential neural node to target using neuromodulation tools. • Hippocampus and dlPFC structural alterations observed in anxiety disorders. • Structural alterations associated with extinction-induced functional activations. • Distinct associative patterns between structure and function were noted in controls and patients. [ABSTRACT FROM AUTHOR]

Stress has profound effects on fear extinction, a form of learning that is essential to behavioral therapies for trauma-related and stressor-related disorders. Recent work reveals that acute footshock stress reduces medial prefrontal cortex (mPFC) activity that is critical for extinction learning. Reductions in mPFC activity may be mediated by parvalbumin (PV)-containing interneurons via feedforward inhibition imposed by amygdala afferents. To test this hypothesis, footshock stress-induced Fos expression was characterized in PV1 and PV-neurons in the prelimbic (PL) and infralimbic (IL) cortices. Footshock stress increased the proportion of PV1 cells expressing Fos in both male and female rats; this effect was more pronounced in IL compared with PL. To determine whether PV1 interneurons in the mPFC mediate stress-induced extinction impairments, we chemogenetically silenced these neurons before an immediate extinction procedure in PV-Cre rats. Clozapine-N-oxide (CNO) did not affect conditioned freezing during the extinction procedure. However, CNO exacerbated extinction retrieval in both male and female rats with relatively high PL expression of designer receptors exclusively activated by designer drugs (DREADD). In contrast, in rats with relatively high IL DREADD expression, CNO produced a modest facilitation of extinction in the earliest retrieval trials, but in male rats only. Conversely, excitation of IL PV interneurons was sufficient to impair delayed extinction in both male and female rats. Finally, chemogenetic inhibition of IL-projecting amygdala neurons reduced the immediate extinction deficit in male, but not female rats. These results reveal that PV interneurons regulate extinction learning under stress in a sex-dependent manner, and this effect is mediated by amygdaloprefrontal projections. [ABSTRACT FROM AUTHOR]

The role of the cerebellum in emotional control has gained increasing interest, with studies showing it is involved in fear learning and memory in both humans and rodents. This review will focus on the contributions of the cerebellum to the extinction of learned fear responses. Extinction of fearful memories is critical for adaptive behaviour, and is clinically relevant to anxiety disorders such as post-traumatic stress disorder, in which deficits in extinction processes are thought to occur. We present evidence that supports cerebellar involvement in fear extinction, from rodent studies that investigate molecular mechanisms and functional connectivity with other brain regions of the known fear extinction network, to fMRI studies in humans. This evidence is considered in relation to the theoretical framework that the cerebellum is involved in the formation and updating of internal models of the inner and outer world by detecting errors between predicted and actual outcomes. In the case of fear conditioning, these internal models are thought to predict the occurrence of an aversive unconditioned stimulus (US), and when the aversive US is unexpectedly omitted during extinction learning the cerebellum uses prediction errors to update the internal model. Differences between human and rodent studies are highlighted to help inform future work. [ABSTRACT FROM AUTHOR]

• Rat microglia express more P2X7Rs and inflammatory cytokines 3 days after SPS. • Serum inflammatory cytokines increase 3 days after SPS exposure. • Auditory fear extinction recall is impaired 7 but not 3 days after SPS. • Microglial and peripheral inflammation precede the onset of impaired fear extinction. • Blocking P2X7Rs prevented SPS from impairing fear extinction recall in both sexes. Clinical evidence has linked increased peripheral pro-inflammatory cytokines with post-traumatic stress disorder (PTSD) symptoms. However, whether inflammation contributes to or is a consequence of PTSD is still unclear. Previous research shows that stress can activate purinergic P2X7 receptors (P2X7Rs) on microglia to induce inflammation and behavioral changes. In this investigation, we examined whether P2X7Rs contribute to the development of PTSD-like behaviors induced by single prolonged stress (SPS) exposure in rats. Consistent with the literature, exposing adult male and female rats to SPS produced a PTSD-like phenotype of impaired fear extinction and extinction of cue-induced center avoidance one week after exposure. Next, we examined if inflammation precedes the behavioral manifestations. Three days after SPS exposure, increased inflammatory cytokines were found in the blood and hippocampal microglia showed increased expression of the P2X7R, IL-1β, and TNF-α, suggesting increased peripheral and central inflammation before the onset of impaired fear extinction. In addition, SPS-exposed animals with impaired fear extinction recall also had more Iba1-positive microglia expressing the P2X7R in the ventral hippocampus. To determine whether P2X7Rs contribute to the PTSD-related behaviors induced by SPS exposure, we gave ICV infusions of the P2X7R antagonist, A-438079, for one week starting the day of SPS exposure. Blocking P2X7Rs prevented the SPS-induced impaired fear extinction and extinction of cue-induced center avoidance in male and female rats, suggesting that SPS activates P2X7Rs which increase inflammation to produce a PTSD-like phenotype. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

IntroductionAnxiety and anxiety-influenced disorders are sexually dimorphic with women being disproportionately affected compared to men. Given the increased prevalence in women and the documented differences in anxiety and trauma behavior between male and female rats this paper sought to examine the link between stress, anxiety, and fear learning and extinction in female rats. We tested the hypothesis that a mild stressor will induce short-and long-term increases in anxiety and produce long term effects on subsequent fear learning and extinction behavior.MethodsWe induced anxiety in female Sprague– Dawley rats with a short (3 min) exposure to a ball of cat hair infused with 150 μl of cat urine (mild stressor) that elicits innate fear but does not cause fear conditioning. The control group was exposed to fake cat hair. Anxiety was assessed in the Light-Dark Open Field (LDOF) or Elevated Plus Maze (EPM) before, immediately after and 4 days after stimulus exposure. Two weeks later, all animals were subject to Contextual Fear Conditioning (CFC) in the Shock Arm of a Y-maze, blocked off from the rest of the maze. Memory and fear extinction (learning of safety) was assessed in the following four days by placing each rat in one of the Safe Arms and measuring avoidance extinction (time spent and number of entries in the Shock Arm).ResultsCat hair exposure induced changes in anxiety-like behavior in the short-term that appeared resolved 4 days later. However, the cat-hair exposed rats had long-term (2 weeks) phenotypic changes expressed as altered exploratory behavior in an emotionally neutral novel place. Fear learning and extinction were not impaired. Yet, using avoidance extinction, we demonstrated that the phenotypic difference induced by the mild stressor could be documented and dissociated from learning and memory.DiscussionThese findings demonstrate that the history of stress, even mild stress, has subtle long-term effects on behavior even when short-term anxiety appears resolved.

Posttraumatic stress disorder (PTSD) is a widespread fear-related psychiatric affection associated with fear extinction impairments and important avoidance behaviors. Trauma-related exposure therapy is the current first-hand treatment for PTSD, yet it needs to be improved to shorten the time necessary to reach remission and increase responsiveness. Additional studies to decipher the neurobiological bases of extinction and effects on PTSD-like symptoms could therefore be of use. However, a PTSD-like animal model exhibiting pronounced PTSD-related phenotypes even after an extinction training directly linked to the fearful event is necessary. Thus, using a contextual fear conditioning model of PTSD, we increased the severity of stress during conditioning to search for effects on extinction acquisition and on pre- and post-extinction behaviors. During conditioning, mice received either two or four electrical shocks while a control group was constituted of mice only exposed to the context. Stressed mice exhibited important fear generalization, high fear reaction to the context and selective avoidance of a contextual reminder even after the extinction protocol. Increasing the number of footshocks did not induce major changes on these behaviors.

Background and purpose: Post-traumatic stress disorder (PTSD) is a mental and physical complication. Fluoxetine (FLX) as a selective serotonin reuptake inhibitor is considered as the first line of treatment for PTSD. Exercise can improve the symptoms of PTSD. The aim of this study was to determine the effects of exercise and FLX on testicular tissue and sex hormones in rats with PTSD. Materials and methods: In this experimental study, 80 adult male rats were divided into two groups: PTSD and healthy. Then, each group was divided into four subgroups: control, exercise, fluoxetine, and fluoxetine + exercise. PTSD was induced by single prolonged stress. Fourteen days after induction of PTSD, moderate forced treadmill exercise was performed for 4 weeks, 5 days/week. Fluoxetine was administered at 10 mg/kg/day dissolved in drinking water for 4 weeks. Four weeks after treatment, the fear extinction test, testicular structure, and testosterone and FSH levels were evaluated. Results: PTSD decreased testosterone level and fear extinction but increased follicle-stimulating hormone. Fluoxetine and exercise had protective effect on testicular damage and also increased testosterone level and extinction index but decreased FSH level. Findings showed that co-administration of exercise and fluoxetine was more effective on these parameters. Combination of exercise and fluoxetine significantly increased fear extinction in PTSD rats (P

The role of the cerebellum in emotional control has gained increasing interest, with studies showing it is involved in fear learning and memory in both humans and rodents. This review will focus on the contributions of the cerebellum to the extinction of learned fear responses. Extinction of fearful memories is critical for adaptive behaviour, and is clinically relevant to anxiety disorders such as post-traumatic stress disorder, in which deficits in extinction processes are thought to occur. We present evidence that supports cerebellar involvement in fear extinction, from rodent studies that investigate molecular mechanisms and functional connectivity with other brain regions of the known fear extinction network, to fMRI studies in humans. This evidence is considered in relation to the theoretical framework that the cerebellum is involved in the formation and updating of internal models of the inner and outer world by detecting errors between predicted and actual outcomes. In the case of fear conditioning, these internal models are thought to predict the occurrence of an aversive unconditioned stimulus (US), and when the aversive US is unexpectedly omitted during extinction learning the cerebellum uses prediction errors to update the internal model. Differences between human and rodent studies are highlighted to help inform future work.

Background: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. Methods: In total, 1937 twins aged 22–25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. Results: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4–0.5). Conclusions: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences. [ABSTRACT FROM AUTHOR]

The recall of conditioned fear extinction exhibits a circadian rhythm in humans and rodents, with optimal extinction recall occurring during the early active phase. However, it remains unclear whether this rhythm depends on the circadian modulation of mechanisms supporting memory consolidation versus memory maintenance and retrieval. Here, adult male rats underwent conditioned fear extinction at one of four times throughout the day and then, starting 24 h after extinction, were repeatedly tested for extinction recall over the next 24 h. Rats undergoing extinction learning during the early active phase tended toward accelerated extinction learning compared with rats in other groups, pointing to rhythms in mechanisms that support extinction memory encoding. The next day, the strength of extinction recall followed a 24-h cycle that depended not on the time of day of extinction learning but, instead, on the time of day of extinction recall. This latter finding indicates a rhythm in mechanisms supporting extinction memory maintenance and/or retrieval. Subsequent testing for fear relapse in the conditioning context suggested reduced fear in rats tested during the early active phase. These results lay the groundwork for mechanistic investigations of circadian rhythms in fear extinction memory. [ABSTRACT FROM AUTHOR]

The cholinergic system is a critical regulator of Pavlovian fear learning and extinction. As such, we have begun investigating the cholinergic system's involvement in individual differences in cued fear extinction using a transgenic ChAT::Cre rat model. The current study extends behavioral phenotyping of a transgenic ChAT::Cre rat line by examining both freezing behavior and ultrasonic vocalizations (USVs) during a Pavlovian cued fear learning and extinction paradigm. Freezing, 22 kHz USVs, and 50 kHz USVs were compared between male and female transgenic ChAT::Cre+ rats and their wildtype (Cre‐) littermates during fear learning, contextual and cue‐conditioned fear recall, cued fear extinction, and generalization to a novel tone. During contextual and cued fear recall ChAT::Cre+ rats froze slightly more than their Cre‐ littermates, and displayed significant sex differences in contextual and cue‐conditioned freezing, 22 kHz USVs, and 50 kHz USVs. Females showed more freezing than males in fear recall trials, but fewer 22 kHz distress calls during fear learning and recall. Females also produced more 50 kHz USVs during exposure to the testing chambers prior to tone (or shock) presentation compared with males, but this effect was blunted in ChAT::Cre+ females. Corroborating previous studies, ChAT::Cre+ transgenic rats overexpressed vesicular acetylcholine transporter immunolabeling in basal forebrain, striatum, basolateral amygdala, and hippocampus, but had similar levels of acetylcholinesterase and numbers of ChAT+ neurons as Cre‐ rats. This study suggests that variance in behavior between ChAT::Cre+ and wildtype rats is sex dependent and advances theories that distinct neural circuits and processes regulate sexually divergent fear responses. [ABSTRACT FROM AUTHOR]

Background: Using a foreign language can influence emotion modulation, but whether different psychotherapy processes would be affected by a foreign language is still unclear. The current study explored the foreign language effect on the extinction of fear. Method: During the conditioning phase, part of the neutral stimuli presented to the participants were associated with a threat, while they performed a countdown task in their native language. In the extinction phase, participants performed the same task either in their native/foreign language and were informed that the threat would no longer appear. We collected self-reports of fear, and pupil dilation and electrodermal activity as physiological measures of arousal. Results: Extinction was successful, indicated by greater self-reported fear and pupil dilation during the threat condition compared to neutral in the conditioning phase, but no significant differences during extinction. Although the foreign language group presented higher arousal, fear extinction occurred regardless of the linguistic context. Conclusions: Fear extinction via verbal instructions is equally effective in a foreign and a native language context. These results indicate that evidence should be continue to be gathered on the role of foreign languages using basic paradigms with clinical applications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hormone therapy (HT) has failed to improve learning and memory in postmenopausal women according to recent clinical studies; however, the reason for failure of HT in improving cognitive performance is unknown. In our research, we found cognitive flexibility was improved by 17β-Estradiol (E2) in mice 1 week after ovariectomy (OVXST), but not in mice 3 months after ovariectomy (OVXLT). Isobaric tags for relative and absolute quantitation (iTRAQ) revealed increased cannabinoid receptor interacting protein 1 (CNRIP1) in E2-treated OVXLT mice compared with E2-treated OVXST mice. Adeno-associated virus 2/9 (AAV2/9) delivery of Cnrip1 short-hairpin small interfering RNA (Cnrip1-shRNA) rescued the impaired cognitive flexibility in E2 treated OVXLT mice. This effect is dependent on CB1 function, which could be blocked by AM251—a CB1 antagonist. Our results indicated a new method to increasing cognitive flexibility in women receiving HT by disrupting CNRIP1.

• This review highlights human research on augmented extinction learning. • We focus on behaviorally-augmented forms of extinction, like counterconditioning. • Other methods of augmenting extinction are also reviewed. • Future directions for augmented extinction research are discussed. Several leading therapies for anxiety-related disorders rely on the principles of extinction learning. However, despite decades of development and research, many of these treatments remain only moderately effective. Developing techniques to improve extinction learning is an important step towards developing improved and mechanistically-informed exposure-based therapies. In this review, we highlight human research on strategies that might augment extinction learning through reward neurocircuitry and dopaminergic pathways, with an emphasis on counterconditioning and other behaviorally-augmented forms of extinction learning (e.g., novelty-facilitated extinction, positive affect training). We also highlight emerging pharmacological and non-pharmacological methods of augmenting extinction, including L-DOPA and aerobic exercise. Finally, we discuss future directions for augmented extinction learning and memory research, including the need for more work examining the influence of individual differences and psychopathology. [ABSTRACT FROM AUTHOR]

Personality traits linked to internalizing disorders influence the way we develop fears, but also how we regain a sense of safety. In the present study, we investigated the effect of intolerance of uncertainty (IU) on defensive responses using a differential fear conditioning protocol with an extinction phase. The conditioned stimulus was associated with an aversive sound (90 dB) in 75 % of the presentations during acquisition. A final sample of 176 participants completed the experiment. We measured self-reports of associative (expectancy of the unconditioned stimulus in acquisition) and evaluative learning (arousal and valence), and both physiological (skin conductance response) and electrocortical responses (steady-state visually evoked potentials, ssVEPs; late positive potentials, LPP) to the conditioned stimuli. Our results show that IU's impact is limited, with no effect in both acquisition and extinction. These findings emphasize the necessity of large samples in research on inter-individual differences and contribute to our understanding of how IU may or may not be involved in fear and safety learning processes considering multiple aspects of fear responding. • Intolerance of Uncertainty (IU) is marked by discomfort or avoidance of uncertain situations. • Multiple ratings and physiological measures recorded. • IU has no impact on fear acquisition responses. • IU shows no effect during or after the uninstructed extinction phase. [ABSTRACT FROM AUTHOR]

Single prolonged stress (SPS) is a preclinical rodent model for studying post-traumatic stress disorder (PTSD)-like behaviors. Previously we found that increased expression of the microglial marker Iba-1 in the ventral hippocampus after SPS exposure was associated with impaired fear extinction, suggesting that microglial activity contributed to the SPS-induced behavioral changes. To test this, we examined whether reducing microglia with the colony-stimulating factor 1 receptor blocker, PLX3397, in the diet would prevent the SPS-induced extinction impairment. Male rats exposed to SPS showed enhanced fear acquisition and impaired fear extinction memory. Adding PLX3397 to the diet prevented these behavioral changes. In contrast, PLX3397 did not prevent SPS from impairing fear extinction memory in the female rats. Despite the sex-dependent behavioral effects, we found a reduced number and area fraction of Iba-1+ microglia in both male and female rats suggesting that PLX3397 had similar effects on microglia in both sexes. Altogether, these results suggest that microglia contribute to the behavioral changes induced by SPS in male but not female rats.

Following treatment of fear-related disorders, return of fear remains a common occurrence. Currently, the presence of safety signals during treatment procedures is considered harmful, yet recent findings have demonstrated that certain safety signals (social-support figures) lead to enhanced fear extinction and thus might reduce return of fear. Here, we tested the effect of social-support-figure (vs. stranger) images on fear extinction outcomes. We found that, for conditional fear stimuli paired with social-support-figure images during extinction, return of fear was inhibited both immediately after extinction and during a fear reinstatement test 24 hr later; however, return of fear occurred for conditional stimuli paired with images of strangers. These findings suggest that social-support stimuli have unique safety-signaling properties that might enhance fear extinction and improve treatment outcomes for individuals with fear-related disorders.

PTSD has been associated consistently with abnormalities in fear acquisition and extinction learning and retention. Fear acquisition refers to learning to discriminate between threat and safety cues. Extinction learning reflects the formation of a new inhibitory-memory that competes with a previously learned threat-related memory. Adjudicating the competition between threat memory and the new inhibitory memory during extinction may rely, in part, on cognitive processes such as working memory (WM). Despite significant shared neural circuits and signaling pathways the relationship between WM, fear acquisition, and extinction is poorly understood. Here, we analyzed data from a large sample of healthy Marines who underwent an assessment battery including tests of fear acquisition, extinction learning, and WM (N-back). Fear potentiated startle (FPS), fear expectancy ratings, and self-reported anxiety served as the primary dependent variables. High WM ability (N = 192) was associated with greater CS + fear inhibition during the late block of extinction and greater US expectancy change during extinction learning compared to individuals with low WM ability (N = 204). WM ability was not associated with magnitude of fear conditioning/expression. Attention ability was unrelated to fear acquisition or extinction supporting specificity of WM associations with extinction. These results support the conclusion that individual differences in WM may contribute to regulating fear responses.

Although the presence of social-support figures (e.g., close friends and family members) is known to increase feelings of safety, reduce threat responses, and improve health, the route by which these effects occur is not well understood. One explanation is that social-support figures are members of a powerful category of safety signals—prepared safety stimuli. Here, we review research demonstrating that social-support figures act as prepared safety stimuli and explore the impact that these unique safety stimuli have on fear-learning processes. According to recent work, the presence of social-support figures both reduces fear acquisition and enhances fear extinction, ultimately decreasing perceptions of threat. These findings shed light on the route by which social support buffers against threat and illustrate the unique properties of prepared safety stimuli and how they might be used to improve mental and physical health outcomes.

BackgroundRisk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma.MethodsMale Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points.ResultsBefore deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals.ConclusionsThese findings support the hypothesis that G × E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies.

Thanks to the latest progress in the complex science of fear extinction, we know now that the efficacy of exposure therapy (which represents its clinical application) would not be due to the deletion of excitatory memories, as it was previously believed, rather to the formation of new inhibitory memories. It emerges, from this new conceptual model, that the weak point of the therapy, namely the return of fear, would be mainly due to a certain intrinsic fragility of the extinction process, that is its dependence on the context. Therefore, targeted behavioural strategies have been developed to compensate for the renewal of the context and facilitate the recovery of the inhibitory memory. In order to maximize exposure therapy, scientific evidence is also suggesting the presence of an additional element to be taken into consideration: the differences in how patients respond to the therapy. These variations, which represent a completely extrinsic dimension to the extinction process, would be due to biological (e.g. genetic and hormonal), psychological (e.g. anxious traits or poor/lack of motivation for treatment) and environmental (e.g. anxiety in the therapist or family members). This evidence suggests the need for a new way of practising exposure that should incorporate, in addition to the limits that are inherent to the extinction itself, also the individual differences involved in the process. In light of these findings, it is therefore no longer possible to continue to think in terms of mere habituation to and/or restructuring of the patient's "cognitive set" and it is no longer sensible to apply a standard approach (albeit evidence based) that is the same for all patients. The article intends to provide useful insights for the future development of an increasingly personalized and effective exposure therapy. [ABSTRACT FROM AUTHOR]

Purpose of Review: Exposure therapy is an effective treatment for anxiety-related disorders, but many individuals do not achieve full symptom relief, and return of fear is a common occurrence. Understanding how exposure therapy works enables further development of strategies to improve its effectiveness. Recent Findings: Recent studies have examined mechanisms of exposure-based interventions across multiple levels of analysis, from cognitive and behavioral changes that occur during treatment to the neurobiological mechanisms underlying fear extinction. Summary: Belief change and reductions in safety behaviors and avoidance mediate symptom improvements during exposure therapy, suggesting plausible cognitive and behavioral mechanisms. On the neural level, increased activation of prefrontal regions during extinction learning is a likely mechanism of exposure. Improved understanding of the biological mechanisms of exposure have led to exciting developments in clinical research, including pharmacological augmentation, though clinical translation of basic research has produced mixed results. Though still in development, such translational research is a promising future direction for exposure-based interventions. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder afflictingmillions of people around the world. Characterized by severe anxiety, intrusive thoughts, pervasive nightmares, an assortment of somatic symptoms, associations with severe long-term health problems, and an elevated risk of suicide, as much as 40-70% of patients suffer from refractory disease. 3,4-Methylenedioxy-methamphetamine (MDMA), like classic psychedelics such as psilocybin, have been used to enhance the efficacy of psychotherapy almost since their discovery, but due to their perceived potential for abuse and inclusion on USFDA (United States Food and Drug Administration) schedule 1, research into the mechanism by which they produce improvements in PTSD symptomology has been limited. Nevertheless, several compelling rationales have been explored, with the pro-social effects of MDMA thought to enhance therapeutic alliance and thus facilitate therapist-assisted trauma processing. This may be insufficient to fully explain the efficacy of MDMA in the treatment of psychiatric illness. Molecular mechanisms such as the MDMA mediated increase of brain-derived neurotrophic factor (BDNF) availability in the fear memory learning pathways combined with MDMA's pro-social effects may provide a more nuanced explanation for the therapeutic actions of MDMA. [ABSTRACT FROM AUTHOR]

Sevoflurane anesthesia during neonatal period was reported to sensitize the rodent animals to stress later in life. The authors tested the hypothesis that repeated sevoflurane exposures in neonatal rats increased the brain vulnerability to future stress exposure and resulted in fear extinction deficit and investigated whether the neonatal brain depolarizing γ-aminobutyric acid type A receptor (GABAAR) is involved in mediating these abnormalities. Neonatal Sprague–Dawley male rats, pretreated with vehicle or the NKCC1 inhibitor, bumetanide, received sequential exposures to 3% sevoflurane for 2 h on postnatal days (P) 5, P6, and P7 and then were exposed to electric foot shock stress in fear conditioning training at P14. Juvenile rats at different developmental brain stage receiving identical sevoflurane exposures on P25, P26, and P27 were also studied. The results showed repeated sevoflurane exposures in neonatal rats and increased the cation-chloride cotransporters NKCC1/KCC2 ratio in the PFC at P14. Repeated exposures to sevoflurane in neonatal rather than juvenile rats enhanced the stress response and exacerbated neuroapoptosis in the PFC after exposed to electric foot shock in fear conditioning training. Neonatal rather than juvenile sevoflurane-exposed rats exhibited deficits in fear extinction training and recall. Pretreatment of neonatal rats prior to sevoflurane exposures with bumetanide reduced the NKCC1/KCC2 ratio at P14 and ameliorated most of the subsequent adverse effects. Our study indicates that repeated sevoflurane exposures in neonatal rats might increase the brain vulnerability to future stress exposure and resulted in fear extinction deficit, which might be associated with the neonatal enhanced brain depolarizing GABAAR activity. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that rapid eye movement sleep (REM) supports the consolidation of extinction memory. REM is disrupted in posttraumatic stress disorder (PTSD), and REM abnormalities after traumatic events increase the risk of developing PTSD. Therefore, it was hypothesized that abnormal REM in trauma-exposed individuals may pave the way for PTSD by interfering with the processing of extinction memory. In addition, PTSD patients display reduced vagal activity. Vagal activity contributes to the strengthening of memories, including fear extinction memory, and recent studies show that the role of vagus in memory processing extends to memory consolidation during sleep. Therefore, it is plausible that reduced vagal activity during sleep in trauma-exposed individuals may be an additional mechanism that impairs extinction memory consolidation. However, to date, the contribution of sleep vagal activity to the consolidation of extinction memory or any emotional memory has not been investigated., Methods: Trauma-exposed individuals ( n = 113) underwent a 2-day fear conditioning and extinction protocol. Conditioning and extinction learning phases were followed by extinction recall 24 h later. The association of extinction recall with REM characteristics and REM vagal activity (indexed as heart rate variability) during the intervening consolidation night was examined., Results: Consistent with our hypotheses, REM disruption was associated with poorer physiological and explicit extinction memory. Furthermore, higher vagal activity during REM was associated with better explicit extinction memory, and physiological extinction memory in males., Conclusions: These findings support the notion that abnormal REM, including reduced REM vagal activity, may contribute to PTSD by impairing the consolidation of extinction memory.

Aims: Posttraumatic stress disorder (PTSD) is a debilitating neuropsychiatric illness caused by traumatic or life-threatening events and manifesting as various symptoms, including intrusive re-experiences of trauma, avoidance behaviors, hyperarousal, and negative changes in perception and mood., Main Methods: Current monoamine-based medications commonly exhibit limited efficacy and significant side effects, which hamper their clinical utility. To address this unmet need, we explored 4-methoxycinnamic acid (4-MCA) as a potential novel treatment for PTSD in a single prolonged stress (SPS)-induced animal model., Key Findings: Administration of 4-MCA (3 and 10 mg/kg, p.o.) significantly mitigated anxiety-like behaviors, alleviated depression-like behaviors, and improved cognitive function in an SPS-treated PTSD mouse model. Further, 4-MCA treatment effectively rectified the fear extinction deficits in the fear conditioning test. Molecular analyses revealed that 4-MCA normalized the elevated corticotropin-releasing hormone (CRH) levels as well as the phosphorylation of protein kinase A (PKA) and cAMP response element-binding protein (CREB) in the amygdala, a pivotal region for fear memory formation. Co-administration of 4-MCA and the CRFR1 antagonist antalarmin at subeffective doses facilitated fear memory extinction., Significance: These findings suggest that 4-MCA alleviates SPS-induced PTSD-like behaviors by regulating the CRH-CRFR1-PKA-CREB signaling pathway in the amygdala, and that 4-MCA may be a potential candidate for future PTSD treatment., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this study to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The basolateral amygdala (BLA) is a dynamic brain region involved in emotional experiences and subject to long-term plasticity. The BLA also modulates activity, plasticity, and related behaviors associated with other brain regions, including the mPFC and hippocampus. Accordingly, intra-BLA plasticity can be expected to alter both BLA-dependent behaviors and behaviors mediated by other brain regions. Lasting intra-BLA plasticity may be considered a form of metaplasticity, since it will affect subsequent plasticity and response to challenges later on. Activity within the BLA is tightly modulated by GABAergic interneurons, and thus inducing lasting alteration of GABAergic modulation of principal neurons may have an impactful metaplastic effect on BLA functioning. Previously, we demonstrated that intra-BLA knockdown (KD) of neurofascin (NF) reduced GABAergic synapses exclusively at the axon initial segment (AIS). Here, by reducing the expression of the tyrosine kinase receptor ephrin A7 (EphA7), we selectively impaired the modulatory function of a different subpopulation of interneurons, specifically targeting the soma and proximal dendrites of principal neurons. This perturbation induced an expected reduction in the spontaneous inhibitory synaptic input and an increase in the excitatory spontaneous synaptic activity, most probably due to the reduction of inhibitory tone. Moreover, this increased synaptic activity was followed by a reduction in intrinsic excitability. While intra-BLA NF-KD resulted in impaired extinction learning, without increased symptoms of anxiety, intra-BLA reduction of EphA7 expression resulted in increased symptoms of anxiety, as measured in the elevated plus maze, but without affecting fear conditioning or extinction learning. These results confirm the role of the BLA and intra-BLA metaplasticity in stress-induced increased anxiety symptoms and in impaired fear extinction learning but reveals a difference in intra-BLA mechanisms involved. The results also confirm the contribution of GABAergic interneurons to these effects but indicate selective roles for different subpopulations of intra-BLA interneurons., Competing Interests: Intra-BLA alteration of interneurons’ modulation of activity in rats, reveals a dissociation between effects on anxiety symptoms and extinction learning., (© 2024 The Authors.)

Study Objectives: To describe nightmare phenomenology among community dwelling elderly and to test the hypothesis that reduction in cognitive control is associated with nightmare-related phenomenology including nightmare frequency and severity, greater emotional reactivity, imagery immersion, and dream enactment behaviors (DEBs)., Methods: Study 1: Survey with multiple regression and ANOVAs on N = 56 people with frequent nightmares plus N = 62 age- and gender-matched controls to quantify the strength of the association between cognitive control variables and nightmare phenomenology. Study 2: Computational simulation of nightmare phenomenology in relation to cognitive control to simulate the empirical findings and to assess the underlying causal theory through computationally supported causal inference., Results: Study 1: Regressions demonstrated a strong association between reduction in cognitive control and more extreme nightmare phenomenology, including severity, frequency, daytime effects, and DEBs. Study 2: The computational simulation of nightmare phenomenology in relation to cognitive control is validated relative to regressions from study 1 and offers computational support for the causal theory explaining the associations in study 1., Conclusions: In aging people, decline in executive cognitive functions, cognitive control, and inhibitory processes reduce cognitive control over emotions, thus contributing to unusual nightmare activity, including more extreme nightmare phenomenology such as more severe nightmares, greater emotional reactivity, deeper imagery immersion, and DEBs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patrick McNamara reports financial support was provided by John Templeton Foundation. Wesley J. Wildman reports financial support was provided by John Templeton Foundation. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fear acquisition and fear extinction are the most widely used experimental models to study anxiety related disorders, with the medial prefrontal cortex (mPFC) playing an important role in this process. Previous research suggests that trait self-compassion is associated with lower anxiety, but the neural mechanisms underlying this relationship remain unclear. Women generally exhibit lower self-compassion than men, making them more vulnerable to fear and anxiety. In this study, female participants were divided into two groups - high and low trait self-compassion, based on their scores on the Self-Compassion Scale-Short Form (SCS-SF). Both groups completed fear acquisition and fear extinction tasks, during which conditioned responses (CRs) were measured using self-reported unconditioned stimulus (US) expectancy ratings, skin conductance response (SCR), and functional near-infrared spectroscopy (fNIRS). The results showed that in the fear acquisition phase, all participants successfully acquired fear, showing greater responses to threat stimuli than safety stimuli. However, participants with high trait self-compassion exhibited lower SCR than those with low trait self-compassion. In the fear extinction phase, compared to individuals with low trait self-compassion, individuals with high trait self-compassion exhibited more effective fear extinction learning, characterized by lower US expectancy ratings, lower SCR, and higher mPFC activation. Moreover, trait self-compassion was significantly correlated with the behavioral extinction ability and the mPFC activation during the late phase of fear extinction, and behavioral extinction ability was significantly correlated with mPFC activation. The findings of this study suggest individuals with high trait self-compassion have better physiological flexibility during fear acquisition and fear extinction, and may through enhancing mPFC activation to facilitate fear extinction. The results provide new insights into the pathological mechanisms of anxiety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All authors have approved this manuscript., (© 2024 The Authors. Published by Elsevier B.V.)

Abstract The ability to extinguish aversive memories when they are no longer associated with danger is critical for balancing survival with competing adaptive demands. Previous studies demonstrated that the infralimbic cortex (IL) is essential for extinction of learned fear, while neural activity in the prelimbic cortex (PL) facilitates fear responding and is negatively correlated with the strength of extinction memories. Though these adjacent regions in the prefrontal cortex maintain mutual synaptic connectivity, it has been unclear whether PL and IL interact functionally with each other during fear extinction learning. Here we addressed this question by recording local field potentials (LFPs) simultaneously from PL and IL of awake behaving rats during extinction of auditory fear memories. We found that LFP power in the fast gamma frequency (100–200 Hz) in both PL and IL regions increased during extinction learning. In addition, coherency analysis showed that synchronization between PL and IL in the fast gamma frequency was enhanced over the course of extinction. These findings support the hypothesis that interregional interactions between PL and IL increase as animals extinguish aversive memories.

Persistent cognitive impairment(s) can be a significant consequence of traumatic brain injury (TBI) and can markedly compromise quality of life. Unfortunately, identifying effective treatments to alleviate memory impairments in the chronic stage of TBI has proven elusive. Several studies have demonstrated that insulin-like growth factor-2 (IGF-2) can enhance memory in both normal animals and in experimental models of disease. In this study, we questioned whether IGF-2, when administered before learning, could enhance memory performance in the chronic stage of TBI. Male C57BL/6 mice (n?=?7 per group) were injured using an electronic cortical impact injury device. Four months later, mice were tested for their cognitive performance in the fear memory extinction, novel object recognition (NOR), and Morris water maze tasks. Twenty minutes before each day of training, mice received a subcutaneous injection of either 30??g/kg of IGF-2 or an equal volume of vehicle. Memory testing was carried out 24?h after training in the absence of the drug. Uninjured sham animals treated with IGF-2 (or vehicle) were trained and tested in the fear memory extinction task as a positive control. Our data show that although IGF-2 (30??g/kg) improved memory extinction in uninjured mice, it was ineffective at improving fear memory extinction in the chronic stage of TBI. Similarly, IGF-2 administration to chronically injured animals did not improve TBI-related deficits in either NOR or spatial memory. Our results indicate that IGF-2, administered in the chronic stage of injury, is ineffective at enhancing memory performance and therefore may not be a beneficial treatment option for lingering cognitive impairments after a TBI.

Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder afflicting millions of people around the world. Characterized by severe anxiety, intrusive thoughts, pervasive nightmares, an assortment of somatic symptoms, associations with severe long-term health problems, and an elevated risk of suicide, as much as 40–70% of patients suffer from refractory disease. 3,4-Methylenedioxy-methamphetamine (MDMA), like classic psychedelics such as psilocybin, have been used to enhance the efficacy of psychotherapy almost since their discovery, but due to their perceived potential for abuse and inclusion on USFDA (United States Food and Drug Administration) schedule 1, research into the mechanism by which they produce improvements in PTSD symptomology has been limited. Nevertheless, several compelling rationales have been explored, with the pro-social effects of MDMA thought to enhance therapeutic alliance and thus facilitate therapist-assisted trauma processing. This may be insufficient to fully explain the efficacy of MDMA in the treatment of psychiatric illness. Molecular mechanisms such as the MDMA mediated increase of brain-derived neurotrophic factor (BDNF) availability in the fear memory learning pathways combined with MDMA's pro-social effects may provide a more nuanced explanation for the therapeutic actions of MDMA.