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Background and Purpose Experimental Approach Key Results Conclusion and Implications The dorsal hippocampus (dHIP) is pivotal for learning, memory, and defensive responses. Transient receptor potential vanilloid type 1 (TRPV1) receptors in the dHIP modulate contextual fear conditioning by triggering a cascade involving glutamate release, nitric oxide (NO) formation and cyclic guanosine monophosphate (cGMP) production. The present study investigated the involvement of dHIP TRPV1 receptors and their interaction with the glutamate/NO/cGMP signalling pathway in modulating the expression of contextual fear conditioning (CFC).Male Wistar rats were submitted to an aversive contextual conditioning session and, 48 h later, were re‐introduced to the same aversive environment where the freezing response and autonomic activity (evidenced by increased arterial pressure and heart rate and a decrease in tail temperature) were measured.The results demonstrated that the TRPV1 antagonist 6‐I‐CPS in dHIP reduced the expression of CFC, whereas the agonist capsaicin had the opposite effect. Furthermore, dHIP pre‐treatment with an NMDA receptor antagonist (AP7), neuronal NO synthase inhibitor (N‐propyl‐L‐arginine), NO scavenger (c‐PTIO) or guanylate cyclase inhibitor (ODQ) attenuated capsaicin‐induced increases in CFC. Finally, we observed that re‐exposure to the aversive chamber increased dHIP NO levels in conditioned animals compared with a non‐conditioned group, which was prevented by the administration of the TRPV1 antagonist, 6‐I‐CPS.Our study revealed that TRPV1 receptors in the dHIP play a crucial role in modulating contextual fear expression by acting through the NMDA receptor/NO/cGMP signalling pathway, providing important insights into the underlying mechanisms and potential therapeutic avenues associated with these pathways. [ABSTRACT FROM AUTHOR]

Learning safe versus dangerous cues is crucial for survival. During development, parents can influence fear learning by buffering their children's stress response and increasing exploration of potentially aversive stimuli. Rodent findings suggest that these behavioral effects are mediated through parental presence modulation of the amygdala and medial prefrontal cortex (mPFC). Here, we investigated whether similar parental modulation of amygdala and mPFC during fear learning occurs in humans. Using a within‐subjects design, behavioral (final N = 48, 6–17 years, mean = 11.61, SD = 2.84, 60% females/40% males) and neuroimaging data (final N = 39, 6–17 years, mean = 12.03, SD = 2.98, 59% females/41% males) were acquired during a classical fear conditioning task, which included a CS+ followed by an aversive noise (US; 75% reinforcement rate) and a CS−. Conditioning occurred once in physical contact with the participant's parent and once alone (order counterbalanced). Region of interest analyses examined the unconditioned stress response by BOLD activation to the US (vs. implicit baseline) and learning by activation to the CS+ (vs. CS−). Results showed that during US presentation, parental presence reduced the centromedial amygdala activity, suggesting buffering of the unconditioned stress response. In response to learned stimuli, parental presence reduced mPFC activity to the CS+ (relative to the CS−), although this result did not survive multiple comparisons' correction. These preliminary findings indicate that parents modulate amygdala and mPFC activity during exposure to unconditioned and conditioned fear stimuli, potentially providing insight into the neural mechanisms by which parents act as a social buffer during fear learning. Research Highlights: This study used a within‐participant experimental design to investigate how parental presence (vs. absence) affects youth's neural responses in a classical fear conditioning task.Parental presence reduced the youth's centromedial amygdala activation to the unconditioned stimulus (US), suggesting parental buffering of the neural unconditioned response (UR).Parental presence reduced the youth's mPFC activation to a conditioned threat cue (CS+) compared to a safety cue (CS−), suggesting possible parental modulation of fear learning. [ABSTRACT FROM AUTHOR]

Safety learning allows the identification of non-threatening situations, a learning process instrumental for survival and psychic health. In contrast to fear learning, in which a sensory cue (conditioned stimulus, CS) is temporally linked to a mildly aversive stimulus (US), safety learning is studied by presenting the CS and US in an explicitly unpaired fashion. This leads to conditioned inhibition of fear responses, in which sensory cues can acquire a safety meaning (CS-). In one variant of safety learning, an auditory CS- was shown to reduce contextual fear responses during recall, as measured by freezing of mice. Here, we performed control experiments to test whether auditory stimuli might interfere with freezing by mechanisms other than safety learning, a phenomenon also called external inhibition. Surprisingly, when auditory stimulation was omitted during training (US-only controls), such stimuli still significantly suppressed contextual freezing during recall, indistinguishable from the reduction of freezing after regular safety training. The degree of this external inhibition was positively correlated with the levels of contextual freezing preceding the auditory stimulation. Correspondingly, in fear learning protocols which employ a new context during recall and therefore induce lower contextual freezing, auditory stimuli did not induce significant external inhibition. These experiments show that in safety learning protocols that employ contextual freezing, the freezing reduction caused by auditory stimuli during recall is dominated by external inhibition, rather than by learned safety. Thus, in safety learning experiments extensive controls should be performed to rule out possible intrinsic effects of sensory cues on freezing behavior. [ABSTRACT FROM AUTHOR]

In recent years, research has progressively increased the importance of considering sex differences in stress and fear memory studies. Many studies have traditionally focused on male subjects, potentially overlooking critical differences with females. Emerging evidence suggests that males and females can exhibit distinct behavioral and neurophysiological responses to stress and fear conditioning. These differences may be attributable to variations in hormone levels, brain structure, and neural circuitry, particularly in regions such as the prefrontal cortex (PFC). In the present study, we explored sex differences in prelimbic cortex (PL) calcium activity in animals submitted to immobilization stress (IMO), fear conditioning (FC), and fear extinction (FE). While no significant sex differences were found in behavioral responses, we did observe differences in several PL calcium activity parameters. To determine whether these results were related to behaviors beyond stress and fear memory, we conducted correlation studies between the movement of the animals and PL activity during IMO and freezing behavior during FC and FE. Our findings revealed a clear correlation between PL calcium activity with movement during stress exposure and freezing behavior, with no sex differences observed in these correlations. These results suggest a significant role for the PL in movement and locomotion, in addition to its involvement in fear-related processes. The inclusion of both female and male subjects is crucial for studies like this to fully understand the role of the PFC and other brain areas in stress and fear responses. Recognizing sex differences enhances our comprehension of brain function and can lead to more personalized and effective approaches in the study and treatment of stress and fear-related conditions. Plain English summary: In recent years, researchers have started paying more attention to the differences between males and females in how they handle stress and remember fearful events. Traditionally, many studies focused mainly on males, which might have missed important differences in females. New findings seem to suggest that males and females can respond differently to stress and fear due to differences in hormone levels, brain structure, and brain circuits, especially in the prefrontal cortex (PFC). In this study, we looked at how male and female animals' brains reacted to being restrained, experiencing a strong trauma, and then trying to learn a new fearful memory. While their behaviors didn't show significant differences between sexes, their brain activities did. We found that the prelimbic area of the brain shows calcium activity linked to the animals' movements during stress and their freezing behavior during fear-related tests. These results show that the PL is involved in both movement and fear responses. Including both male and female subjects in such studies is vital to fully understand how the prefrontal cortex and other brain areas work in stress and fear situations. Recognizing these differences helps improve our understanding of brain function and can lead to better, more personalized treatments for stress and fear-related conditions. Highlights: • Sex differences were found in the animals' calcium activity in the prelimbic cortex (PL) during IMO. Females showed higher frequency, but lower amplitude of calcium events in early IMO. • No significant sex or stage differences were found in high movement periods during IMO. However, a positive correlation between calcium activity in the PL, and movement was observed in both sexes. • Both sexes showed increased freezing during fear conditioning (FC). Sex differences were noted during the second extinction session (FE2), with males showing significant changes across tones. • A negative correlation between calcium activity in the PL and freezing behavior was identified during FC and both extinction phases (FE1 and FE2). • Significant sex differences in the percentage of excited neurons were observed during FC, but not in inhibited neurons. Differences were also noted in the percentage of excited neurons during FE1, but not during FE2. [ABSTRACT FROM AUTHOR]

It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified de novo loss‐of‐function (dnLoF) mutations in the Down Syndrome Cell Adhesion Molecule (DSCAM) as a strong risk factor for ASD. Previous research has shown that DSCAM ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent DSCAM underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of DSCAM, as in the DSCAM2J+/−, that is, DSCAM heterozygous mice, displayed hyperactivity, increased anxiety‐like behavior, and motor coordination deficits. Additionally, hippocampal‐dependent learning and memory was affected, including impairments in working memory, long‐term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, DSCAM LoF produces autistic‐like behaviors that are similar to those observed in human cases of ASD. These findings further support a role for DSCAM dnLoF mutations in ASD and suggest DSCAM2J+/− as a suitable model for ASD research. [ABSTRACT FROM AUTHOR]

Abstract In recent years, research has progressively increased the importance of considering sex differences in stress and fear memory studies. Many studies have traditionally focused on male subjects, potentially overlooking critical differences with females. Emerging evidence suggests that males and females can exhibit distinct behavioral and neurophysiological responses to stress and fear conditioning. These differences may be attributable to variations in hormone levels, brain structure, and neural circuitry, particularly in regions such as the prefrontal cortex (PFC). In the present study, we explored sex differences in prelimbic cortex (PL) calcium activity in animals submitted to immobilization stress (IMO), fear conditioning (FC), and fear extinction (FE). While no significant sex differences were found in behavioral responses, we did observe differences in several PL calcium activity parameters. To determine whether these results were related to behaviors beyond stress and fear memory, we conducted correlation studies between the movement of the animals and PL activity during IMO and freezing behavior during FC and FE. Our findings revealed a clear correlation between PL calcium activity with movement during stress exposure and freezing behavior, with no sex differences observed in these correlations. These results suggest a significant role for the PL in movement and locomotion, in addition to its involvement in fear-related processes. The inclusion of both female and male subjects is crucial for studies like this to fully understand the role of the PFC and other brain areas in stress and fear responses. Recognizing sex differences enhances our comprehension of brain function and can lead to more personalized and effective approaches in the study and treatment of stress and fear-related conditions.

Background Fear learning is a core component of conceptual models of how adverse experiences may influence psychopathology. Specifically, existing theories posit that childhood experiences involving childhood trauma are associated with altered fear learning processes, while experiences involving deprivation are not. Several studies have found altered fear acquisition in youth exposed to trauma, but not deprivation, although the specific patterns have varied across studies. The present study utilizes a longitudinal sample of children with variability in adversity experiences to examine associations among childhood trauma, fear learning, and psychopathology in youth. Methods The sample includes 170 youths aged 10–13 years (M = 11.56, s.d. = 0.47, 48.24% female). Children completed a fear conditioning task while skin conductance responses (SCR) were obtained, which included both acquisition and extinction. Childhood trauma and deprivation severity were measured using both parent and youth report. Symptoms of anxiety, externalizing problems, and post-traumatic stress disorder (PTSD) were assessed at baseline and again two-years later. Results Greater trauma-related experiences were associated with greater SCR to the threat cue (CS+) relative to the safety cue (CS−) in early fear acquisition, controlling for deprivation, age, and sex. Deprivation was unrelated to fear learning. Greater SCR to the threat cue during early acquisition was associated with increased PTSD symptoms over time controlling for baseline symptoms and mediated the relationship between trauma and prospective changes in PTSD symptoms. Conclusions Childhood trauma is associated with altered fear learning in youth, which may be one mechanism linking exposure to violence with the emergence of PTSD symptoms in adolescence. [ABSTRACT FROM AUTHOR]

Safety learning allows the identification of non-threatening situations, a learning process instrumental for survival and psychic health. In contrast to fear learning, in which a sensory cue (conditioned stimulus, CS) is temporally linked to a mildly aversive stimulus (US), safety learning is studied by presenting the CS and US in an explicitly unpaired fashion. This leads to conditioned inhibition of fear responses, in which sensory cues can acquire a safety meaning (CS-). In one variant of safety learning, an auditory CS- was shown to reduce contextual fear responses during recall, as measured by freezing of mice. Here, we performed control experiments to test whether auditory stimuli might interfere with freezing by mechanisms other than safety learning, a phenomenon also called external inhibition. Surprisingly, when auditory stimulation was omitted during training (US-only controls), such stimuli still significantly suppressed contextual freezing during recall, indistinguishable from the reduction of freezing after regular safety training. The degree of this external inhibition was positively correlated with the levels of contextual freezing preceding the auditory stimulation. Correspondingly, in fear learning protocols which employ a new context during recall and therefore induce lower contextual freezing, auditory stimuli did not induce significant external inhibition. These experiments show that in safety learning protocols that employ contextual freezing, the freezing reduction caused by auditory stimuli during recall is dominated by external inhibition, rather than by learned safety. Thus, in safety learning experiments extensive controls should be performed to rule out possible intrinsic effects of sensory cues on freezing behavior.

Abstract Background Latent inhibition occurs when exposure to a stimulus prior its direct associative conditioning impairs learning. Results from naturalistic studies suggest that latent inhibition disrupts the learning of dental fear from aversive associative conditioning and thereby reduces the development of dental phobia. Although theory suggests latent inhibition occurs because pre-exposure changes the expected relevance and attention directed to the pre-exposed stimulus, evidence supporting these mechanisms in humans is limited. The aim of this study is to determine if two variables, pre-exposure session spacing and multiple context pre-exposure, potentiate the hypothesized mechanisms of expected relevance and attention and, in turn, increase latent inhibition of dental fear. Methods In a virtual reality simulation, child and adult community members (ages 6 to 35) will take part in pre-exposure and conditioning trials, followed by short- and long-term tests of learning. A 100ms puff of 60 psi air to a maxillary anterior tooth will serve as the unconditioned stimulus. Pre-exposure session spacing (no spacing vs. sessions spaced) and multiple context pre-exposure (single context vs. multiple contexts) will be between-subject factors. Stimulus type (pre-exposed to-be conditioned stimulus, a non-pre-exposed conditioned stimulus, and an unpaired control stimulus) and trial will serve as within-subject factors. Baseline pain sensitivity will also be measured as a potential moderator. Discussion It is hypothesized that spaced pre-exposure and pre-exposure in multiple contexts will increase the engagement of the mechanisms of expected relevance and attention and increase the latent inhibition of dental fear. It is expected that the findings will add to theory on fear learning and provide information to aid the design of future interventions that leverage latent inhibition to reduce dental phobia.

Abstract Background Dental stimuli can evoke fear after being paired - or conditioned - with aversive outcomes (e.g., pain). Pre-exposing the stimuli before conditioning can impair dental fear learning via a phenomenon known as latent inhibition. Theory suggests changes in expected relevance and attention are two mechanisms responsible for latent inhibition. In the proposed research, we test whether pre-exposure dose and degree of pre-exposure novelty potentiate changes in expected relevance and attention to a pre-exposed stimulus. We also assess if the manipulations alter latent inhibition and explore the possible moderating role of individual differences in pain sensitivity. Methods Participants will be healthy individuals across a wide range of ages (6 to 35 years), from two study sites. Participants will undergo pre-exposure and conditioning followed by both a short-term and long-term test of learning, all in a novel virtual reality environment. The unconditioned stimulus will be a brief pressurized puff of air to a maxillary anterior tooth. Pre-exposure dose (low vs. high) and pre-exposure novelty (element stimulus vs. compound stimuli) will be between-subject factors, with stimulus type (pre-exposed to-be conditioned stimulus, a non-pre-exposed conditioned stimulus, and an unpaired control stimulus) and trial as within-subject factors. Pain sensitivity will be measured through self-report and a cold pressor test. It is hypothesized that a larger dose of pre-exposure and compound pre-exposure will potentiate the engagement of the target mechanisms and thereby result in greater latent inhibition in the form of reduced fear learning. Further, it is hypothesized that larger effects will be observed in participants with greater baseline pain sensitivity. Discussion The proposed study will test whether pre-exposure dose and compound stimulus presentation change expected relevance and attention to the pre-exposed stimulus, and thereby enhance latent inhibition of dental fear. If found, the results will add to our theoretical understanding of the latent inhibition of dental fear and inform future interventions for dental phobia prevention.

Adults quickly orient toward sources of danger and deploy fight-or-flight tactics to manage threatening situations. In contrast, infants who cannot implement the safety strategies available to adults and depend heavily on caregivers for survival are more likely to turn toward familiar adults, such as their parents, to help them navigate threatening circumstances. However, work has yet to investigate how readily children and adolescents orient toward their parents in threatening or fearful contexts. The current work addressed this question using a visual search paradigm that included arrays of parents and strangers faces as target and distractor stimuli, preceded by a fear or neutral emotional priming procedure. Linear mixed-effects models showed that children and adolescents (N = 88, age range = 4-17 years; 42M/46F) were faster to search for the face of their parent than of a stranger. However, fear priming attenuated this effect of the parent on search times, such that children and adolescents were significantly slower to orient toward their parent in an array of strangers faces if they were first primed with fear as opposed to a neutral video. This work indicates that fear priming may phasically interfere with parental orienting during childhood and adolescence, possibly because fear reallocates attention away from parents and toward (potentially threatening) unfamiliar people in the environment to facilitate the development of independent threat learning and coping systems.

• Deletion of Foxp2 in NAc alters social novelty behavior. • Deletion of Foxp2 in NAc impairs appetitive reward learning. • Deletion of Foxp2 in NAc enhances fear learning and impairs fear extinction. • Foxp2 plays a physiological role in NAc-mediated multifaceted limbic function. The forkhead box protein P2 (Foxp2), initially identified for its role in speech and language development, plays an important role in neural development. Previous studies investigated the function of the Foxp2 gene by deleting or mutating Foxp2 from developmental stages. Little is known about its physiological function in adult brains. Although Foxp2 has been well studied in the dorsal striatum, its function in the nucleus accumbens (NAc) of the ventral striatum remains elusive. Here, we examine the physiological function of Foxp2 in NAc of mouse brains. We conditionally knocked out Foxp2 by microinjections of AAV-EGFP-Cre viruses into the medial shell of NAc of Foxp2 floxed (cKO) mice. Immunostaining showed increased c-Fos positive cells in cKO NAc at basal levels, suggesting an abnormality in Foxp2 -deficient NAc cells. Unbiased behavioral profiling of Foxp2 cKO mice showed abnormalities in limbic-associated function. Foxp2 cKO mice exhibited abnormal social novelty without preference for interaction with strangers and familiar mice. In appetitive reward learning, Foxp2 cKO mice failed to learn the time expectancy of food delivery. In fear learning, Foxp2 cKO mice exhibited abnormal increases in freezing levels in response to tone paired with foot shock during fear conditioning. The extinction of the fear response was also altered in Foxp2 cKO mice. In contrast, conditional knockout of Foxp2 in NAc did not affect locomotion, motor coordination, thermal pain sensation, anxiety- and depression-like behaviors. Collectively, our study suggests that Foxp2 has a multifaceted physiological role in NAc in the regulation of limbic function in the adult brain. [ABSTRACT FROM AUTHOR]

The central amygdala (CeA) is crucial in integrating sensory and associative information to mediate adaptive responses to emotional stimuli. Recent advances in genetic techniques like optogenetics and chemogenetics have deepened our understanding of distinct neuronal populations within the CeA, particularly those involved in fear learning and memory consolidation. However, challenges remain due to overlapping genetic markers complicating neuron identification. Furthermore, a comprehensive understanding of molecularly defined cell types and their projection patterns, which are essential for elucidating functional roles, is still developing. Recent advancements in transcriptomics are starting to bridge these gaps, offering new insights into the functional dynamics of CeA neurons. In this review, we provide an overview of the expanding genetic markers for amygdala research, encompassing recent developments and current trends. We also discuss how novel transcriptomic approaches are redefining cell types in the CeA and setting the stage for comprehensive functional studies. [ABSTRACT FROM AUTHOR]

Rationale: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. Objective: We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. Methods: We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. Results: Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. Conclusions: This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs. [ABSTRACT FROM AUTHOR]

Rationale and objectives: Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear. Methods: Following a comprehensive search in Medline and Embase, we included 68 research articles that reported on 103 drugs, covering 56 different drug classes. The systematic review was limited to studies using acute, systemic drug administration in naive animals. Results: Qualitative data synthesis showed that most clinically active anxiolytics, but not serotonin-reuptake inhibitors, reduced cued fear. Anxiogenic drugs increased fear potentiation in 35% of the experiments, reduced fear potentiation in 29% of the experiments, and were without effect in 29% of the experiments. Meta-analyses could be performed for five drug classes and showed that benzodiazepines, buspirone, 5-HT1A agonists, 5-HT1A antagonists, and mGluR2,3 agonists reduced cued conditioned fear. The non-cued baseline startle response, which may reflect contextual anxiety, was only significantly reduced by benzodiazepines and 5-HT1A antagonists. No associations were found between drug effects and methodological characteristics, except for strain. Conclusions: The fear-potentiated startle test appears to have moderate to high predictive validity and may serve as a valuable tool for the development of novel anxiolytics. Given the limited available data, the generally low study quality and high heterogeneity additional studies are warranted to corroborate the findings of this review. [ABSTRACT FROM AUTHOR]

Introduction: New learning results in modulation of intrinsic plasticity in the underlying brain regions. Such changes in intrinsic plasticity can influence allocation and encoding of future memories such that new memories encoded during the period of enhanced excitability are linked to the original memory. The temporal window during which the two memories interact depends upon the time course of intrinsic plasticity following new learning. Methods: Using the well-characterized lateral amygdala-dependent auditory fear conditioning as a behavioral paradigm, we investigated the time course of changes in intrinsic excitability within lateral amygdala neurons. Results: We found transient changes in the intrinsic excitability of amygdala neurons. Neuronal excitability was increased immediately following fear conditioning and persisted for up to 4 days post-learning but was back to naïve levels 10 days following fear conditioning. We also determined the relationship between learning-induced intrinsic and synaptic plasticity. Synaptic plasticity following fear conditioning was evident for up to 24 h but not 4 days later. Importantly, we demonstrated that the enhanced neuronal intrinsic excitability was evident in many of the same neurons that had undergone synaptic plasticity immediately following fear conditioning. Interestingly, such a correlation between synaptic and intrinsic plasticity following fear conditioning was no longer present 24 h post-learning. Discussion: These data demonstrate that intrinsic and synaptic changes following fear conditioning are transient and co-localized to the same neurons. Since intrinsic plasticity following fear conditioning is an important determinant for the allocation and consolidation of future amygdala-dependent memories, these findings establish a time course during which fear memories may influence each other. [ABSTRACT FROM AUTHOR]

Deficits in associative and Pavlovian learning are thought to lie at the center of anxiety-related disorders. However, the majority of studies have been carried out in adult populations. The aim of this review was to critically examine the behavioral and neuroimaging literature on Pavlovian learning in pediatric anxiety disorders. We conclude that although there is evidence for deficits in Pavlovian processes (e.g., heightened reactivity to safety cues in anxious samples), the extant literature suffers from key methodological and theoretical issues. We conclude with theoretical and methodological recommendations for future research in order to further elucidate the role of Pavlovian learning in the etiology, maintenance, and treatment of pediatric anxiety disorders.

IntroductionNew learning results in modulation of intrinsic plasticity in the underlying brain regions. Such changes in intrinsic plasticity can influence allocation and encoding of future memories such that new memories encoded during the period of enhanced excitability are linked to the original memory. The temporal window during which the two memories interact depends upon the time course of intrinsic plasticity following new learning.MethodsUsing the well-characterized lateral amygdala-dependent auditory fear conditioning as a behavioral paradigm, we investigated the time course of changes in intrinsic excitability within lateral amygdala neurons.ResultsWe found transient changes in the intrinsic excitability of amygdala neurons. Neuronal excitability was increased immediately following fear conditioning and persisted for up to 4 days post-learning but was back to naïve levels 10 days following fear conditioning. We also determined the relationship between learning-induced intrinsic and synaptic plasticity. Synaptic plasticity following fear conditioning was evident for up to 24 h but not 4 days later. Importantly, we demonstrated that the enhanced neuronal intrinsic excitability was evident in many of the same neurons that had undergone synaptic plasticity immediately following fear conditioning. Interestingly, such a correlation between synaptic and intrinsic plasticity following fear conditioning was no longer present 24 h post-learning.DiscussionThese data demonstrate that intrinsic and synaptic changes following fear conditioning are transient and co-localized to the same neurons. Since intrinsic plasticity following fear conditioning is an important determinant for the allocation and consolidation of future amygdala-dependent memories, these findings establish a time course during which fear memories may influence each other.

Background: The association between anxious mood and aberrant fear learning mechanisms has not been fully elucidated. Studying how fear conditioning and extinction constructs relate to anxiety symptoms and reactivity to stressful and benign moments in everyday life provides a powerful addition to experimental paradigms. Method: Fifty-one young adults completed laboratory-based differential conditioning and extinction tasks with (CS +) and without (CS-) an aversive unconditional stimulus (US). Electrodermal skin conductance responses were measured during each phase, followed by ecological momentary assessment (EMA) tapping anxiety and stressors six times daily for seven days (2, 142 moments). Results: Conditioned electrodermal reactivity to the CS + and overgeneralisation to the CS- were associated with greater change in anxiety (measured via EMA), across non-stressful situations, remaining the same across stressful situations. Likewise, during extinction when the CS + is now safe, more electrodermal reactivity to the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations. Also, during extinction when threat is absent, more electrodermal reactivity at the late stage of the CS- was associated with less momentary anxiety change in response to stressful situations; more electrodermal activity at the late stage of the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations. Conclusions: Sampling 'in vivo' emotion and stress experiences, study findings revealed links between conditioned electrodermal reactivity and overgeneralisation to safe stimuli and heightened anxious reactivity during non-stressful (i.e. safe) moments in daily life, coupled with less change in response to actual stressors. [ABSTRACT FROM AUTHOR]

A central question in Pavlovian conditioning concerns the critical conditions that drive the acquisition and maintenance of the stimulus-outcome association. The spatial relationship between the conditioned (CS) and unconditioned (US) stimuli is considered to exert strong effects on learning. However, how spatial information modulates Pavlovian learning remains mostly unexplored in humans. Here, we test how the compatibility between the CS and the US location influences the acquisition, extinction, and recovery (following reinstatement) of Pavlovian conditioned threat. Participants (N = 20) completed a differential threat conditioning task in which visual CSs appeared on the same (compatible) or opposite (incompatible) hemispace as the US delivery (aversive shock to one hand), while their skin conductance response served as an index of learning. Results show that initial threat expectations were biased in favor of compatible CSs before conditioning. Nevertheless, this bias was revised during acquisition to reflect current stimulus-outcome contingencies. Computational modeling suggested that this effect occurred through a higher reliance on positive aversive prediction errors for incompatible CSs, thereby facilitating learning of their association with the US. Additionally, the conditioned response to incompatible CSs was associated with initially slower extinction and a greater recovery after threat reinstatement. These findings suggest that spatial information conveyed by stimuli and outcomes can be flexibly used to enact defensive responses to the current source of danger, highlighting the adaptive nature of Pavlovian learning. • Stimulus-outcome spatial relationship strongly influences associative learning. • Initial threat expectations are biased for stimuli compatible with the outcome. • This bias is revised during learning to reflect stimulus-outcome contingencies. • Thus, learning is not a passive reflection of initial expectations. • Spatial information of stimuli and outcomes is adaptively used during learning. [ABSTRACT FROM AUTHOR]

Persistent fear is a cardinal feature of posttraumatic stress disorder (PTSD), and deficient fear extinction retention is a proposed illness mechanism and target of exposure‐based therapy. However, evidence for deficient fear extinction in PTSD has been mixed using laboratory paradigms, which may relate to underidentified methodological variation across studies. We reviewed the literature to identify parameters that differ across studies of fear extinction retention in PTSD. We then performed Multiverse Analysis in a new sample, to quantify the impact of those methodological parameters on statistical findings. In 25 PTSD patients (15 female) and 36 trauma‐exposed non‐PTSD controls (TENC) (20 female), we recorded skin conductance response (SCR) during fear acquisition and extinction learning (day 1) and extinction recall (day 2). A first Multiverse Analysis examined the effects of methodological parameters identified by the literature review on comparisons of SCR‐based fear extinction retention in PTSD versus TENC. A second Multiverse Analysis examined the effects of those methodological parameters on comparisons of SCR to a danger cue (CS+) versus safety cue (CS−) during fear acquisition. Both the literature review and the Multiverse Analysis yielded inconsistent findings for fear extinction retention in PTSD versus TENC, and most analyses found no statistically significant group difference. By contrast, significantly elevated SCR to CS+ versus CS− was consistently found across all analyses in the literature review and the Multiverse Analysis of new data. We discuss methodological parameters that may most contribute to inconsistent findings of fear extinction retention deficit in PTSD and implications for future clinical research. In a systematic literature review, we show that findings and methodologies are inconsistent across prior skin conductance response analyses of fear extinction retention in PTSD. In the first application of multiverse analysis to clinical fear learning data, we show that the findings of any given analysis of fear extinction retention in PTSD may depend, in part, on the study's methodology and approach. [ABSTRACT FROM AUTHOR]

Abstract Background Evidence suggests that dental anxiety and phobia are frequently the result of direct associative fear conditioning but that pre-exposure to dental stimuli prior to conditioning results in latent inhibition of fear learning. The mechanisms underlying the pre-exposure effect in humans, however, are poorly understood. Moreover, pain sensitivity has been linked to dental fear conditioning in correlational investigations and theory suggests it may moderate the latent inhibition effect, but this hypothesis has not been directly tested. These gaps in our understanding are a barrier to the development of evidence-based dental phobia prevention efforts. Methods Healthy volunteers between the ages of 6 and 35 years will be enrolled across two sites. Participants will complete a conditioning task in a novel virtual reality environment, allowing for control over pre-exposure and the examination of behaviour. A dental startle (a brief, pressurized puff of air to a tooth) will serve as the unconditioned stimulus. Using a within-subjects experimental design, participants will experience a pre-exposed to-be conditioned stimulus, a non-pre-exposed to-be conditioned stimulus, and a neutral control stimulus. Two hypothesized mechanisms, changes in prediction errors and attention, are expected to mediate the association between stimulus condition and fear acquisition, recall, and retention. To ascertain the involvement of pain sensitivity, this construct will be measured through self-report and the cold pressor task. Discussion Dental phobia negatively affects the dental health and overall health of individuals. This study aims to determine the mechanisms through which pre-exposure retards conditioned dental fear acquisition, recall, and retention. A randomized control trial will be used to identify these mechanisms so that they can be precisely targeted and maximally engaged in preventative efforts.

The anterior cingulate cortex (ACC) plays a crucial role in encoding, consolidating and retrieving memories related to emotionally salient experiences, such as aversive and rewarding events. Various studies have highlighted its importance for fear memory processing, but its circuit mechanisms are still poorly understood. Cortical layer 1 (L1) of the ACC might be a particularly important site of signal integration, since it is a major entry point for long-range inputs, which is tightly controlled by local inhibition. Many L1 interneurons express the ionotropic serotonin receptor 3a (5HT3aR), which has been implicated in posttraumatic stress disorder and in models of anxiety. Hence, unraveling the response dynamics of L1 interneurons and subtypes thereof during fear memory processing may provide important insights into the microcircuit organization regulating this process. Here, using 2-photon laser scanning microscopy of genetically encoded calcium indicators through microprisms in awake mice, we longitudinally monitored over days the activity of L1 interneurons in the ACC in a tone-cued fear conditioning paradigm. We observed that tones elicited responses in a substantial fraction of the imaged neurons, which were significantly modulated in a bidirectional manner after the tone was associated to an aversive stimulus. A subpopulation of these neurons, the neurogliaform cells (NGCs), displayed a net increase in tone-evoked responses following fear conditioning. Together, these results suggest that different subpopulations of L1 interneurons may exert distinct functions in the ACC circuitry regulating fear learning and memory. [ABSTRACT FROM AUTHOR]

Exposure therapy is an evidence-based psychotherapeutic technique for anxiety and related disorders. However, the dropout rate ranges from 10%–30%, and poor outcomes such as dropout are predicted by lower resting heart rate variability (HRV), which, in turn, predicts neural correlates of anxiety. Incorporating biofeedback into traditional exposure therapy has the potential to improve patient outcomes and experience through two protocols: (a) framing respiration and HRV biofeedback as a preparatory intervention for exposure therapy and (b) integrating selected biofeedback modalities into traditional exposure therapy sessions. [ABSTRACT FROM AUTHOR]

Fear learning is mediated by a large network of brain structures and the understanding of their roles and interactions is constantly progressing. There is a multitude of anatomical and behavioral evidence on the interconnection of the cerebellar nuclei to other structures in the fear network. Regarding the cerebellar nuclei, we focus on the coupling of the cerebellar fastigial nucleus to the fear network and the relation of the cerebellar dentate nucleus to the ventral tegmental area. Many of the fear network structures that receive direct projections from the cerebellar nuclei are playing a role in fear expression or in fear learning and fear extinction learning. We propose that the cerebellum, via its projections to the limbic system, acts as a modulator of fear learning and extinction learning, using prediction-error signaling and regulation of fear related thalamo-cortical oscillations. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) has a profound contextual component, and has been demonstrated to alter future contextual learning. However, the mechanism by which a single traumatic event affects subsequent contextual experiences has not been isolated. Acetylcholine (ACh) is an important modulator of hippocampus-dependent learning such as contextual memory strength. Using Stress-Enhanced Fear Learning (SEFL), which models aspects of PTSD in rats, we tested whether muscarinic acetylcholine receptors (mAChR) in dorsal hippocampus (DH) are required during trauma for the effect of trauma on subsequent contextual fear learning. We infused scopolamine or vehicle into DH immediately before stress, and tested fear in both the trauma context and a novel context after a mild stressor. The results show that during learning, ACh acting on mAChR within the DH is required for sensitization of future contextual fear learning. However, this effect is selective for contextual learning, as this blockade leaves discrete cue sensitization intact. Rather than simply sensitizing the BLA, as previous studies have suggested, SEFL requires cholinergic signaling in DH for contextual sensitization.

The anterior cingulate cortex (ACC) plays a crucial role in encoding, consolidating and retrieving memories related to emotionally salient experiences, such as aversive and rewarding events. Various studies have highlighted its importance for fear memory processing, but its circuit mechanisms are still poorly understood. Cortical layer 1 (L1) of the ACC might be a particularly important site of signal integration, since it is a major entry point for long-range inputs, which is tightly controlled by local inhibition. Many L1 interneurons express the ionotropic serotonin receptor 3a (5HT3aR), which has been implicated in post-traumatic stress disorder and in models of anxiety. Hence, unraveling the response dynamics of L1 interneurons and subtypes thereof during fear memory processing may provide important insights into the microcircuit organization regulating this process. Here, using 2-photon laser scanning microscopy of genetically encoded calcium indicators through microprisms in awake mice, we longitudinally monitored over days the activity of L1 interneurons in the ACC in a tone-cued fear conditioning paradigm. We observed that tones elicited responses in a substantial fraction of the imaged neurons, which were significantly modulated in a bidirectional manner after the tone was associated to an aversive stimulus. A subpopulation of these neurons, the neurogliaform cells (NGCs), displayed a net increase in tone-evoked responses following fear conditioning. Together, these results suggest that different subpopulations of L1 interneurons may exert distinct functions in the ACC circuitry regulating fear learning and memory.

Fear learning is mediated by a large network of brain structures and the understanding of their roles and interactions is constantly progressing. There is a multitude of anatomical and behavioral evidence on the interconnection of the cerebellar nuclei to other structures in the fear network. Regarding the cerebellar nuclei, we focus on the coupling of the cerebellar fastigial nucleus to the fear network and the relation of the cerebellar dentate nucleus to the ventral tegmental area. Many of the fear network structures that receive direct projections from the cerebellar nuclei are playing a role in fear expression or in fear learning and fear extinction learning. We propose that the cerebellum, via its projections to the limbic system, acts as a modulator of fear learning and extinction learning, using prediction-error signaling and regulation of fear related thalamo-cortical oscillations.

Learning to recognize and respond to potential threats is crucial for survival. Pavlovian threat conditioning represents a key paradigm for investigating the neurobiological mechanisms of fear learning. In this review, we address the role of specific neuropharmacological adjuvants that act on neurochemical synaptic transmission, as well as on brain plasticity processes implicated in fear memory. We focus on novel neuropharmacological manipulations targeting glutamatergic, noradrenergic, and endocannabinoid systems, and address how the modulation of these neurobiological systems affects fear extinction learning in humans. We show that the administration of N-methyl-D-aspartate (NMDA) agonists and modulation of the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition can boost extinction learning through the stabilization and regulation of the receptor concentration. On the other hand, elevated noradrenaline levels dynamically modulate fear learning, hindering long-term extinction processes. These pharmacological interventions could provide novel targeted treatments and prevention strategies for fear-based and anxiety-related disorders. [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]

Meta-analyses indicate differences in Pavlovian fear responses between anxious and non-anxious individuals using electrodermal activity (EDA). Recent research, however, has cast doubt on whether these effects are robust to different analytic choices. Using the multiverse approach conceived by Steegen et al. (2016), we surveyed analytic choices typically implemented in clinical fear conditioning research by conducting 1240 analyses reflecting different choice permutations. Only 1.45% of our analyses produced theoretically congruent statistically significant effects, and the strength and direction of the estimated effects varied substantially across EDA processing methods. We conclude that EDA-estimated fear learning differences are vulnerable to researcher degrees of freedom and make recommendations regarding which analytical choices should be approached with a high degree of caution. • Anxiety has been linked to fear learning measured via electrodermal activity. • It is not clear whether this relationship is robust to different analytic choices. • We conducted a multiverse analysis comprising 1240 typical analytic choices. • Only 1.45% of analyses produced theoretically consistent, significant effects. • Findings depend on researchers' choices that vary in their validity. [ABSTRACT FROM AUTHOR]

Snakes and spiders are two of the most commonly feared animals worldwide, yet we know very little about the mechanisms by which such fears are acquired. We explored whether negative information about snakes and spiders from parents shapes children's fear beliefs. Study 1 included 27 parents (22 mothers, five fathers) and children (12 female, 15 male, Mage = 5.33 years, 18 White, one Hispanic, eight more than one race). Most parents reported having an advanced degree (78%) and an annual household income of above $100,000 (74%). Participants read an animal picture book and then rated their fear toward each animal. Study 2 included 54 parents (44 mothers, eight fathers, two legal guardians) and children (27 female, 27 male, Mage = 5.52 years, 30 White, one Hispanic, seven Asian/Pacific Islander, four South Asian/Indian, 12 more than one race). Most parents reported holding an AA/BA degree (28%) or an advanced degree (59%) and reported an annual household income of $60,000-$100,000 (28%) or above $100,000 (59%). In Study 2, half of the parents were primed about how their conversations might shape children's fear prior to reading the book. Across both studies, we found that participants provided more negative than positive information about snakes and spiders and provided less positive (Study 1) and more negative (Study 2) information compared to other animals. Our results highlight the prominence of negative information in conversations about snakes and spiders and suggest that the way parents talk about these animals may shape the development of children's fears. [ABSTRACT FROM AUTHOR]

To survive predation, animals must be able to detect and appropriately respond to predator threats in their environment. Such defensive behaviors are thought to utilize hard-wired neural circuits for threat detection, sensorimotor integration, and execution of ethologically relevant behaviors. Despite being hard-wired, defensive behaviors (i.e. fear responses) are not fixed, but rather show remarkable flexibility, suggesting that extrinsic factors such as threat history, environmental contexts, and physiological state may alter innate defensive behavioral responses. The goal of the present study was to examine how extrinsic and intrinsic factors influence innate defensive behaviors in response to visual threats. In the absence of a protective shelter, our results indicate that mice showed robust freezing behavior following both looming (proximal) and sweeping (distal) threats, with increased behavioral vigor in response to looming stimuli, which represent a higher threat imminence. Repeated presentation of looming or sweeping stimuli at short inter-trial intervals resulted in robust habituation of freezing, which was accelerated at longer inter-trial intervals, regardless of contextual cues. Finally, physiological factors such as acute stress further disrupted innate freezing habituation, resulting in a delayed habituation phenotype, consistent with a heightened fear state. Together, our results indicate that extrinsic factors such as threat history, environmental familiarity, and physiological stressors have robust and diverse effects on defensive behaviors, highlighting the behavioral flexibility in how mice respond to predator threats.

In this study we aimed to investigate gender differences in fear generalization tendencies in humans and, inspired by recent findings in animal research, examine whether any such differences could stem from differences in memory precision. Forty men and forty women underwent a differential fear conditioning procedure using geometric shapes as cues. Subsequently, generalized fear responses were assessed across a spectrum of perceptually similar shapes. Throughout generalization testing, perceptual memory accuracy was repeatedly probed using a stimulus recreation task. Using statistical and computational modeling, we found strong evidence for the absence of gender differences in fear learning and generalization behavior. The evidence for gender differences in related processes such as perception and memory was inconclusive. Although some of our findings hinted at the possibility that women may be more perceptive of physical differences between stimuli and have more accurate memory than men, those observations were not consistently replicated across experimental conditions and analytical approaches. Our results contribute to the emerging literature on gender differences in perceptual fear generalization in humans and underscore the need for further systematic research to explore the interplay between gender and mechanisms associated with fear generalization across different experimental contexts., Competing Interests: Declaration of competing interest The 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 Ltd. All rights reserved.)

Understanding the neural basis for individual differences in the skin conductance response (SCR) during discriminative fear conditioning may inform on our understanding of autonomic regulation in fear-related psychopathology. Previous region-of-interest (ROI) analyses have implicated the amygdala in regulating conditioned SCR, but whole brain analyses are lacking. This study examined correlations between individual differences in SCR during discriminative fear conditioning to social stimuli and neural activity throughout the brain, by using data from a large functional magnetic resonance imaging study of twins (N = 285 individuals). Results show that conditioned SCR correlates with activity in the dorsal anterior cingulate cortex/anterior midcingulate cortex, anterior insula, bilateral temporoparietal junction, right frontal operculum, bilateral dorsal premotor cortex, right superior parietal lobe, and midbrain. A ROI analysis additionally showed a positive correlation between amygdala activity and conditioned SCR in line with previous reports. We suggest that the observed whole brain correlates of SCR belong to a large-scale midcingulo-insular network related to salience detection and autonomic-interoceptive processing. Altered activity within this network may underlie individual differences in conditioned SCR and autonomic aspects of psychopathology.

The lateral habenula (LHb) is a small, bilateral, epithalamic nucleus which processes aversive information. While primarily glutamatergic, LHb neurons express genes coding for many neuropeptides, such as Adcyap1 the gene encoding pituitary adenylate cyclase‐activating polypeptide (PACAP), which itself has been associated with anxiety and stress disorders. Using Cre‐dependent viral vectors, we targeted and characterized these neurons based on their anatomical projections and found that they projected to both the raphe and rostromedial tegmentum but only weakly to ventral tegmental area. Using RiboTag to capture ribosomal‐associated mRNA from these neurons and reanalysis of existing single cell RNA sequencing data, we did not identify a unique molecular phenotype that characterized these PACAP‐expressing neurons in LHb. In order to understand the function of these neurons, we conditionally expressed hM3Dq DREADD selectively in LHb PACAP‐expressing neurons and chemogenetically excited these neurons during behavioral testing in the open field test, contextual fear conditioning, sucrose preference, novelty suppressed feeding, and conditioned place preference. We found that Gq activation of these neurons produce behaviors opposite to what is expected from the LHb as a whole—they decreased anxiety‐like and fear behavior and produced a conditioned place preference. In conclusion, PACAP‐expressing neurons in LHb represents a molecularly diverse population of cells that oppose the actions of the remainder of LHb neurons by being rewarding or diminishing the negative consequences of aversive events. [ABSTRACT FROM AUTHOR]

Long-term memory formation relies on synaptic plasticity, neuronal activity-dependent gene transcription, and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional, and epigenetic responses that are induced by CI-994, a class I HDACi, combined with contextual fear conditioning (CFC) in mice. We show that CI-994-mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in fear learning. Furthermore, using a combination of bulk and single-cell RNA-sequencing, we find that, when paired with CFC, HDACi treatment engages synaptic plasticity-promoting gene expression more strongly in the hippocampus, specifically in the dentate gyrus (DG). Finally, using chromatin immunoprecipitation-sequencing (ChIP-seq) of DG neurons, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that underlie improved memory performance. Together, these results indicate that systemic HDACi administration amplifies brain region-specific processes that are naturally induced by learning. [ABSTRACT FROM AUTHOR]

This mini review presents the current state of the art in studies on the personalization of virtual reality for basic research and treatment of fear-related disorders. Of particular interest to the review are the choice of self-report measures and manipulations of contextual factors that researchers are using in their virtual reality procedures. As this mini review will show, work is starting to emerge on the area of the interaction between context and individual differences, yet this topic remains a current gap in the literature on fear learning mechanisms and therapies for fear-related disorders. Studies in this review conclude that virtual reality environments offer many advantages, as they can be adjusted to model different contexts with great precision and control of the experimental context. Virtual reality is also seen by researchers as an opportunity to decrease the translational gap that exists between the research laboratories and the practical use for therapy treatments in clinics. However, the heterogeneity of methodological approaches that have created replicability as well as comparability issues in the field of fear learning is also a concern in studies using virtual reality. Thus, another, albeit secondary, aim of this mini review will be to point out some of the methodological challenges that should be addressed in future research aimed at the personalization of virtual reality for the research and treatment of fear-related disorders. Factors that will be addressed are 1) the use of self-report measures, and 2) interactivity aspects of contextual factor design in the virtual reality environment.

Acid sphingomyelinase (ASM) regulates a variety of physiological processes and plays an important role in emotional behavior. The role of ASM in fear-related behavior has not been investigated so far. Using transgenic mice overexpressing ASM (ASMtg) and ASM deficient mice, we studied whether ASM regulates fear learning and expression of cued and contextual fear in a classical fear conditioning paradigm, a model used to investigate specific attributes of post-traumatic stress disorder (PTSD). We show that ASM does not affect fear learning as both ASMtg and ASM deficient mice display unaltered fear conditioning when compared to wild-type littermates. However, ASM regulates the expression of contextual fear in a sex-specific manner. While ASM overexpression enhances the expression of contextual fear in both male and female mice, ASM deficiency reduces the expression of contextual fear specifically in male mice. The expression of cued fear, however, is not regulated by ASM as ASMtg and ASM deficient mice display similar tone-elicited freezing levels. This study shows that ASM modulates the expression of contextual fear but not of cued fear in a sex-specific manner and adds a novel piece of information regarding the involvement of ASM in hippocampal-dependent aversive memory. [ABSTRACT FROM AUTHOR]

Background: Fear learning is a core component of conceptual models of how adverse experiences may influence psychopathology. Specifically, existing theories posit that childhood experiences involving childhood trauma are associated with altered fear learning processes, while experiences involving deprivation are not. Several studies have found altered fear acquisition in youth exposed to trauma, but not deprivation, although the specific patterns have varied across studies. The present study utilizes a longitudinal sample of children with variability in adversity experiences to examine associations among childhood trauma, fear learning, and psychopathology in youth., Methods: The sample includes 170 youths aged 10-13 years ( M = 11.56, s.d. = 0.47, 48.24% female). Children completed a fear conditioning task while skin conductance responses (SCR) were obtained, which included both acquisition and extinction. Childhood trauma and deprivation severity were measured using both parent and youth report. Symptoms of anxiety, externalizing problems, and post-traumatic stress disorder (PTSD) were assessed at baseline and again two-years later., Results: Greater trauma-related experiences were associated with greater SCR to the threat cue (CS+) relative to the safety cue (CS-) in early fear acquisition, controlling for deprivation, age, and sex. Deprivation was unrelated to fear learning. Greater SCR to the threat cue during early acquisition was associated with increased PTSD symptoms over time controlling for baseline symptoms and mediated the relationship between trauma and prospective changes in PTSD symptoms., Conclusions: Childhood trauma is associated with altered fear learning in youth, which may be one mechanism linking exposure to violence with the emergence of PTSD symptoms in adolescence.

Pavlovian fear conditioning serves as a valuable method for investigating species-specific defensive reactions (SSDRs) such as freezing and flight responses. The present study examines the role of white noise under different experimental conditions. Given that white noise has been shown to elicit both conditional (associative) and unconditional (nonassociative) defensive responses, we compared the response to noise following three separate training conditions: shock-only, white noise paired with shock, and context-only. Results showed that baseline freezing level significantly changed across groups: Both the shock-only group and the white noise paired with shock group froze more than the context-only group on the test day. White noise evoked differential freezing between groups on day 2: The shock-only group froze more than the context-only group although both groups were never exposed to white noise during training. Further, an activity burst triggered by white noise was similar for the shock-only and white noise paired with shock groups during testing, although shock-only group was never exposed to white noise stimuli during training. This aligned with c-fos data, indicating similar c-fos activity levels across different periaqueductal gray (PAG) regions for both shock-only and white noise paired with shock groups. However, the driving force behind c-fos activation-whether freezing, activity burst, or a combination of both-remains uncertain, warranting further analysis to explore specific correlations between SSDRs and c-fos activity within the PAG and related brain areas., (© 2024 The Author(s). Integrative Zoology published by International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)