Search

Pituitary adenylate cyclase-activating polypeptide (PACAP) has a broad spectrum of biological functions including neurotransmitter, neurotrophic and neuroprotective. Moreover, it has been suggested that PACAP plays a role in the modulation of learning and memory as well as on the modulation of glutamate signaling. Thus, in the current study we investigated in the CA1 region of hippocampus and in the basolateral amygdala (BLA) the role of PACAP in the consolidation and extinction of contextual fear conditioning (CFC) and the interaction between PACAP and NMDA receptors. Male rats with cannulae implanted in the CA1 region of the hippocampus or in the BLA received immediately after the training or extinction training of the CFC infusions of the Vehicle, PACAP-38 (40 pg/side), PACAP 6-38 (40 pg/side) or PACAP 6-38 plus D-serine (50 μg/side). After 24 h, the animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of hippocampus, PACAP participates in the consolidation and extinction of the CFC, and in the BLA, PACAP participates only in the consolidation of the CFC. Additionally, the results suggest that the action of PACAP on the consolidation and extinction of the CFC is mediated by the glutamate NMDA receptors. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) and other anxiety disorders stemming from dysregulated fear memory are problematic and costly. Understanding the molecular mechanisms that contribute to the formation and maintenance of these persistent fear associations is crucial to developing treatments for PTSD. Epigenetic mechanisms, which control gene expression to produce long-lasting changes in cellular function, may support the formation of fear memory underlying PTSD. We address here the role of epigenetic mechanisms in the formation, storage, updating, and extinction of fear memories. We also discuss methods of targeting these epigenetic mechanisms to reduce the initial formation of fear memory or to enhance its extinction. Epigenetic mechanisms may provide a novel target for pharmaceutical and other treatments to reduce aversive memory contributing to PTSD. [ABSTRACT FROM AUTHOR]

Background Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. Conclusions These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. [ABSTRACT FROM AUTHOR]

A series of experiments used rats to examine renewal and reinstatement of extinguished second-order conditioned fear (freezing) responses. The initial experiment demonstrated that freezing responses to a stimulus (S2) were contingent on its pairings with a second stimulus (SI) and on the prior pairings of SI and an aversive unconditioned stimulus (US). Subsequent experiments showed that these freezing responses extinguished across S2 alone presentations, but were renewed when: S2-S1 pairings and S2 alone presentations occurred in the same context and testing of S2 occurred elsewhere; S2--SI pairings and testing were in the same context and S2 alone presentations were elsewhere; and when S2-S1 pairings, S2 alone presentations and testing occurred in different contexts. Freezing responses to an extinguished S 1 were reinstated by US alone presentations. However, these responses were not reinstated to an extinguished S2 by US or SI alone presentations, and, conversely, freezing to a nonextinguished S2 was unaffected by extinction of SI. The results were interpreted to mean that S2-S1 pairings produced an association between S2 and the fear responses elicited by SI and that extinction of this association is controlled by context. The failure to reinstate fear responses to S2 is discussed in terms of theories developed to explain reinstatement of SI. [ABSTRACT FROM AUTHOR]

Several studies have examined the acquisition and extinction of fear in PTSD in the context of Pavlovian conditioning. However, research examining reconditioning of fear following extinction, a form of post-extinction re-emergence of conditioned behavior is limited. Although the 5-HT3A receptor gene polymorphism has been linked to trauma responses, its influence on the re-emergence of conditioned fear among those exposed to trauma remain unclear. In the present study, combat-exposed veterans (N = 114) completed a differential fear conditioning task in which one colored rectangle (CS+) predicted a loud scream (US), whereas a different colored rectangle (CS-) predicted no US. Acquisition, extinction, and post-extinction reconditioning effects indexed by conditioned anxiety, US expectancy, and skin conductance response were examined. Associations with allelic variation in the serotonin 5-HT 3 gene, HTR3A (rs1062613) were also examined. Participants rated the CS+ as significantly more anxiety inducing and associated with greater US expectancy than the CS- during acquisition. The CS+ also elicited a stronger skin conductance response than the CS- during acquisition. A significant decrease in anxiety and US expectancy in response to the CS+ was observed after extinction and a re-emergence of conditioned responses to the CS+ was observed during reacquisition. Although a diagnosis of PTSD was characterized by greater anxiety to the CS + but not the CS- during acquisition and extinction, those with and without a PTSD diagnosis did not differ in the reacquisition of fear following extinction. Subsequent preliminary analysis did show that increased posttraumatic symptoms and cognitions were associated with increased US expectancy at reacquisition for the CS+ and CS- among CC carriers but not among T carriers of HTR3A (rs1062613). These findings suggest that posttraumatic symptoms among trauma exposed veterans with the CC polymorphism of the HTR3A gene may be associated with stronger reconditioning of fear following extinction. • CS + rated as more anxiety inducing and associated with greater US expectancy at acquisition. • Decrease in anxiety and US expectancy to CS + observed after extinction. • Re-emergence of conditioned responses to the CS+ was observed during reacquisition. • PTSD diagnosis characterized by greater anxiety to the CS+ during acquisition and extinction. • Increased PTSD symptoms associated with US expectancy at reacquisition among CC carriers of HTR3A (rs1062613). [ABSTRACT FROM AUTHOR]

Virtual Reality (VR) is a promising tool for the study of cued fear conditioning in humans because it allows the use of complex and realistic experimental situations. The present study aims to validate a task for the acquisition and extinction of cued fear learning through VR with ecologically relevant Unconditional Stimuli (USs). In a first experiment (n = 69), we evaluated the effectiveness of six USs specially created to be presented in a virtual environment and to provoke physiological and affective reactions of fear. The two stimuli that evoked significantly higher than baseline electromyographic responses during three trials were then selected to be used as the USs in a second experiment. Experiment 2 (n = 51) aimed to determine if the previously selected US could generate a conditioned response (CR) when associated with another visual stimulus (Conditioned Stimulus; CS) in a differential conditioning paradigm, and subsequently go through extinction. We measured physiological, subjective and behavioral responses of fear, and evaluated their relationship to trait anxiety. This study showed that visual CSs in a VR environment can potentiate a startle reflex during acquisition, but we observed no discrimination between stimuli that signaled the US (fear cues CS+) and stimuli that signaled the absence of the US (safety cue CS-). Nevertheless, differential learning was observed in subjective measures (US expectancy and retrospective anxiety ratings) during acquisition, where participants responded differently to fear and safety cues. Subjective CRs, but not physiological, were reduced during extinction. No changes were observed in response suppression presented with CS, and no relationship was found between trait anxiety and fear responses. We conclude that VR is an appropriate model to elicit valid unconditioned fear responses (URs). The results of the present experiments are particularly important given that subjective CRs (observed in Experiment 2) account for an important part of the clinical experience of anxiety-related disorders, which may help to translate the use of VR to exposure therapy. Future research could improve the task to effectively generate differential physiological and behavioral responses with greater sensitivity to individual differences. • Cued fear conditioning is a widely accepted model for specific phobias. • Virtual reality allows the development of more ecological experimental situations with humans. • We created two contextually integrated stimuli (US) in a virtual reality environment. • US were effective in evoking unconditioned responses which were resistant to habituation. • Differential learning and extinction were found in subjective measures. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that conscious visual awareness is not a prerequisite for human fear learning. For instance, humans can learn to be fearful of subliminal fear relevant images – images depicting stimuli thought to have been fear relevant in our evolutionary context, such as snakes, spiders, and angry human faces. Such stimuli could have a privileged status in relation to manipulations used to suppress usually salient images from awareness, possibly due to the existence of a designated sub-cortical ‘fear module’. Here we assess this proposition, and find it wanting. We use binocular masking to suppress awareness of images of snakes and wallabies (particularly cute, non-threatening marsupials). We find that subliminal presentations of both classes of image can induce differential fear conditioning. These data show that learning, as indexed by fear conditioning, is neither contingent on conscious visual awareness nor on subliminal conditional stimuli being fear relevant. [ABSTRACT FROM AUTHOR]

Abstract: Disruption of the reconsolidation of conditioned fear memories has been suggested as a non-pharmacological means of preventing the return of learned fear in human populations. A reconsolidation update paradigm was developed in which a reconsolidation window is opened by a single isolated retrieval trial of a previously reinforced CS+ which is then followed by Extinction Training within that window. However, follow-up studies in humans using multi-methods fear conditioning indices (e.g., fear-potentiated startle, skin conductance, US-expectancy) have failed to replicate the retrieval+extinction effects. In the present study, we further investigated the retrieval+extinction reconsolidation update paradigm by directly comparing the acquisition, extinction, and return of fear-potentiated startle in the absence or presence of US-expectancy measures (using a trial-by-trial response keypad) with and without retrieval of a previously acquired CS-US association. Participants were fear conditioned to two visual cue CS+’s, one of which was presented as a single, isolated retrieval trial before Extinction Training and one that was extinguished as usual. The results show that the inclusion of US-expectancy measures strengthens the CS–US association to provide enhanced fear conditioning and maintenance of fear memories over the experimental sessions. In addition, in the groups that used on-line US-expectancy measures, the retrieval+extinction procedure reduced reinstatement of fear-potentiated startle to both previously reinforced CS+’s, as compared to the extinction as usual group. [Copyright &y& Elsevier]

Abstract: Although conditioned fear can be effectively extinguished by unreinforced exposure to a threat cue, fear responses tend to return when the cue is encountered some time after extinction (spontaneous recovery), in a novel environment (renewal), or following presentation of an aversive stimulus (reinstatement). As extinction represents a context-dependent form of new learning, one possible strategy to circumvent the return of fear is to conduct extinction across several environments. Here, we tested the effectiveness of multiple context extinction in a two-day fear conditioning experiment using 3-D virtual reality technology to create immersive, ecologically-valid context changes. Fear-potentiated startle served as the dependent measure. All three experimental groups initially acquired fear in a single context. A multiple extinction group then underwent extinction in three contexts, while a second group underwent extinction in the acquisition context and a third group underwent extinction in a single different context. All groups returned 24h later to test for return of fear in the extinction context (spontaneous recovery) and a novel context (renewal and reinstatement/test). Extinction in multiple contexts attenuated reinstatement of fear but did not reduce spontaneous recovery. Results from fear renewal were tendential. Our findings suggest that multi-context extinction can reduce fear relapse following an aversive event – an event that often induces return of fear in real-world settings – and provides empirical support for conducting exposure-based clinical treatments across a variety of environments. [Copyright &y& Elsevier]

Abstract: Little is known about the role of discrete stimulus features in the regulation of fear. This study examined the effects of feature learning on the acquisition and extinction of fear conditioning. Human participants were fear conditioned to a yellow triangle (CS+) using an electrical shock. We manipulated feature learning through differential conditioning. The nonconditioned control stimulus (CS−) was a red triangle in one group (Color-Relevant), but a yellow circle in the other group (Shape-Relevant). Next, two generalization stimuli were tested that shared the shape- or color-feature with the CS+ (a blue triangle and a yellow square). Online shock-expectancy ratings and skin conductance responding showed that the CS− determined the pattern of fear generalization: the same-color stimulus elicited more fear in Group Color-Relevant, versus the same-shape stimulus in group Shape-Relevant. Furthermore, extinguishing these two generalization stimuli had no detectable effect on fear of the CS+. These results show that fear generalization is influenced by feature learning through differential conditioning, and that exposures to different features of a stimulus are not sufficient to extinguish fear of that stimulus as a whole. [Copyright &y& Elsevier]

Highlights: [•] Amygdala gamma oscillations are enhanced following auditory fear conditioning. [•] Amygdala gamma oscillations during extinction learning are associated with spontaneous fear recovery. [•] Amygdala gamma oscillations are locally generated. [•] Maintenance of amygdala gamma oscillations during extinction learning linearly predicts spontaneous fear recovery. [Copyright &y& Elsevier]

Abstract: A number of studies have reported that d-cycloserine (DCS), a partial agonist of the N-methyl-d-aspartate glutamate receptor, can facilitate the loss of conditioned fear if it is administered during an extinction trial. Here we examine the effects of DCS injected into the hippocampus or amygdala on extinction of context-evoked freezing after contextual fear conditioning in C57BL/6 mice. We find that DCS administered prior to an extinction session decreased freezing from the outset of the session regardless of which brain region was targeted. Retention tests revealed opposite effects on fear expression despite identical behavioral treatments: intra-hippocampal DCS inhibited fear expression while intra-amygdala DCS potentiated fear expression. Following post-extinction session injections of DCS, we found a similar though less pronounced effect. Closer inspection of the data revealed that the effects of DCS interacted with the behavior of the subjects during extinction. Intra-hippocampal injections of DCS enhanced extinction in those mice that showed the greatest amount of within-session extinction, but had less pronounced effects on mice that showed the least within-session extinction. Intra-amygdala injections of DCS impaired extinction in those mice that showed the least within-session extinction, but there was some evidence that the effect in the amygdala did not depend on behavior during extinction. These findings demonstrate that even with identical extinction trial durations, the effects of DCS administered into the hippocampus and amygdala can heavily depend on the organism’s behavior during the extinction session. The broader implication of these findings is that the effects of pharmacological treatments designed to enhance extinction by targeting hippocampal or amygdalar processes may depend on the responsivity of the subject to the behavioral treatment. [Copyright &y& Elsevier]

Highlights: [•] Fear conditioning enhances PPI without exhibiting a spatial location specificity. [•] Perceptual spatial separation between the conditioned prepulse and the noise masker enhances PPI with a spatial location specificity. [•] Both types of PPI enhancements can be abolished by extinction learning, which depends on metabotropic glutamate receptors subtype 5. [ABSTRACT FROM AUTHOR]

Reactivation of an already consolidated memory makes it labile for a period of several hrs, which are required for its reconsolidation. Evidence suggests that the return of conditioned fear through sponta-neous recovery, reinstatement, or renewal can be prevented by blockading this reconsolidation process using pharmacological or behavioral interventions. Postretrieval-extinction learning has been shown to prevent the return of cued fear in humans using fear-irrelevant stimuli, as well as cued and contextual fear in rodents. The effects of postretrieval extinction on human contextually controlled cued fear to fear-relevant stimuli remain unknown, and are the focus of the present study. The experimental design was based on 3 consecutive days: acquisition, reactivation and extinction, and re-extinction. For the fear conditioning, 2 zoo frames served as different contexts, 5 fear-relevant stimuli (aversive animal pictures) served as conditioned stimuli (CS), electric shocks served as unconditioned stimuli (UCS). Expectancy ratings and skin-conductance response (SCR) were used as measures of fear responses; spontaneous recovery and renewal were used as indicators of the return of fear. The expectancy ratings and SCR results indicated spontaneous recovery on the third day, regardless of retrieval prior to extinction. No robust renewal effect was seen. It is suggested that the use of fear-relevant stimuli, the context salience, or reactivation context may explain the lack of reconsolidation effect. Our study indicates that the beneficial effects of postretrieval-extinction learning are sensitive to subtle methodological changes. [ABSTRACT FROM AUTHOR]

Maladaptive fear, such as fear that is persistent or easily generalized to a nonthreatening stimuli, is associated with anxiety-related disorders in humans. In the laboratory, maladaptive fear can be modeled in rodents using Pavlovian fear conditioning. Recently, an inbred mouse strain known as 129S1/SvImJ, or 129S1 has been reported as exhibiting impairments in fear extinction and enhanced fear generalization. With a long-term goal of identifying segregating genetic markers of maladaptive fear, we used Pavlovian fear conditioning to characterize a closely related substrain designated as 129S6/SvEvTac, or 129S6. Here we report that, like 129S1 animals, 129S6 mice exhibit appropriate levels of fear upon conditioning, but are unable to extinguish fear memories once they are consolidated. Importantly, the maladaptive fear phenotype in this inbred stain can be segregated by sub-strain when probed using conditioning protocols designed to assess generalized fear. We find that unlike the 129S1 substrain, mice from the 129S6 sub-strain do not generalize conditioned fear to previously novel contexts and can learn to discriminate between two similar contexts when trained using a discrimination protocol. These results suggest that at least two forms of maladaptive fear (deficits in fear extinction and fear generalization) can be can be functionally segregated, further suggesting that the underlying neurobiology is heritable. Given the observation that two closely related sub-strains can exhibit different constellations of maladaptive fear suggests that these findings could be exploited to facilitate the identification of candidate genes for anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Renewal has been observed in several protocols. One, termed ABA, trains a conditioned stimulus (CS) in one context, A, extinguishes the CS in a second context, B, and tests either in A or B. We used between- and within-subjects designs in three experiments with rats to study how a history of cue pre-exposure affects extinction and renewal of conditioned fear responses (freezing). In each experiment, a stimulus was pre-exposed in either context B or context C, paired with an aversive unconditioned stimulus (US) in a third context, A, extinguished in B, and finally tested in A. Freezing declined at the same rate when extinction occurred in the same or a different context as pre-exposure in between-subjects designs (Experiments 1 and 2), but declined faster when extinction and pre-exposure occurred in the same than in a different context in a within-subjects design (Experiment 3). In each experiment, renewal of freezing responses in the conditioning context, A, was greater when subjects were tested with the CS extinguished in its pre-exposure context than with the CS extinguished outside its pre-exposure context. The results were interpreted to mean that what was learned about the context-stimulus relation in pre-exposure enhanced control by that context over what was learned in extinction, thereby enhancing renewal when the rats were returned to the conditioning context for testing. [ABSTRACT FROM AUTHOR]

Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10-17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses. [ABSTRACT FROM AUTHOR]

The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. [ABSTRACT FROM AUTHOR]

Abstract: Fear-conditioning experiments in the anxiety disorders focus almost exclusively on passive-emotional, Pavlovian conditioning, rather than active-behavioral, instrumental conditioning. Paradigms eliciting both types of conditioning are needed to study maladaptive, instrumental behaviors resulting from Pavlovian abnormalities found in clinical anxiety. One such Pavlovian abnormality is generalization of fear from a conditioned danger-cue (CS+) to resembling stimuli. Though lab-based findings repeatedly link overgeneralized Pavlovian-fear to clinical anxiety, no study assesses the degree to which Pavlovian overgeneralization corresponds with maladaptive, overgeneralized instrumental-avoidance. The current effort fills this gap by validating a novel fear-potentiated startle paradigm including Pavlovian and instrumental components. The paradigm is embedded in a computer game during which shapes appear on the screen. One shape paired with electric-shock serves as CS+, and other resembling shapes, presented in the absence of shock, serve as generalization stimuli (GSs). During the game, participants choose whether to behaviorally avoid shock at the cost of poorer performance. Avoidance during CS+ is considered adaptive because shock is a real possibility. By contrast, avoidance during GSs is considered maladaptive because shock is not a realistic prospect and thus unnecessarily compromises performance. Results indicate significant Pavlovian-instrumental relations, with greater generalization of Pavlovian fear associated with overgeneralization of maladaptive instrumental-avoidance. [Copyright &y& Elsevier]

Experimental fear conditioning in humans is widely used as a model to investigate the neural basis of fear learning and to unravel the pathogenesis of anxiety disorders. It has been observed that fear conditioning depends on stimulus salience and subject vulnerability to fear. It is further known that the prevalence of dental-related fear and phobia is exceedingly high in the population. Dental phobia is unique as no other body part is associated with a specific phobia. Therefore, we hypothesized that painful dental stimuli exhibit an enhanced susceptibility to fear conditioning when comparing to equal perceived stimuli applied to other body sites. Differential susceptibility to pain-related fear was investigated by analyzing responses to an unconditioned stimulus (UCS) applied to the right maxillary canine (UCS-c) versus the right tibia (UCS-t). For fear conditioning, UCS-c and USC-t consisted of painful electric stimuli, carefully matched at both application sites for equal intensity and quality perception. UCSs were paired to simple geometrical forms which served as conditioned stimuli (CS+). Unpaired CS+ were presented for eliciting and analyzing conditioned fear responses. Outcome parameter were 1) skin conductance changes and 2) time-dependent brain activity (BOLD responses) in fear-related brain regions such as the amygdala, anterior cingulate cortex, insula, thalamus, orbitofrontal cortex and medial prefrontal cortex. A preferential susceptibility of dental pain to fear conditioning was observed, reflected by heightened skin conductance responses and enhanced time-dependent brain activity (BOLD responses) in the fear network. For the first time, this study demonstrates fear-related neurobiological mechanisms that point towards a superior conditionability of tooth pain. Beside traumatic dental experiences our results offer novel evidence that might explain the high prevalence of dental-related fears in the population. [ABSTRACT FROM AUTHOR]

Highlights: [•] 5-HT showed differential effects on the conditioned fear response. [•] In the prelimbic cortex, 5-HT1A activation reduces potentiated startle in HA rats. [•] 5-HT1A agonism into the basolateral amygdala and DPAG reduces fear in LA rats. [•] Treatments do not alter the unconditioned fear response. [ABSTRACT FROM AUTHOR]

Highlights: [•] Systems consolidation predicts that retrieval of remote memories can occur independent of the hippocampus. [•] Hippocampal inactivation impairs expression of recent and remote cocaine CPP, but only affects only recent contextual fear. [•] We discuss models of substance abuse and issues in the translation of memory mechanisms to clinical therapies. [ABSTRACT FROM AUTHOR]

Rationale: Oxytocin receptors (Oxtr) are important mediators of social learning and emotion, with bidirectional effects on fear and anxiety. Contrary to the anxiolytic actions of Oxtr in the amygdala, we recently showed that Oxtr in the lateral septum mediate the enhancement of fear conditioning by social defeat in mice. Objectives: Using positive social interactions, which impair fear conditioning, here we attempted to delineate whether the role of septal Oxtr in fear regulation depends on the valence of the social memory. Methods: Pharmacological and genetic manipulations of lateral septal Oxtr were combined with the social buffering of fear paradigm, in which pre-exposure to nonfearful conspecifics reduces subsequent contextual fear conditioning, as revealed by decreased freezing behavior. Results: Antagonism and down-regulation of Oxtr in the lateral septum abolished, while oxytocin (Oxt) administration before pre-exposure to nonfearful conspecifics facilitated the decrease of freezing behavior. Conclusions: The septal oxytocin system enhances memory of social interactions regardless of their valence, reducing fear after positive and enhancing fear after negative social encounters. These findings explain, at least in part, the seemingly bidirectional role of Oxt in fear regulation. [ABSTRACT FROM AUTHOR]

Highlights: [•] The amygdala is important for acquisition and expression of conditioned fear. [•] SSTR2 is expressed in the amygdala, however, its role is poorly understood. [•] We show that amygdaloid SSTR2 is important for the expression of conditioned fear. [•] However, amygdaloid SSTR2 seems to play no role in fear acquisition. [ABSTRACT FROM AUTHOR]

The dorsolateral periaqueductal grey (dlPAG) plays an essential role in unconditioned fear responses and could also be involved in the expression of contextual fear responses. Activation of glutamate N-methyl-D-aspartate (NMDA) receptors and the nitric oxide (NO) pathway in this region facilitates anxiety-like responses. In the present study we investigated if antagonism of NMDA receptors or inhibition of the NO pathway in the dlPAG would attenuate behavioral and cardiovascular responses of rats submitted to a contextual fear-conditioning paradigm. Male Wistar rats with unilateral cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Ten min before the test the animals received an intra-dlPAG injection of vehicle, AP7 (NMDA receptor antagonist), N-propyl-L-arginine (neuronal NO synthase inhibitor), carboxy-PTIO (NO scavenger) or 1H-[1,2,4] oxadiazolol [4,3-a]quinoxalin-1-one (ODQ) (guanylate cyclase inhibitor). Freezing and cardiovascular responses were recorded continuously for 10 min. Intra-dlPAG administration of AP7 before re-exposure to the aversively conditioned context attenuated these responses. Similar effects were observed after the NO synthase inhibitor, NO scavenger or guanylate cyclase inhibitor. Our findings suggest that activity of dlPAG NMDA/NO/cyclic guanosine monophosphate (cGMP) pathway facilitates the expression of contextual fear responses. [ABSTRACT FROM PUBLISHER]

Highlights: [•] Conditioned fear behavior of GAD65−/− mice depends on circadian rhythm. [•] Circadian modulation of freezing vs. flight in GAD65−/− mice is state-specific. [•] Conditioned fear induces general hyperactivity of limbic brain areas in GAD65−/− mice. [•] Ventromedial hypothalamus hyperactivity is seen with low freezing/flight. [•] Fear circuits are under control of GAD65-mediated GABA synthesis. [ABSTRACT FROM AUTHOR]

Fear memories guide adaptive behavior in contexts associated with aversive events. The hippocampus forms a neural representation of the context that predicts aversive events. Representations of context incorporate multisensory features of the environment, but must somehow exclude sensory features of the aversive event itself. We investigated this selectivity using cell type-specific imaging and inactivation in hippocampal area CA1 of behaving mice. Aversive stimuli activated CA1 dendrite-targeting interneurons via cholinergic input, leading to inhibition of pyramidal cell distal dendrites receiving aversive sensory excitation from the entorhinal cortex. Inactivating dendrite-targeting interneurons during aversive stimuli increased CA1 pyramidal cell population responses and prevented fear learning. We propose subcortical activation of dendritic inhibition as a mechanism for exclusion of aversive stimuli from hippocampal contextual representations during fear learning. [ABSTRACT FROM AUTHOR]

Rationale: Recent evidence suggests that in addition to controlling emotional behavior in general, endocannabinoid signaling is engaged in shaping behavioral responses to challenges. This important function of endocannabinoids is still poorly understood. Objectives: Here we investigated the impact of blockade of fatty acid amide hydrolase (FAAH), the degrading enzyme of anandamide on behavioral responses induced by challenges of different intensity. Methods: Mice treated with FAAH inhibitor URB597 were either manually restrained on their backs (back test) or received foot-shocks. Results: The behavior of mice showed bimodal distribution in the back test: they either predominantly showed escape attempts or equally distributed time between passivity and escape. URB597 increased escapes in animals with low escape scores. No effects were noticed in mice showing high escape scores, which is likely due to a ceiling effect. We hypothesized that stronger stressors would wash out individual differences in coping; therefore, we exposed mice to foot-shocks that decreased locomotion and increased freezing in all mice. URB597 ameliorated both responses. The re-exposure of mice to the shock cage 14 days later without delivering shocks or treatment was followed by reduced and fragmented sleep as shown by electrophysiological recordings. Surprisingly, sleep was more disturbed after the reminder than after shocks in rats receiving vehicle before foot-shocks. These reminder-induced disturbances were abolished by URB597 administered before shocks. Conclusions: These findings suggest that FAAH blockade has an important role in the selection of behavioral responses under challenging conditions and-judging from its long-term effects-that it influences the cognitive appraisal of the challenge. [ABSTRACT FROM AUTHOR]

Highlights: [•] We studied physiological role of Cav2.1 in consolidation of extinction. [•] Mice received ω-agatoxin IVA showed impaired extinction and increased Arc expression. [•] Lower dose of intra-mPFC injections of MK-801 blocked extinction in Cav2.1 mutant. Cav2.1-mediated glutamatergic pathway plays role in mPFC-dependent fear extinction. Combined pharmacological and genetic approach is useful to study neuronal circuits. [ABSTRACT FROM AUTHOR]

Facial cues of racial outgroup or anger mediate fear learning that is resistant to extinction. Whether this resistance is potentiated if fear is conditioned to angry, other race faces has not been established. Two groups of Caucasian participants were conditioned with two happy and two angry face conditional stimuli ( CSs). During acquisition, one happy and one angry face were paired with an aversive unconditional stimulus whereas the second happy and angry faces were presented alone. CS face race ( Caucasian, African American) was varied between groups. During habituation, electrodermal responses were larger to angry faces regardless of race and declined less to other race faces. Extinction was immediate for Caucasian happy faces, delayed for angry faces regardless of race, and slowest for happy racial outgroup faces. Combining the facial cues of other race and anger does not enhance resistance to extinction of fear. [ABSTRACT FROM AUTHOR]

Abstract: An early finding in the behavioral analysis of learning was that conditioned responding weakens as the conditioned stimulus (CS) and unconditioned stimulus (US) are separated in time. This “trace” conditioning effect has been the focus of years of research in associative learning. Theoretical accounts of trace conditioning have focused on mechanisms that allow associative learning to occur across long intervals between the CS and US. These accounts have emphasized degraded contingency effects, timing mechanisms, and inhibitory learning. More recently, study of the neurobiology of trace conditioning has shown that even a short interval between the CS and US alters the circuitry recruited for learning. Here, we review some of the theoretical and neurobiological mechanisms underlying trace conditioning with an emphasis on recent studies of trace fear conditioning. Findings across many studies have implications not just for how we think about time and conditioning, but also for how we conceptualize fear conditioning in general, suggesting that circuitry beyond the usual suspects needs to be incorporated into current thinking about fear, learning, and anxiety. [Copyright &y& Elsevier]

Highlights: [•] Interval timing with intrudes results in a wide range of behavioral responses such as, run (ignore the intruder), stop (retain the state of the clock and restart after intruder), and reset. [•] The striatal beat frequency (SBF) is a simple, neurobiologically inspired, computational model that produces both precise and time-scale invariant interval timing and can explain the intruders’ effects. [•] A reset is implemented in SBF model by a strong hyperpolarization of neural oscillators followed by a rapid postinhibitory rebound. [•] The SBF model explains the over-reset induced by fear-evoking distracters assuming a strong inhibition (similar to reset) with a duration approximately gauged by the relaxation time constant associated to the long-lasting behavioral freeze. [•] The effect of dopamine/norepinephrine reuptake inhibitor nomifensine was modeled by speeding-up the oscillators of the SBF mode which produced an advance of the peak response similar to the experimental data. [ABSTRACT FROM AUTHOR]

Over the past few years multiple studies have attempted to uncover molecular signatures of memory reconsolidation when compared to consolidation. In the present study we used immunocytochemical detection of the MAPK/ERK1/2 pathway, to track activated neuronal circuits in the hippocampus and amygdala recruited during the consolidation and reconsolidation of a contextual fear conditioning (CFC) memory. We report selective differences in magnitude and temporal dynamics of activated ERK1/2 signalling in different subregions of these two structures between the post-training and post-retrieval periods, except in the dentate gyrus, where the patterns of activation were similar. We then focused on this brain area to dissect out the patterns of downstream ERK1/2 signalling components, including the phosphorylation of MSK-1 and histone H3 on ser10, along with the induction of the Immediate Early Genes (IEGs) Arc/Arg3.1, c-Fos and Zif268/Egr1 following CFC training and retrieval. We found that the completion of the nucleosomal response as well as the induction of IEGs shorter during the reconsolidation period as compared to consolidation. Our results shed new light on the cellular mechanisms underlying the consolidation and reconsolidation processes engaged following CFC training and retrieval and further extend the notion that memory reconsolidation is not mechanistically a repetition of consolidation. In addition, we provide evidence that the strength of a previously established CFC memory is characterized by distinct patterns of ERK1/2 activation in different hippocampal and amygdalar subfields upon CFC memory recall. Our results emphasize the differences between consolidation and reconsolidation processes in relation to contextual fear memories. [ABSTRACT FROM AUTHOR]

Highlights: [•] In rats, we evaluated the impact of mild TBI on conditioned fear. [•] Conditioned fear was implemented using a conditioned suppression procedure. [•] Mild TBI was produced through multiple blast overpressure exposures. [•] Mild TBI blunted the expression of a conditioned fear while not delaying extinction. [•] Results are relevant to a possible relationship between mTBI and PTSD. [Copyright &y& Elsevier]

The extinction of learned associations has traditionally been considered to involve new learning, which competes with the original memory for control over behavior. However, a recent resurgence of interest in reactivation-dependent amnesia has revealed that the retrieval of fear-related memory (with what is essentially a brief extinction session) can result in its destabilization. This review discusses some of the cellular and molecular mechanisms that are involved in the destabilization of a memory following its reactivation and/or extinction, and investigates the evidence that extinction may involve both new learning as well as a partial destabilization-induced erasure of the original memory trace. [ABSTRACT FROM AUTHOR]

The amygdala has traditionally been associated with fear, mediating the impact of negative emotions on memory. However, this view does not fully encapsulate the function of the amygdala, nor the impact that processing in this structure has on the motivational limbic corticostriatal circuitry of which it is an important structure. Here we discuss the interactions between different amygdala nuclei with cortical and striatal regions involved in motivation; interconnections and parallel circuitries that have become increasingly understood in recent years. We review the evidence that the amygdala stores memories that allow initially motivationally neutral stimuli to become associated through pavlovian conditioning with motivationally relevant outcomes which, importantly, can be either appetitive (e.g. food) or aversive (e.g. electric shock). We also consider how different psychological processes supported by the amygdala such as conditioned reinforcement and punishment, conditioned motivation and suppression, and conditioned approach and avoidance behavior, are not only psychologically but also neurobiologically dissociable, being mediated by distinct yet overlapping neural circuits within the limbic corticostriatal circuitry. Clearly the role of the amygdala goes beyond encoding aversive stimuli to also encode the appetitive, requiring an appreciation of the amygdala's mediation of both appetitive and fearful behavior through diverse psychological processes. [ABSTRACT FROM AUTHOR]

Highlights: [•] Haloperidol did not cause 22kHz USVs during catalepsy or open-field test. [•] Pre-training haloperidol did not change USVs or conditioned freezing response. [•] Pre-testing haloperidol decreased USVs. [•] D2 receptors seem to be important for the expression of conditioned fear. [•] Dopamine mechanisms in catalepsy seem to be dissociated from those related to fear. [ABSTRACT FROM AUTHOR]

Highlights: [•] Lactating rats infused with a CB1 agonist had a reduction in maternal parameters. [•] Male offspring from mothers with infusion of WIN showed increased responsiveness to fear. [•] CB1 agonist changes maternal behavior can influence offspring in adulthood. [ABSTRACT FROM AUTHOR]

Highlights: [•] The role of the GABAB receptor in regulating conditioned anxiety behaviour is unclear. [•] We assessed the effects of GABAB receptor ligands on fear conditioning in BALB/c mice. [•] GS39783 failed to alter the acquisition, recall or extinction of freezing behaviour. [•] CGP52432 also did not alter the freezing response. [•] These findings suggest limitations to the potential role of GABAB receptor active drugs as anxiolytics. [ABSTRACT FROM AUTHOR]

Highlights: [•] Social housing after fear conditioning induces housing-type social buffering. [•] Physical interactions were not necessary for the induction of social buffering. [•] The induction of Fos expression by such social cohabitation was observed. [•] These results provide information about the induction of social buffering. [ABSTRACT FROM AUTHOR]

Highlights: [•] CB1 receptor antagonist blocked extinction process in contextual fear conditioning. [•] TRPV1 channel antagonist favored short-term extinction of aversive memories. [•] ECS activation influenced the extinction process of fear memories. [•] ECS activation contrasted the stress effects on fear memory. [ABSTRACT FROM AUTHOR]

Highlights: [•] Context fear retention was disrupted after early adolescent ethanol exposure. [•] Mid-adolescent and adult ethanol-exposed animals showed delayed context extinction. [•] Thus, long-term effects of ethanol exposure differ depending on age of exposure. [ABSTRACT FROM AUTHOR]

Intrusive memories – a hallmark symptom of posttraumatic stress disorder (PTSD) – are often triggered by stimuli possessing similarity with cues that predicted or accompanied the traumatic event. According to learning theories, intrusive memories can be seen as a conditioned response to trauma reminders. However, direct laboratory evidence for the link between fear conditionability and intrusive memories is missing. Furthermore, fear conditioning studies have predominantly relied on standardized aversive stimuli (e.g. electric stimulation) that bear little resemblance to typical traumatic events. To investigate the general relationship between fear conditionability and aversive memories, we tested 66 mentally healthy females in a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with neutral sounds as conditioned stimuli and short violent film clips as unconditioned stimuli. Subsequent aversive memories were assessed through a memory triggering task (within 30 minutes, in the laboratory) and ambulatory assessment (involuntary aversive memories in the 2 days following the experiment). Skin conductance responses and subjective ratings demonstrated successful differential conditioning indicating that naturalistic aversive film stimuli can be used in a fear conditioning experiment. Furthermore, aversive memories were elicited in response to the conditioned stimuli during the memory triggering task and also occurred in the 2 days following the experiment. Importantly, participants who displayed higher conditionability showed more aversive memories during the memory triggering task and during ambulatory assessment. This suggests that fear conditioning constitutes an important source of persistent aversive memories. Implications for PTSD and its treatment are discussed. [ABSTRACT FROM AUTHOR]

Fear memories are notoriously difficult to erase, often recovering over time. The longstanding explanation for this finding is that, in extinction training, a new memory is formed that competes with the old one for expression but does not otherwise modify it. This explanation is at odds with traditional models of learning such as Rescorla-Wagner and reinforcement learning. A possible reconciliation that was recently suggested is that extinction training leads to the inference of a new state that is different from the state that was in effect in the original training. This solution, however, raises a new question: under what conditions are new states, or new memories formed? Theoretical accounts implicate persistent large prediction errors in this process. As a test of this idea, we reasoned that careful design of the reinforcement schedule during extinction training could reduce these prediction errors enough to prevent the formation of a new memory, while still decreasing reinforcement sufficiently to drive modification of the old fear memory. In two Pavlovian fear-conditioning experiments, we show that gradually reducing the frequency of aversive stimuli, rather than eliminating them abruptly, prevents the recovery of fear. This finding has important implications for theories of state discovery in reinforcement learning. [ABSTRACT FROM AUTHOR]

Studies on fear conditioning have made important contributions to the understanding of affective learning mechanisms as well as its applications (e.g., anxiety disorders, post-traumatic stress disorder). Regarding fear conditioning as a specific form of learning, animal studies suggest a critical role of REM sleep in fear memory traces consolidation. In our experiment event-related brain potentials (ERP), heart rate variability (HRV) and behavioral responses were recorded during a fear conditioning procedure presented twice, before sleep or control intervention and after. [Extracted from the article]