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Procedural extinction is sometimes associated with a temporary increase in responding known as an extinction burst. Extinction bursts present unique challenges in the context of treating behavior targeted for reduction. The present study updates the prevalence of extinction bursts using a clinical sample (N = 108) receiving treatment for targeted behavior. The prevalence of extinction bursts in our sample (24%) was consistent with that in prior literature. The extinction‐burst magnitude decreased across sessions after extinction was contacted during treatment, but this sample did not demonstrate decreased persistence or magnitude of extinction bursts across successive transitions from baseline to treatment. We also examined the prevalence and magnitude of extinction bursts based on the function and topography of targeted behavior and treatment components and found no consistent relation among these variables. These findings should lead clinicians to prepare for transient extinction bursts when implementing extinction‐based treatment for challenging behavior. [ABSTRACT FROM AUTHOR]

Rationale: The mammalian target of rapamycin (mTOR) kinase is known to mediate consolidation and reconsolidation of aversive memories. Most studies in this area use a forward conditioning paradigm in which the conditioned stimulus (CS) precedes the unconditioned stimulus (US). Little is known, however, about the neurobiological underpinnings of backwards (BW) conditioning paradigms, particularly in female mice. In BW conditioning, the CS does not become directly associated with the US; it instead evokes conditioned fear by reactivating a memory of the conditioning context and indirectly retrieving a memory of the aversive US. Objectives: We sought to examine BW conditioned fear memory processes in female mice. First, we examined whether freezing to a BW CS is mediated by fear to the conditioning context. Second, we tested whether blocking consolidation of a BW CS attenuated memory of the CS and conditioning context. Finally, we tested whether blocking reconsolidation of a BW CS attenuated memory of the conditioning context. Results: We show that conditioned freezing to a BW CS is mediated by fear to the conditioning context. Furthermore, rapamycin—an mTOR inhibitor, when given immediately following BW conditioning, impairs consolidation of both cued and contextual fear memory. Similarly, rapamycin given following retrieval of a BW CS blocks context recall. Rapamycin is acting on reconsolidation as CS retrieval is necessary to see the effects of rapamycin on context memory recall. Conclusions: Our study provides novel evidence that indirect retrieval cues are sensitive to rapamycin in female mice. The capacity to indirectly reactivate memories and render them susceptible to disruption is critical in the translation of reconsolidation-based approaches to the clinic. [ABSTRACT FROM AUTHOR]

Extinction training has proved effective to diminish the expectancy of the aversive unconditioned stimulus (US). However, the negative valence of the conditioned stimulus (CS) may still stay intact. In fact, several studies have suggested that the CS negative valence may be a factor that promotes the return of fear. Our study focuses on the role of changes in the CS valence as a potential mechanism to reduce the spontaneous recovery of threat expectancies. To do that, we evaluated counterconditioning (CC), a technique aimed to reduce the CS negative valence by paring it with a positive stimulus and compared its efficacy to that of a novelty-facilitated extinction (NFE) and a standard extinction interventions. Using a 2-day protocol, participants first learned the relationship between a figure and an aversive sound, using a differential conditioning paradigm, and were then randomly assigned to one of three different groups. For the CC group, CS+ or cue A was paired with a positive US. The standard extinction group was exposed to cue A alone. For a third NFE group, cue A was followed by a neutral US. Finally, on the second day, spontaneous recovery was tested. Our findings did not provide evidence to suggest that CC could be more effective to prevent or reduce the return of threat expectancies or influence valence ratings when compared with NFE and standard extinction. [ABSTRACT FROM AUTHOR]

• Male and female rats have comparable startle amplitudes when corrected for body weight. • Female rats show higher foot-shock reactivity than males during fear-conditioning. • Male and female rats show comparable levels of cued, non-cued, and contextual fear. • Wistar females show higher startle after fear-conditioning vs. males, regardless of trial type. • Unpredictable threats further increase startle reactivity and contextual fear in Wistar females vs. males. Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock un-paired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females consistently demonstrate higher shock reactivity during fear-conditioning. Both sexes and strains demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS and FPS following fear-conditioning with 70% contingency or backward order (cue co-starts with shock). However, in the classic FPS, Sprague-Dawley females show reduced proportion between cued fear and cue-elicited vigilant state than males. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning (cue and shock un-paired), with Wistar, but not Sprague-Dawley, females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women. [ABSTRACT FROM AUTHOR]

The classical fear conditioning is extensively used in preclinical studies as an animal model for post-traumatic stress disorder (PTSD). During the reconsolidation process, when memories are retrieved, the memory becomes susceptible to change and amenable to intervention. Interventions applied during the reconsolidation process triggered by exposure to a conditioned stimulus (CS) primarily lead to a decrease in fear responses triggered only by the exposed CS, without generalizing to other fear-related cues. However, in real-life scenarios, multiple CS's can be linked to fear-inducing events. Therefore, recent studies have focused on the reactivation procedure with an unconditioned stimulus (US), which is believed to result in the reconsolidation of the entire fear memory. Interventions applied during the reconsolidation process that are triggered by US-based retrieval are considered more effective. Grounding on the fear memory studies activated by either CS or US, this review study discussed how acquired fear can be extinguished through behavioral and pharmacological interventions. Additionally, the brain regions involved in fear memory and the impact of gender differences on fear memory were also addressed. The aim of this review was to contribute to the field by exploring more effective treatment approaches for fear disorders. [ABSTRACT FROM AUTHOR]

Rationale: The medial subregion of the orbitofrontal cortex (mOFC) is thought to play an important role representing the expected outcome of a given course of action, as lesioning or inactivating this cortical region results in the adoption of choice strategies based more on observable (rather than previously learned) information. Despite this, its role in mediating basic associative learning remains to be fully clarified. Objective: The present series of experiments examined the role of the mOFC in (1) Pavlovian conditioned approach, (2) conditioned reinforcement, (3) extinction, and (4) cue-induced reinstatement of food-seeking behavior. Methods: Separate cohorts of rats went through Pavlovian or instrumental training. Intra-mOFC infusions of either saline or GABA agonists (to temporarily inactivate neural activity) were given prior to Pavlovian approach, conditioned reinforcement, first or second day of instrumental extinction training, or cue-induced reinstatement test days. Results: mOFC inactivation increased lever-CS contacts in Pavlovian conditioned approach and (2) had no effect on conditioned reinforcement. These manipulations (3) accelerated within-session instrumental extinction during the initial extinction session, but impaired subsequent extinction learning on drug-free days. (4) mOFC inactivation induced differential effects on reinstatement that depended on baseline performance. mOFC inactivation abolished reinstatement in "Reinstater" rats (who displayed robust responding under control conditions) and robustly increased reinstatement in "Non-Reinstater" rats (who showed little reinstatement under control conditions) suggesting that individual differences in reinstatement may be supported by differences in mOFC mediated representations of expected outcomes. Conclusions: These findings have important implications for understanding how the mOFC uses stimulus-outcome and action-outcome expectancies to guide behavior, and how dysfunction within this region may contribute to pathological patterns of reward seeking. [ABSTRACT FROM AUTHOR]

• Acute inflammation impacts on neural circuitry during interoceptive fear extinction. • Timing of inflammatory insult relative to fear learning and extinction is critical. • Altered fear extinction circuitry may contribute to enhanced interoceptive perception. • Inflammation as risk factor for atypical interoception in psychiatric conditions. Inflammation could impact on the formation and persistence of interoceptive fear and hypervigilance, with relevance to psychiatric disorders and chronic pain. To systematically analyze effects of inflammation on fear learning and extinction, we performed two complementary randomized, double-blind, placebo-controlled functional magnetic resonance imaging (fMRI) studies combining experimental endotoxemia as a translational model of acute systemic inflammation with a two-day multiple-threat fear conditioning paradigm involving interoceptive and exteroceptive unconditioned stimuli (US). Healthy volunteers (N = 95) were randomized to receive intravenous injections of either endotoxin (lipopolysaccharide, LPS; 0.4 ng/kg) or placebo prior to fear acquisition (study 1) or extinction training (study 2). Treatment effects on behavioral and neural responses to conditioned stimuli (CS) predicting interoceptive or exteroceptive threat were assessed during fear learning and extinction phases, along with US valence ratings. Despite robust inflammatory and emotional responses triggered by LPS, no direct effects of inflammation on US ratings or on the formation or extinction of conditioned fear, as assessed with CS valence ratings, were observed. However, in the group treated with LPS prior to acquisition (i.e., study 1), we found enhanced neural responses to the interoceptive but not the exteroceptive CS in key regions of the central fear circuitry during extinction learning. After extinction, this group further showed enhanced negative valence ratings selectively for the interoceptive US during unexpected US re-exposure when compared to the placebo group. Together, inflammation during fear acquisition may promote the establishment of a more robust neural signature of the interoceptive fear memory trace, which may contribute to altered interoceptive pain perception. The fear extinction circuitry engaged during interoceptive fear memory processing may be particularly vulnerable to inflammation, with transdiagnostic implications for gut-brain mechanisms underlying disturbed interoception in psychiatric conditions and chronic visceral pain. [ABSTRACT FROM AUTHOR]

Major theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes. Youths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8–50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients. Patients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome. ITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety. • Prior work on anxiety differences in differential threat learning yields mixed results. • Approaches for indexing threat learning may not be sufficiently sensitive to detect anxiety effects. • We explored threat conditioning and extinction using ITI-normalized fear-potentiated startle. • This approach reveals diminished threat extinction in pathological anxiety. [ABSTRACT FROM AUTHOR]

Caffeine is the most widely consumed psychostimulant drug which could affect learning and memory acting through central adenosine receptors. Although caffeine has been suggested to impair the acquisition and the expression of auditory fear conditioning, its effect on the extinction has not been elucidated. To address this issue, in the present study, we investigated whether caffeine affects the extinction of conditioned fear in an auditory fear conditioning paradigm. During conditioning, rats received pairings of auditory cues (conditioned stimulus, CS) and foot shocks (unconditioned stimulus). On the next day, the rats were intraperitoneally administrated saline or caffeine (5 or 10 mg/kg) and then subjected to the extinction training, in which CSs were repeatedly presented without the foot shocks. Twenty‐four hours later, the rats were re‐exposed to the presentations of CSs (retrieval test). We found an acute caffeine administration dose‐dependently decreased freezing rates during the presentations of CS in the extinction training. Furthermore, caffeine‐treated animals showed lower conditioned freezing responses in the retrieval test. These findings suggest that caffeine facilitates the extinction of conditioned fear. [ABSTRACT FROM AUTHOR]

Objective: We sought to determine whether acute delta 9‐tetrahyrdrocannabidol (THC) administration would facilitate fear extinction in young occasional cannabis users, given that animal models indicate THC facilitates extinction learning, and recent studies indicate THC administration may also enhance threat memory extinction in humans. Methods: On each of the 2 days, 24+ hour THC‐deprived participants were conditioned to fear visual stimuli in a delay conditioning and extinction paradigm. Both CS+ and CS− were faces of negative emotional valence, with the CS+ paired with mild electric shock. Throughout both conditioning and extinction paradigms, EEG was measured to quantify event‐related potentials for these learning processes. Following conditioning, individuals, in a randomized and counter‐balanced order, smoked either an active THC cigarette (26.25 mg/2.7% THC) or a placebo marijuana cigarette (0.002% THC) on 1 day and the opposite cigarette on the second day. After smoking, CS+ and CS− were presented without shock, resulting in extinction of conditioned fear. Results: Relative to placebo, THC facilitated extinction of the conditioned response to the CS+, as reflected by reductions in late positive potential amplitude during extinction learning. Conclusions: The results indicate that acute THC administration may facilitate extinction of the conditioned fear response in humans. [ABSTRACT FROM AUTHOR]

Various studies demonstrated that extinction training taking place shortly after the activation of the acquired fear could weaken the conditioned fear. The procedure is called post-retrieval extinction (PRE). However, from the time it emerged, it has suffered from inconsistencies in the ability of researchers to replicate the seemingly established effects. Extant literature implies that conditioned fear might be differentially sensitive to the nature of conditioned stimuli (CS) used. The aim of the present study, therefore, is threefold. First, we aimed to replicate Schiller et al. (Nature, 463, 49–53. 2010) procedure in which the PRE had produced positive results with arbitrary CSs only. Also, we examined the PRE as a function of CS type (ecological-fear-relevant (images of spider and snake) vs. arbitrary (images of yellow and blue circles)). Finally, we aimed to investigate the long-term effects of the PRE (i.e., 24 h, 15 d, and 3 mo). The study consisted of acquisition, re-activation and extinction, and re-extinction phases. Dependent measure was the recovery of fear responses as indexed by the skin conductance responses (SCRs) and arousal ratings of the participants at the last trial of the extinction and the first trial of the re-extinction. All groups showed significant acquisition and extinction patterns, compared to the other two groups (i.e., 6 h after the activating CS and without an activating stimulus) only the group that undertook extinction trials 10 min after the activating CS showed a sustained extinction. Thus, our findings provided further evidence for the robustness of the PRE paradigm in preventing the recovery of extinguished fears behaviorally, both with ecological and arbitrary stimuli. [ABSTRACT FROM AUTHOR]

Four experiments with rat subjects asked whether a partial reinforcement extinction effect (PREE) occurs in taste aversion learning. The question has received little attention in the literature, and to our knowledge no taste aversion experiment has previously demonstrated a PREE. In each of the present experiments, experimental groups received a taste mixed in drinking water for 20 min; such taste exposures were sometimes paired with a lithium chloride (LiCl) injection and sometimes not. Control groups received only taste-LiCl pairings. There was evidence that each reinforced and non-reinforced trial produced increments and decrements in aversion strength (respectively), and trials mattered more than accumulated time during the conditioned stimulus and during the background (as emphasized in time-accumulation models like those of Gallistel and Gibbon, Psychological Review, 107, 289-344, 2000, and Gibbon and Balsam, Autoshaping and conditioning theory, Academic Press, New York, pp. 219-235, 1981). In addition, a partial reinforcement extinction effect was observed when there was a relatively large number of conditioning trials. The results extend our understanding of extinction in taste aversion learning and provide more evidence that aversion learning might follow rules that are qualitatively similar to those of other forms of learning. [ABSTRACT FROM AUTHOR]

• The taste of alcoholic beverages induce craving and are prominent relapse triggers. • Mice increase the duration of bouts of alcohol consumption over time. • Long duration bouts are transiently supported by an alcohol-paired flavor. • Increases in bout duration are consistent with increases in palatability. • Conditioned palatability likely contributes to binge alcohol consumption. The orosensory features of alcoholic drinks are potent relapse triggers because they acquire incentive properties during consumption, including enhanced palatability. Whether mice similarly perceive alcoholic drinks to be more palatable after repeated consumption is complicated by reports showing that alcohol elicits aversive taste reactivity responses and conditions flavor avoidance. Here, by analyzing the microstructure of alcohol consumption, we report a gradual increase in lick bout duration relative to water that is partially maintained by an alcohol-paired flavor in extinction. We interpret lick bout duration to reflect an increase in the palatability alcohol and an alcohol-paired flavor. This finding demonstrates that bout duration is amenable to Pavlovian conditioning and highlights the importance of considering the microstructure of alcohol consumption in preclinical models of alcohol misuse. [ABSTRACT FROM AUTHOR]

Disgust imagery represents a potential pathological mechanism for disgust-related disorders. However, it remains controversial as to whether disgust can be conditioned with disgust-evoking mental imagery serving as the unconditioned stimulus (US). Therefore, we examined this using a conditioned learning paradigm in combination with event-related potential (ERP) analysis in 35 healthy college students. The results indicated that the initial neutral face (conditioned stimulus, CS+) became more disgust-evoking, unpleasant, and arousing after pairing with disgust-evoking imagery (disgust CS+), compared to pairing with neutral (neutral CS+) and no (CS−) imagery. Moreover, we observed that mental imagery-based disgust conditioning was resistant to extinction. While the disgust CS + evoked larger P3 and late positive potential amplitudes than CS− during acquisition, no significant differences were found between disgust CS+ and neutral CS+, indicating a dissociation between self-reported and neurophysiological responses. Future studies may additionally acquire facial EMG as an implicit index of conditioned disgust. This study provides the first neurobiological evidence that associative disgust learning can occur without aversive physical stimuli, with implications for understanding how disgust-related disorders may manifest or deteriorate without external perceptual aversive experiences, such as in obsessive-compulsive disorder (OCD). • Disgust conditioning can occur without the physical presence of disgusting stimuli. • Conditioned disgust response was difficult to extinguish. • Dissociative consequences of behavioral and neural mechanisms exist in disgust extinction. • Imaginary procedures may have therapeutic potential in disorders associated with disgust conditioning. [ABSTRACT FROM AUTHOR]

Disgust can be acquired via evaluative conditioning; a process by which a neutral stimulus (conditioned stimulus; CS) comes to be evaluated as disgusting due to its pairing with an inherently disgusting stimulus (unconditioned stimulus; US). Research has shown that conditioned disgust responses are resistant to extinction which may have implications for disorders (i.e., contamination-based obsessive-compulsive disorder, specific phobias, and post-traumatic stress disorder) in which heightened disgust has been implicated. Importantly, extinction is the primary mechanism by which exposure therapies are thought to achieve symptom reduction for these disorders. Exposure therapies were originally modeled on fear extinction, whereas disgust extinction was largely overlooked until recently. Accordingly, differences in the degree to which learned disgust and fear can be attenuated via extinction learning remains unclear. The present investigation was a meta-analysis directly comparing the degree of extinction of conditioned disgust (n = 14) and conditioned fear (n = 14) in laboratory paradigms. Extinction was operationalized as the standardized mean difference (SMD) in evaluative ratings between the CS+ (the CS paired with the US) and CS- (the unpaired CS) after extinction training. Results of a subgroup analysis indicated that disgust (SMD = 0.52) was significantly more resistant to extinction than fear (SMD = 0.37). Additionally, a series of meta-regression analyses indicated that extinction was not influenced by important study characteristics (e.g., sex, age, number of conditioning and extinction trials). The findings suggest that extinction-based approaches may be less effective at attenuating learned disgust and research is needed to better optimize treatments for disgust-related disorders. • Meta-analysis comparing extinction of conditioned disgust and fear in laboratory paradigms. • Disgust significantly more resistant to extinction than fear. • Degree of extinction not influenced by study characteristics. [ABSTRACT FROM AUTHOR]

Across social species, the presence of another individual can reduce stress reactions to adverse stimuli, a phenomenon known as social buffering. The present study investigated whether social buffering influences the expression and extinction of learned fear in adolescence, a developmental period of diminished fear inhibition and increased social interaction. Quality of maternal care and degree of social investigation were examined as factors that may influence social buffering. In adolescence, male rats were fear conditioned and then given extinction training either in the presence of a same-age rat or alone. Animals were then tested alone for extinction retention. In two experiments, the presence of a conspecific robustly reduced conditioned fear responses during extinction training. Interestingly, a persistent social buffering effect was observed when the extinction and conditioning contexts had prominent differences in features (Experiment 1), but not when these contexts were relatively similar (Experiment 2). Neither quality of maternal care nor degree of social investigation predicted the effects of social buffering. These findings suggest that social buffering robustly dampens fear responses during adolescence when a peer is present and this suppression can persist, in some instances, even when the peer is absent. [Display omitted] • Social buffering during adolescence reduced learned fear responses at extinction. • In some cases, this effect persisted. • Social buffering did not influence renewal. • Maternal care and social investigation did not predict social buffering. [ABSTRACT FROM AUTHOR]

In rodents, exposure to electrical shock and creating a strong fear memory using fear-conditioning model can induce PTSD-like behavior. In this study, we induced a fear-conditioning model in rats and investigated freezing (PTSD-like) behavior, 21 days after three shocks exposure (0.6 mA, 3 s, 30 seconds interval) in both male and female rats. Lithium was injected intraperitoneally (100 mg/kg) in three protocols: (1) 1 h after fear-conditioning (2) 1 h, 24 h, and 48 h after fear-conditioning (3), 1 h, 24 h, 48 h, 72 h, and 96 h after fear-conditioning. Extinction training (20 sounds without shocks, 75 dB, 3 s, 30 seconds interval) was performed in three protocols: (1) 1 h after fear-conditioning (one session), (2) 1 h, 24 h, and 48 h after fear-conditioning (three sessions), (3), 1 h, 24 h, 48 h, 72 h, and 96 h after fear-conditioning (five sessions). Forced swim test (FST) and hot plate were used to assess behavior. Results showed that lithium in all protocols had no effect on freezing behavior, FST, and pain subthreshold in all rats. Extinction training decreased freezing behavior, with more efficacy in females. In males, only 5-session training was effective, while in females all protocols were effective. Extinction training also altered pain perception and the results of FST, depending on the sessions and was different in males and females. Brain-derived neurotrophic factor (BDNF) mRNA level was increased in females following 3 and 5 sessions, and in males following 5 sessions extinction training. In conclusion, we suggested that there is a sex difference for the effect of extinction training on freezing behavior and BDNF mRNA level in a rat model of fear-conditioning. • Lithium (100 mg/kg, all protocols) had no effect on PTSD-like behavior in both sexes. • All extinction protocols significantly eliminated PTSD-like behavior in females. • Extinction training (only 5 sessions) eliminated PTSD-like behavior in males. • Extinction training had more efficacy in females than in males. • There is a sex difference for the effect of extinction training on BDNF level. [ABSTRACT FROM AUTHOR]

Imagery‐based extinction procedures have long been used in the treatments of fear‐related conditions. The assumption is that imagery can substitute for the perceptual stimuli in the extinction process. Yet, experimental validations of this assumption have been limited in number and some have relied exclusively on measures of autonomic reactivity without consideration of conscious feelings of fear. The current investigation sought to assess whether imagery‐based exposure could lead to extinction of conditioned fear to the corresponding perceptual stimulus. Conditioned fear responses were measured by both a physiological (i.e., skin conductance response [SCR]) and a subjective (i.e., self‐reported fear) measure. Participants (N = 56) first underwent perceptual differential fear conditioning, then imagery extinction, then perceptual extinction. SCR evidence was found for successful fear conditioning, generalization of fear from viewing to imagery, and most importantly, the absence of differential fear after imagery extinction upon re‐exposure to the conditioned perceptual stimulus. Self‐reported fear confirmed the acquisition and generalization of fear and provided evidence of a significant reduction in differential fear conditioning across extinction. Consistent with clinical evidence of the efficacy of imagery extinction and the existing limited experimental literature, this study offers support for fear extinction to perceptual stimuli via imagery exposure. The present study provides experimental evidence that imagery of a fear conditioned stimulus can produce differential fear extinction as measured both physiologically (i.e., skin conductance response) and subjectively (i.e., self‐reported fear), which extends the extant literature of mental imagery and fear extinction. These findings provide empirical support for the clinical application of extinction‐based imagery treatments in fear‐related affective disorders. [ABSTRACT FROM AUTHOR]

• Classical conditioning models of OCD inform gold-standard exposure interventions. • First systematic review of classical fear conditioning studies in OCD. • Twelve identified studies yielded mixed evidence for impaired acquisition in OCD, but more consistent evidence for extinction deficits. • Next steps and recommendations for increasingly ecologically-valid laboratory tasks and individual difference assessments to facilitate translational efforts are discussed. Laboratory experiments using fear conditioning and extinction protocols help lay the groundwork for designing, testing, and optimizing innovative treatments for anxiety-related disorders. Yet, there is limited basic research on fear conditioning and extinction in obsessive-compulsive disorder (OCD). This is surprising because exposure-based treatments based on associative learning principles are among the most popular and effective treatment options for OCD. Here, we systematically review and critically assess existing aversive conditioning and extinction studies of OCD. Across 12 studies, there was moderate evidence that OCD is associated with abnormal acquisition of conditioned responses that differ from comparison groups. There was relatively stronger evidence of OCD's association with impaired extinction processes. This included multiple studies finding elevated conditioned responses during extinction learning and poorer threat/safety discrimination during recall, although a minority of studies yielded results inconsistent with this conclusion. Overall, the conditioning model holds value for OCD research, but more work is necessary to clarify emerging patterns of results and increase clinical translational utility to the level seen in other anxiety-related disorders. We detail limitations in the literature and suggest next steps, including modeling OCD with more complex conditioning methodology (e.g., semantic/conceptual generalization, avoidance) and improving individual-differences assessment with dimensional techniques. [ABSTRACT FROM AUTHOR]

• We aimed at sustaining conditioned properties of the mTOR inhibitor rapamycin. • Sub-effective doses of rapamycin (US) were applied with the taste (CS) at retrieval. • Conditioned immunopharmacological responses persisted peripherally and centrally. • Sub-effective US doses strengthen conditioned associations between taste and drug. Peripheral immune responses can be modulated by taste-immune associative learning where the presentation of a sweet taste as conditioned stimulus (CS) is paired with the injection of an immunosuppressive substance as unconditioned stimulus (US). Previous findings demonstrate conditioned immunopharmacological properties of the mechanistic target of rapamycin (mTOR)-inhibitor rapamycin, a drug used to ameliorate neurological diseases and for the prevention of graft rejection. However, conditioned responses gradually weaken over time and eventually disappear following repeated exposure to the CS in the absence of the US. Thus, in order to employ learning paradigms in clinical conditions as supportive immunopharmacological therapy it is important to understand the central and peripheral mechanisms of how learned immune responses can be protected from extinction. Against this background, the present study used a taste-immune learning paradigm with rapamycin as US (5 mg/kg). By applying only 10% (0.5 mg/kg) of the therapeutic dose rapamycin together with the CS (taste stimulus) during eight retrieval trials, conditioned animals still displayed suppressed interleukin-10 production and T cell proliferation in splenocytes as well as diminished activity of the mTOR target protein p70s6k in amygdala tissue samples. Together, these findings indicate that reminder cues in form of only 10% (0.5 mg/kg) of the therapeutic dose rapamycin together with the CS (taste stimulus) at retrieval preserved the memory of conditioned properties of rapamycin, characterizing this approach as a potential supportive tool in peripheral and central pharmacotherapy with the aim to maximize the therapeutic outcome for the patient's benefit. [ABSTRACT FROM AUTHOR]

Individuals, who score high in self‐reported intolerance of uncertainty (IU), tend to find uncertainty anxiety‐provoking. IU has been reliably associated with disrupted threat extinction. However, it is unclear whether IU would be related to disrupted extinction to other arousing stimuli that are not threatening (i.e., rewarding). We addressed this question by conducting a Pavlovian reward conditioning task with acquisition and extinction training phases (n = 58). In the Pavlovian reward conditioning task, we recorded liking ratings, skin conductance response (SCR), and corrugator supercilii activity (i.e., brow muscle indicative or negative and positive affect) to learned reward (CS+) and neutral (CS−) cues. Typical patterns of reward acquisition and extinction training were observed for liking ratings. There was evidence for conditioning in SCR during the extinction training phase but not the acquisition training phase. However, no evidence of conditioning in either the acquisition or extinction training phase was observed for the corrugator supercilii. IU was not related to any measures during the acquisition or extinction training phases. Taken together, these results suggest that the current Pavlovian reward conditioning task was not sufficient for eliciting a reliable conditioned reward response, and therefore, further research with optimized reward conditioning designs are required to test whether IU‐related deficits occur during the extinction of reward. [ABSTRACT FROM AUTHOR]

Aims: To examine two explanations for the observation that cue–exposure treatment has not been clearly effective in the treatment of alcohol dependence: do alcohol‐dependent individuals have either (1) slower extinction and/or (2) greater contextual specificity of extinction than non‐dependent individuals? Design In two exploratory laboratory experiments we used mixed factorial designs with two‐group between‐subjects factors and within‐subjects factors corresponding to performance in different parts of a computer‐based learning task. Setting: University of Southampton psychology research laboratories and two addiction treatment services in the city of Southampton, UK. Participants: Experiment 1: 74 (54 female) undergraduates from the University of Southampton (age mean = 20.4 years). Experiment 2: 102 (40 female) participants from the University of Southampton, the local community, and from two Southampton alcohol treatment services (age mean = 41.3 years). Measurements: The Alcohol Use Disorders Identification Test, a 1‐week time‐line follow‐back alcohol consumption questionnaire, the Barratt Impulsiveness Scale (11th edn), and a computerized learning task. Experiment 2 additionally used the 44‐item Big Five Inventory, a drug use history checklist, and the Hospital Anxiety and Depression Scale. Findings Experiment 1: light and heavy drinkers did not differ significantly in extinction [extinction block × drinking status interaction, P = 0.761, ηp2=0.005, 95% confidence interval (CI) = (0,0.028)] or on contextual control of extinction [recovery block × drinking status interaction, P = 0.514, ηp2=0.009, 95% CI =(0, 0.084)]. Experiment 2: slower extinction in abstinent alcohol‐dependent participants compared with light drinkers [extinction block × drinking status interaction, P = 0.023, ηp2=0.031, 95% CI = 0, 0.069)] but no significant difference on contextual control of extinction [recovery block × drinking status interaction, P = 0.069, ηp2=0.033, 95% CI = (0, 0.125)]. Conclusion: Abstinent alcohol‐dependent people may have slower extinction learning for alcohol‐related cues than non‐dependent light drinkers. [ABSTRACT FROM AUTHOR]

We aimed to investigate the persistent trace of one traumatic event on neurocircuit controls in rats. Conditioning was reflected by reductions in rates of 'freezing' and 'other-than-freezing' motor activities, between which rats could alternate on delivery of pulsed footshocks of intensity 0.5 mA but not 1.0 mA. At the latter intensity, freezing began to suppress motor activity. The conditional responses evident during both the context and tone sessions persisted when the tests were repeated on post-conditioning days 7 and 8. Thus, difficulties with fear extinction/reduction remained. However, persistence was not evident on post-conditioning days 1 and 2. One day after the 1.0 mA pulsed footshock, ibotenate lesions and corresponding sham surgeries were performed in unilateral and bilateral hemispheres of the amygdala, hippocampus, and prefrontal cortex, as well as three different disconnections (one unilateral and another contralateral lesions out of three regions, a total of nine groups), and were tested on days 7-8. The drastic restoration of freezing following bilateral amygdala lesions was also evident in animals with three types of disconnection; however, this was not the case for hypoactivity. These results imply that a serious experience can drive different neurocircuits that all involve the amygdala, forming persistent concurrent memories of explicit (e.g., 'freezing') or implicit (e.g., 'other-than-freezing' motor activity) emotions, which may exhibit mutual interference. [ABSTRACT FROM AUTHOR]

• Intermediate duration retrieval events fail to engage reconsolidation or extinction. • Limbo is present in both vertebrates and invertebrates. • During limbo, conditioned response is resistant to protein synthesis inhibition. • Limbo engagement is modulated by memory strength. • Limbo is an evolutionary conserved feature of memory retrieval. Fully consolidated associative memories may be altered by alternative retrieval dependent memory processes. While a brief exposure to the conditioned stimulus (CS) can trigger reconsolidation of the original memory, a prolonged CS exposure will trigger memory extinction. The conditioned response is maintained after reconsolidation, but is inhibited after extinction, presumably by the formation of a new inhibitory memory trace. In rats and humans, it has been shown that CS exposure of intermediate duration leave the memory in an insensitive or limbo state. Limbo is characterised by the absence of reconsolidation or extinction. Here we investigated the evolutionary conserved nature of limbo using a contextual Pavlovian conditioning (CPC) memory paradigm in the crab Neohelice granulata. In animals with fully consolidated CPC memory, systemic administration of the protein synthesis inhibitor cycloheximide after 1 CS presentation disrupted the memory, presumably by interfering with memory reconsolidation. The same intervention given after 320 CSs prevented CPC memory extinction. Cycloheximide had no behavioural effect when administered after 80 CS presentations, a protocol that failed to extinguish CPC memory. Also, we observed that a stronger CPC memory engaged reconsolidation after 80 CS instead of limbo, indicating that memory strength affects the parametrical conditions to engage either reconsolidation or limbo. Altogether, these results indicate that limbo is an evolutionary conserved memory process segregating reconsolidation from extinction in the number of CSs space. Limbo appears as an intrinsic component of retrieval dependent memory processing, with a key function in the transition from memory maintenance to inhibition. [ABSTRACT FROM AUTHOR]

Previous research has shown that instrumental training can encourage the formation of binary associations between the representations of the elements present at the time of learning, that is, between the discriminative stimulus and the instrumental response (the S-R association), between the stimulus and outcome (the S-O association), and between the response and outcome (the R-O association). Studies with rats have used transfer procedures to explore the effects of discriminative extinction (i.e., extinction that is carried out in the presence of the discriminative stimuli) on these three binary associations. Thus, a reduction in the response rate of the extinguished response (R) can be detected in situations involving a different discriminative stimulus that was associated with the same outcome, and to unextinguished responses controlled by the discriminative stimulus (S) and associated with the outcome (O). These transfer effects suggest that R-O and S-O associations remain active after extinction in nonhuman animals. We carried out an experiment to explore these postextinction transfer effects in humans using a within-subject design. Contrary to nonhuman reports, the S--O association was affected by discriminative extinction, suggesting differences in the associative structure of instrumental conditioning in human and nonhuman animals that should be considered by those therapeutic strategies based in nonhuman animal research aimed to reduce unhealthy instrumental behaviours in human beings. [ABSTRACT FROM AUTHOR]

• Visceral pain-related learning establishes a robust aversive memory trace. • Re-exposure to visceral pain induces return of extinguished conditioned fear. • Acute inflammation does not impair the extinction of aversive gut memories. • Inflammation is not a vulnerability factor for increased return of fear. Impaired extinction of pain-related fear memories can lead to persistent or resurging fear of pain, contributing to the development and maintenance of chronic pain conditions. The mechanisms underlying maladaptive pain-related learning and memory processes remain incompletely understood, particularly in the context of interoceptive, visceral pain. Inflammation is known to interfere with learning and memory, but its effects on the extinction of pain-related fear memories have never been tested. In a randomized, double-blind, placebo-controlled study, we assessed the impact of experimental acute inflammation on the extinction and reinstatement of conditioned visceral pain-related fear. Forty healthy male volunteers underwent differential fear conditioning with visceral pain as clinically relevant unconditioned stimulus (US). Participants then received an intravenous injection of either 0.8 ng/kg lipopolysaccharide (LPS) as inflammatory stimulus or physiological saline as placebo, and extinction training was conducted at the peak of the inflammatory response. Extinction recall and reinstatement test were performed after overnight consolidation. Results showed that visceral pain represents an effective US, eliciting pronounced conditioned pain-related fear responses. Repeated unreinforced presentation of the pain-predictive cue during extinction training resulted in full extinction of the conditioned behavioral response. However, unexpected re-exposure to the US during reinstatement test resulted in return of fear. Despite pronounced LPS-induced effects on inflammatory markers, cortisol, and negative affect, we did not find evidence that acute inflammation resulted in altered fear extinction. The findings support the notion that visceral pain-related fear learning establishes a robust aversive memory trace that remains preserved during inhibitory learning, leaving a latent vulnerability for the return of fear. Inflammation during inhibitory learning did neither weaken nor further amplify this aversive memory trace, suggesting that it is rather resistant to acute inflammation-induced effects, at least in healthy individuals with no additional vulnerability factors. [ABSTRACT FROM AUTHOR]

Background: Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers. Methods: Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall. Results: Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis. Conclusion: Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD. [ABSTRACT FROM AUTHOR]

Background and purpose: Neurobiological changes in memory processes seem to play a role in the pathophysiology of post-traumatic stress disorder (PTSD). Memory itself is influenced by PTSD, too. Histone deacetylase inhibitors (HDAIs) have shown promising results in the extinction of fear-related memories in animals and hence they seem to be important for the treatment of PTSD. Data are scarce about the effect of HDAIs in spatial memory formation/extinction in PTSD models. The main goal of the present work is to find the effect of sodium butyrate (NaBu), as an HDAI, on spatial memory and spatial memory extinction in rats exposed to single prolonged stress procedure (SPS). Experimental approach: Different doses of NaBu were administered subcutaneously for 7 days in different groups of rats after SPS procedure. Learning, memory, and extinction of memory were evaluated in the Morris water maze test of spatial memory in 6 consecutive days. Findings / Results: The results show that NaBu (0.5 mg/kg) alleviates impaired learning and memory in SPS rats. It also facilitates the extinction of newly formed memory in the animals. Conclusion and implications: Our data suggest that the administration of HDAIs after a traumatic experience can prevent the aversive effects of SPS on spatial memory. It also reinforces the notion that extinction of spatial memory involves the same or similar brain circuitry that is involved in the extinction of fear memories in PTSD patients. [ABSTRACT FROM AUTHOR]

While translational theories link neurodevelopmental changes in threat learning to pathological anxiety, findings from studies in patients inconsistently support these theories. This inconsistency may reflect difficulties in studying large patient samples with wide age ranges using consistent methods. A dearth of imaging data in patients further limits translational advances. We address these gaps through a psychophysiology and structural brain imaging study in a large sample of patients across the lifespan. A total of 351 participants (8–50 years of age; 209 female subjects; 195 healthy participants and 156 medication-free, treatment-seeking patients with anxiety) completed a differential threat conditioning and extinction paradigm that has been validated in pediatric and adult populations. Skin conductance response indexed psychophysiological response to conditioned (CS+, CS−) and unconditioned threat stimuli. Structural magnetic resonance imaging data were available for 250 participants. Analyses tested anxiety and age associations with psychophysiological response in addition to associations between psychophysiology and brain structure. Regardless of age, patients and healthy comparison subjects demonstrated comparable differential threat conditioning and extinction. The magnitude of skin conductance response to both conditioned stimulus types differentiated patients from comparison subjects and covaried with dorsal prefrontal cortical thickness; structure–response associations were moderated by anxiety and age in several regions. Unconditioned responding was unrelated to anxiety and brain structure. Rather than impaired threat learning, pathological anxiety involves heightened skin conductance response to potential but not immediately present threats; this anxiety-related potentiation of anticipatory responding also relates to variation in brain structure. These findings inform theoretical considerations by highlighting anticipatory response to potential threat in anxiety. [ABSTRACT FROM AUTHOR]

Trauma and symptoms of posttraumatic stress disorder (PTSD) have repeatedly been linked to impaired cardiovascular functioning. Poor fear extinction is a well-established biomarker of PTSD that may provide insight into mechanisms underlying cardiovascular risk. The current study probed the cardiovascular response to extinction in a sample of trauma-exposed individuals. Participants were 51 trauma-exposed women who underwent a fear conditioning paradigm. Heart rate (HR) during extinction was examined in response to a conditioned stimulus that was previously paired with an aversive unconditioned stimulus (CS+) and one that was never paired (CS-). Heart rate variability (HRV) was calculated at baseline and during the extinction session. Consistent with fear bradycardia, initial HR deceleration (.5-2s) after CS + onset occurred during early extinction and appeared to extinguish over time. Higher baseline HRV was significantly associated with greater fear bradycardia during early extinction. This is the first study to demonstrate a pattern of fear bradycardia in early extinction, which was associated with higher HRV levels and decreased over the course of the extinction phase. These results suggest that increased fear bradycardia may be indicative of greater vagal control (i.e., HRV), both of which are psychophysiological biomarkers that may influence cardiovascular and autonomic disease risk in trauma-exposed individuals. [ABSTRACT FROM AUTHOR]

Several studies have revealed that fear recovery is prevented when extinction training is conducted after retrieval of a fear memory. Postretrieval extinction training is related to modification of memory during reconsolidation. Providing new information during reconsolidation can modify the original memory. We propose that avoidance behavior is a relevant factor that prevents subjects from obtaining new safety information during reconsolidation. Postretrieval extinction training without avoidance behavior reduced the fear response to conditioned stimulus and prevented spontaneous recovery in the current study, which corresponded with previous studies. Under the condition of postretrieval extinction training with avoidance behavior, the fear response was not reduced as much as it was in the condition without avoidance. It is possible that avoidance behavior prevents receiving new safety information during postretrieval extinction training. [ABSTRACT FROM AUTHOR]

Several studies demonstrated that genital arousal and enhanced positive affect toward neutral stimuli due to sexual conditioning did not extinguish during a brief extinction phase, but other studies showed contrasting results. Possible resistance to extinction of conditioned human sexual response has, however, not been studied using extensive extinction trials. To study resistance to extinction of conditioned sexual response in men and women. Healthy sexually functional men (N = 34) and women (N = 32) participated in a differential conditioning experiment, with neutral pictures as conditioned stimuli (CSs) and genital vibrostimulation as unconditioned stimulus. Only one CS (the CS+) was followed by the unconditioned stimulus during the acquisition phase. Penile circumference and vaginal pulse amplitude were assessed, and ratings of affective value and subjective sexual arousal were obtained. In addition, a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. Men and women rated the CS+ as more positive than the CS− during all 24 extinction trials and demonstrated a slight tendency to approach the CS+ directly after the extinction procedure. Participants rated the CS+ as more sexually arousing than the CS− during 20 extinction trials. No evidence was found for conditioned genital sexual response. Learned sexual evaluations may be difficult to modify through an extinction procedure; therefore, unwanted but persistent subjective sexual evaluations may be better targeted by interventions such as the deployment of emotion regulation strategies. Extensive extinction trials were used; however, only relatively short-term effects within one experimental session were studied and there was no (unpaired) control condition. The results provide evidence that conditioned sexual likes are relatively persistent, also at the behavioral level. Both S, Brom M, Laan E, et al. Evidence for Persistence of Sexual Evaluative Learning Effects. J Sex Med 2020;17:505–517. [ABSTRACT FROM AUTHOR]

Stress impairs extinction learning, and these deficits depend, in part, on stress-induced norepinephrine (NE) release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered soon after fear conditioning. Here, we explored whether locus coeruleus (LC)-NE regulates stress-induced changes in spike firing in the BLA and consequent extinction learning impairments. Rats were implanted with recording arrays in the BLA and, after recovery from surgery, underwent a standard auditory fear conditioning procedure. Fear conditioning produced an immediate and dramatic increase in the spontaneous firing of BLA neurons that persisted (and in some units, increased further) up to an hour after conditioning. This stress-induced increase in BLA firing was prevented by systemic administration of propranolol. Conditioning with a weaker footshock caused smaller increases in BLA firing rate, but this could be augmented by chemogenetic activation of the LC. Conditioned freezing in response to a tone paired with a weak footshock was immune to the IED, but chemogenetic activation of the LC before the weak conditioning protocol increased conditioned freezing behavior and induced an IED; this effect was blocked with intra-BLA infusions of propranolol. These data suggest that stressinduced activation of the LC increases BLA spike firing and causes impairments in extinction learning. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with stress- and trauma-related disorders. [ABSTRACT FROM AUTHOR]

• Fear conditioning and extinction was studied on three separate days. • Enhanced amygdala activation during early acquisition in panic disorder patients. • Patients showed attenuated extinction recall on day three. Emotional-associative learning represents a translational model for the development, maintenance and treatment of anxiety disorders such as panic disorder (PD). The exact nature of the underlying fear learning and extinction deficits however, remains under debate. Using a three-day paradigm to separate the distinct learning and consolidation processes, we aimed to gain insights into the neurofunctional substrates of altered fear conditioning, extinction training and recall in PD. In contrast to studies employing one-session fear conditioning paradigms, a differential fear conditioning and delayed extinction task was conducted for the purpose of disentangling neural networks involved in fear acquisition, extinction training and recall of extinction memories. Using functional magnetic resonance imaging (fMRI), quality-controlled datasets from 10 patients with PD and 10 healthy controls were available from three consecutive days (day 1: acquisition; day 2: extinction training; day 3: extinction recall) with neutral faces serving as CSs and an aversive auditory stimulus (panic scream) as US. PD patients showed heightened fear circuitry (e.g. right amygdala and left insula) activation during early acquisition and prolonged activation in the right insula, left inferior frontal operculum and left inferior frontal gyrus during extinction recall compared to healthy controls. Stronger neural activation in structures conferring defensive reactivity during early acquisition and extinction recall may indicate the accelerated acquisition of conditioned responses, while extinction recall may be attenuated as a function of PD pathophysiology. Future studies should investigate the predictive value of experimental measures of extinction recall for clinical relapse. [ABSTRACT FROM AUTHOR]

Rationale: A promising strategy to prevent a return of fear after exposure-based therapy in anxiety disorders is to pharmacologically enhance the extinction memory consolidation presumed to occur after exposure. Accumulating evidence suggests that the effect of a number of pharmacological consolidation enhancers depends on a successful fear reduction during exposure. Here, we employed the dopamine precursor L-DOPA to clarify whether its documented potential to enhance extinction memory consolidation is dependent on successful fear extinction. Methods: In two double-blind, randomized and placebo-controlled experiments (experiment 1: N = 79, experiment 2: N = 32) comprising fear conditioning (day 1), extinction followed by administration of 150 mg L-DOPA or placebo (day 2) and a memory test (day 3) in healthy male adults, conditioned responses were assessed as differential skin conductance responses. We tested whether the effect of L-DOPA on conditioned responses at test depended on conditioned responses at the end of extinction in an experiment with a short (10 trials, experiment 1) and long (25 trials, experiment 2) extinction session. Results: In both experiments, the effect of L-DOPA was dependent on conditioned responses at the end of extinction. That is, post-extinction L-DOPA compared to placebo administration reduced conditioned responses at test only in participants showing a complete reduction of conditioned fear at the end of extinction. Conclusion: The results support the potential use of L-DOPA as a pharmacological adjunct to exposure treatment, but point towards a common boundary condition for pharmacological consolidation enhancers: a successful reduction of fear in the exposure session. [ABSTRACT FROM AUTHOR]

Two high-powered experiments examined the role of evaluative response production in the extinction of evaluative conditioning (EC) by positioning EC in the procedural and conceptual framework of classical conditioning (CC). According to Rescorla's response inhibition hypothesis, more frequent responding during extinction training results in larger extinction during testing. Experiment 1 used three extinction conditions following response acquisition in an EC procedure: evaluative responses were measured only after extinction; after acquisition and after extinction; or were continuously measured after acquisition, during extinction and after extinction. Based on Rescorla's response inhibition hypothesis, we predicted that extinction of EC would be the highest in the third condition. Experiment 2 was aimed at further facilitating extinction of EC by encouraging participants to experience that their evaluation may change over the course of the experiment. To this end, half of the participants completed pre- and post-acquisition ratings prior to practicing continuous response expression in the extinction phase. Contrary to our predictions, no extinction of EC was observed in either of these experiments. We conclude that Rescorla's inhibition response hypothesis may not apply to EC and discuss the theoretical implications of this finding. [ABSTRACT FROM AUTHOR]

• HDAC1 is associated with the promotion of fear and extinction learning. • HDAC2 is associated with the suppression of fear and extinction learning. • Histone acetylation exhibit differential association with HDAC1 and HDAC2. Histone deacetylases (HDACs) regulate gene expression epigenetically through synchronized removal of acetyl groups from histones required towards memory consolidation. Moreover, dysregulated epigenetic machinery during fear or extinction learning may result in altered expression of some of these genes and result in Post Traumatic Stress Disorder (PTSD). In the present study, region-specific expression of Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC2) was correlated to the acetylation of histones H3 and H4 and the resultant conditioned response, in rats undergone fear and extinction learning. The neuronal activation, histone acetylation at H3/H4 and expression of HDAC1/HDAC2 in centrolateral amygdala (CeL) and centromedial amygdala (CeM) of central Amygdala (CeA) and prelimbic (PL) and infralimbic (IL) of Prefrontal cortex (PFC) were found to be associated in a differential manner following fear and extinction learning. Moreover in CeM, the main output of the fear circuitry, the level of HDAC1 was down-regulated following conditioning and up-regulated following extinction as opposed to which HDAC2 was down-regulated in CeM following conditioning but not following extinction. Furthermore, in CeL the HDAC1 was upregulated and HDAC2 was downregulated following conditioning and extinction. This has important implications in speculating of the role of HDACs in fear memory consolidation and its extinction. [ABSTRACT FROM AUTHOR]

Extinction of conditioned aversive responses (CR) has been shown to be context-dependent. The hippocampus and prefrontal cortex are of particular importance. The cerebellum may contribute to context-related processes because of its known connections with the hippocampus and prefrontal cortex. Context dependency of extinction can be demonstrated by the renewal effect. When CR acquisition takes place in context A and is extinguished in context B, renewal refers to the recovery of the CR in context A (A-B-A paradigm). In the present study acquisition, extinction and renewal of classically conditioned eyeblink responses were tested in 18 patients with subacute focal cerebellar lesions and 18 age- and sex-matched healthy controls. Standard delay eyeblink conditioning was performed using an A-B-A paradigm. All cerebellar patients underwent a high-resolution T1-weighted brain MRI scan to perform lesion-symptom mapping. CR acquisition was not significantly different between cerebellar and control participants allowing to draw conclusions on extinction. CR extinction was significantly less in cerebellar patients. Reduction of CR extinction tended to be more likely in patients with lesions in the lateral parts of lobule VI and Crus I. A significant renewal effect was present in controls only. The present data provide further evidence that the cerebellum contributes to extinction of conditioned eyeblink responses. Because acquisition was preserved and extinction took place in another context than acquisition, more lateral parts of the cerebellar hemisphere may contribute to context-related processes. Furthermore, lack of renewal in cerebellar patients suggest a contribution of the cerebellum to context-related processes. [ABSTRACT FROM AUTHOR]

The partial reinforcement extinction effect (PREE) is the observation that, following training in which a response is followed by reward on only a subset of trials, the response is more resistant to extinction following the total removal of reward than it is after training in which reward is presented on all trials. The PREE is almost ubiquitous in instrumental conditioning procedures but only inconsistently observed in Pavlovian conditioning. In his classic review of animal learning, Mackintosh attributes the bulk of the PREE to generalisation decrement relating to the fact that partial reinforcement typically ensures that acquisition of responding has taken place in conditions similar to that of extinction (e.g., in the absence of the reinforcer). We report here that extinction of a conditioned taste aversion is not retarded by partial reinforcement in terms of either consumption of the taste or hedonic reactions to it (assessed through the analysis of licking microstructure). These results are consistent with Mackintosh's analysis of the PREE and the way in which it might differ between instrumental and Pavlovian conditioning. [ABSTRACT FROM AUTHOR]

Abstract The fear conditioning paradigm is one of the most commonly used procedures to examine the etiology and treatment of anxiety disorders in laboratories. However, findings with this procedure often do not generalize to clinical settings. Virtual reality (VR) is a promising tool for improving the ecological and predictive validity of fear conditioning. The current study explored whether a classical differential cue conditioning paradigm with spider-fearful participants can be conducted in a VR-environment. Specifically, 25 spider-fearful and 25 non-fearful female students participated in a fear-conditioning experiment with a virtual spider as an unconditioned stimulus (US). The experiment took place in a virtual office in which participants viewed an avatar of themselves sitting at a desk. Conditioned stimuli (CS) were a blue (CS+; 100% reinforcement) and a green (CS-) light emitted by a desk lamp. Fear reactions were measured by fear ratings, skin conductance responses (SCR), and fear potentiated startle responses (FPS). Our results indicated stronger differential fear conditioning for spider-fearful participants than for non-fearful participants. Furthermore, we demonstrate that these results relate specifically to spider-fear, and not to general trait anxiety. We conclude that fear conditioning in VR is a promising tool to improve the validity of classical fear conditioning procedures. Highlights • Fear conditioning paradigms often lack ecological and predictive validity. • Virtual reality (VR) is a promising technology to improve the validity of fear conditioning. • Current study investigated cued fear conditioning with a VR spider. • 25 high spider-fearful and 25 low spider-fearful participants were tested. • We demonstrate successful fear conditioning, specifically for spider-fearful participants. [ABSTRACT FROM AUTHOR]

Two experiments analyzed the role of extinction cues (EC) and stimuli associated to them in the reacquisition of conditioned ethanol tolerance. Ethanol-induced ataxia was measured in 80 rat subjects using a tilting plane, in a 5-phase procedure. The first experiment (which used 4 contexts and 40 rats) showed that the presentation of the extinction context by itself diminished the effectiveness of ECs in reducing response reacquisition. The second experiment (conducted in a single context with 40 rats and using 2 stimulus paired for some subjects or explicitly unpaired for others) showed that a secondary cue can reduce reacquisition, regardless of whether it was paired with the EC or not. The results of mixed and factor analyses of variance suggest that ECs affect response recovery through an association with the extinction context; however, a second-order cue associated to an EC appears to be unable to activate this association. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory (e.g., by facilitating both destabilization and extinction) with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD. [ABSTRACT FROM AUTHOR]

Rationale: The ability to memorize threat-associated cues and subsequently react to them, exhibiting escape or avoidance responses, is an essential, often life-saving behavioral mechanism that can be experimentally studied using the fear (threat) conditioning training paradigm. Presently, there is substantial evidence supporting the Synaptic Plasticity-Memory (SPM) hypothesis in relation to the mechanisms underlying the acquisition, retention, and extinction of conditioned fear memory.Objectives: The purpose of this review article is to summarize findings supporting the SPM hypothesis in the context of conditioned fear control, applying the set of criteria and tests which were proposed as necessary to causally link lasting changes in synaptic transmission in corresponding neural circuits to fear memory acquisition and extinction with an emphasis on their pharmacological diversity.Results: The mechanisms of synaptic plasticity in fear circuits exhibit complex pharmacological profiles and satisfy all four SPM criteria—detectability, anterograde alteration, retrograde alteration, and mimicry.Conclusion: The reviewed findings, accumulated over the last two decades, provide support for both necessity and sufficiency of synaptic plasticity in fear circuits for fear memory acquisition and retention, and, in part, for fear extinction, with the latter requiring additional experimental work. [ABSTRACT FROM AUTHOR]

Rationale: Memories can return to a labile state and become amenable to modification by pharmacological and behavioral manipulations after retrieval. This process may reduce the impact of aversive memories and provide a promising therapeutic technique for the treatment of anxiety disorders. A growing body of evidence suggests that the mammalian neuropeptide oxytocin (OT) plays a role in the regulation of emotional memories in animals. However, the effects of OT on threat memory in humans remain largely unknown.Objectives: This study aimed to investigate the effects of OT administration following threat memory retrieval on subsequent memory expression in human participants.Methods: In a double-blind, randomized, placebo-controlled, between-subject design, 61 healthy human individuals completed a 3-day experiment. All the participants underwent threat conditioning on day 1. On day 2, the participants were randomized to receive an intranasal dose of OT (40 IU) or placebo after memory retrieval, or an intranasal dose of OT (40 IU) without retrieval. On day 3, the participants were tested for extinction and reinstatement.Results: On day 3, all groups showed equivalent stimulus discrimination during the early phase of extinction. However, the group that received OT following a memory reminder showed a greater decline in stimulus discrimination by the late phase of extinction relative to the two other groups.Conclusions: The results indicate that OT did not block reconsolidation to prevent the return of threat memory but rather interacted with post-retrieval processes to facilitate next day extinction. The study provides novel preliminary evidence for the role of OT in human threat memory. [ABSTRACT FROM AUTHOR]

Rationale: Females are considered more susceptible to the reinforcing effects of drugs and subsequently at increased risk for drug abuse and relapse after treatment. Estrogen is known to facilitate drug effects in females. However, other factors which contribute to the incidence of drug abuse are important to identify in order to recognize early risk factors and develop effective prevention and treatment schemes. Cue-directed behavior (aka sign tracking) has been implicated as a behavioral phenotype which identifies populations susceptible to drug abuse, partly due to its association with impulsivity and heightened dopamine function. Objectives and Methods: In this study, we investigate the viability of conditioned orienting (a form of cue-directed behavior) as a potential phenotype which predicts drug proclivity in female rats. In addition, we examine any influence endogenous female hormones across the estrous cycle may have on conditioned orienting and drug proclivity. Results and Conclusions: Utilizing an amphetamine-conditioned place preference task, results suggest that the orienting phenotype is an effective predictor of drug proclivity in females. Rats exhibiting enhanced orienting behavior show more robust preference for an amphetamine-associated context and are more resistant to extinction of this preference than nonorienting counterparts. Furthermore, both conditioned orienting behavior and conditioned place preference are minimally influenced by the estrous cycle. [ABSTRACT FROM AUTHOR]

Rationale: Many studies have found that ethanol intoxication and withdrawal impair initial acquisition or extinction of learned behaviors. Rapid reconditioning following extinction is a form of post-extinction re-emergence of conditioned behavior that has not been studied for its interaction with ethanol intoxication or withdrawal.Objectives: The goals of this paper were to define the parameters that allow rapid post-extinction reacquisition of fear in mice and investigate the effect of acute ethanol withdrawal and intoxication on acquisition, extinction, and post-extinction reconditioning.Methods: We examined acquisition, extinction, and post-extinction reconditioning of contextual fear in male C57BL/6 mice. Acute ethanol withdrawal occurred 6 h following a 4 g/kg injection of 20% ethanol and acute ethanol intoxication occurred 5 min following a 1.5 g/kg injection of 20% ethanol.Results: A weak context-shock pairing caused rapid reacquisition of conditioned freezing following moderate, but not extensive extinction. Acute ethanol intoxication impaired initial conditioning and acute ethanol withdrawal impaired rapid reacquisition after extinction, but not reconditioning or extinction itself.Conclusions: These findings show that rapid reconditioning occurs following moderate but not extensive extinction in C57BL/6J mice. Additionally, acute ethanol withdrawal and intoxication may differentially affect different phases of conditioning. Results are discussed in terms of current ideas about post-extinction behavior and ethanol's effects on memory. [ABSTRACT FROM AUTHOR]

Background: Stress is associated with cognitive and emotional dysfunction, and increases risk for a variety of psychological disorders, including depression and posttraumatic stress disorder. Prefrontal cortex is critical for executive function and emotion regulation, is a target for stress hormones, and is implicated in many stress-influenced psychological disorders. Extinction of conditioned fear provides an excellent model system for examining how stress-induced changes in corticolimbic structure and function are related to stress-induced changes in neural function and behavior, as the neural circuitry underlying this behavior is well characterized.Objectives: This review examines how acute and chronic stress influences extinction and describes how stress alters the structure and function of the medial prefrontal cortex, a potential neural substrate for these effects. In addition, we identify important unanswered questions about how stress-induced change in prefrontal cortex may mediate extinction deficits and avenues for future research.Key findings: A substantial body of work demonstrates deficits in extinction after either acute or chronic stress. A separate and substantial literature demonstrates stress-induced neuronal remodeling in medial prefrontal cortex, along with several key neurohormonal contributors to this remodeling, and there is substantial overlap in prefrontal mechanisms underlying extinction and the mechanisms implicated in stress-induced dysfunction of—and neuronal remodeling in—medial prefrontal cortex. However, data directly examining the contribution of changes in prefrontal structure and function to stress-induced extinction deficits is currently lacking.Conclusions: Understanding how stress influences extinction and its neural substrates as well as individual differences in this effect will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in extinction. [ABSTRACT FROM AUTHOR]

Background: Comorbidity of anxiety disorders, stressor- and trauma-related disorders, and substance use disorders is extremely common. Moreover, therapies that reduce pathological fear and anxiety on the one hand, and drug-seeking on the other, often prove short-lived and are susceptible to relapse. Considerable advances have been made in the study of the neurobiology of both aversive and appetitive extinction, and this work reveals shared neural circuits that contribute to both the suppression and relapse of conditioned responses associated with trauma or drug use.Objectives: The goal of this review is to identify common neural circuits and mechanisms underlying relapse across domains of addiction biology and aversive learning in preclinical animal models. We focus primarily on neural circuits engaged during the expression of relapse.Key findings: After extinction, brain circuits involving the medial prefrontal cortex and hippocampus come to regulate the expression of conditioned responses by the amygdala, bed nucleus of the stria terminalis, and nucleus accumbens. During relapse, hippocampal projections to the prefrontal cortex inhibit the retrieval of extinction memories resulting in a loss of inhibitory control over fear- and drug-associated conditional responding.Conclusions: The overlapping brain systems for both fear and drug memories may explain the co-occurrence of fear and drug-seeking behaviors. [ABSTRACT FROM AUTHOR]

The basolateral amygdala complex (BLA) and infralimbic region of the prefrontal cortex (IL) play distinct roles in the extinction of Pavlovian conditioned fear in laboratory rodents. In the past decade, research in our laboratory has examined the roles of these brain regions in the re-extinction of conditioned fear: i.e., extinction of fear that is restored through re-conditioning of the conditioned stimulus (CS) or changes in the physical and temporal context of extinction training (i.e., extinction of renewed or spontaneously recovered fear). This paper reviews this research. It has revealed two major findings. First, in contrast to the acquisition of fear extinction, which usually requires neuronal activity in the BLA but not IL, the acquisition of fear re-extinction requires neuronal activity in the IL but can occur independently of neuronal activity in the BLA. Second, the role of the IL in fear extinction is determined by the training history of the CS: i.e., if the CS was novel prior to its fear conditioning (i.e., it had not been trained), the acquisition of fear extinction does not require the IL; if, however, the prior training of the CS included a series of CS-alone exposures (e.g., if the CS had been pre-exposed), the acquisition of fear extinction was facilitated by pharmacological stimulation of the IL. Together, these results were taken to imply that a memory of CS-alone exposures is stored in the IL, survives fear conditioning of the CS, and can be retrieved and strengthened during extinction or re-extinction of that CS (regardless of whether the extinction is first- or second-learned). Hence, under these circumstances, the initial extinction of fear to the CS can be facilitated by pharmacological stimulation of the IL, and re-extinction of fear to the CS can occur in the absence of a functioning BLA. [ABSTRACT FROM AUTHOR]

Rationale: Emotionally traumatic experiences can lead to maladaptive memories that are enduring and intrusive. The goal of exposure-based therapies is to extinguish conditioned fears through repeated, unreinforced exposures to reminders of traumatic events. The extinction of conditioned fear depends upon the consolidation of new memories made during exposure to reminders. An impairment in extinction recall, observed in certain patient populations, can interfere with progress in exposure-based therapies, and the drive to avoid thoughts and reminders of the trauma can undermine compliance and increase dropout rate. Effective adjuncts to exposure-based therapies should improve the consolidation and maintenance of the extinction memory or improve the tolerability of the therapy. Under stressful conditions, the vagus nerve responds to elevations in epinephrine and signals the brain to facilitate the storage of new memories while, as part of the parasympathetic nervous system, it slows the sympathetic response.Objective: Here, we review studies relevant to fear extinction, describing the anatomical and functional characteristics of the vagus nerve and mechanisms of vagus nerve stimulation (VNS)-induced memory enhancement and plasticity.Results: We propose that stimulation of the left cervical vagus nerve during exposure to conditioned cues signals the brain to store new memories just as epinephrine or emotional arousal would do, but bypasses the peripheral sympathetic "fight-or-flight" response.Conclusions: In support of this hypothesis, we have found that VNS accelerates extinction and prevents reinstatement of conditioned fear in rats. Finally, we propose future studies targeting the optimization of stimulation parameters and the search for biomarkers of VNS effectiveness that may improve exposure therapy outcomes. [ABSTRACT FROM AUTHOR]