Stress effects on memory retrieval of aversive and appetitive instrumental counterconditioning in men.

Extinction training creates a second inhibitory memory trace and effectively reduces conditioned responding. However, acute stress inhibits the retrieval of this extinction memory trace. It is not known whether this also applies to other forms of associative learning such as instrumental counterconditioning, where previously learned associations are reversed and paired with the opposite valence. Therefore, the current preregistered study investigates whether stress decreases the retrieval of instrumental counterconditioning memories with aversive and appetitive consequences. Fifty-two healthy men were randomly assigned to either a stress or control group and took part in a two-day instrumental learning paradigm. During a first phase, participants learned that pressing specific buttons in response to the presentation of four neutral stimuli either leads to gaining or losing money. During a second phase, two stimuli reversed their contingencies (counterconditioning). One day later, participants were exposed to acute stress or a control condition prior to the same task, which no longer included feedback about gains or losses. Stressed participants showed more approach behavior towards appetitive and less avoidance behavior towards aversive stimuli as compared to non-stressed participants. Our findings indicate that stress effects on memory retrieval differ depending on the associative learning approach in men. These differences might be related to stress effects on decision making and different motivational systems involved.

The role of glucocorticoids in emotional memory reconsolidation.

Glucocorticoids are secreted following exposure to stressful events. Their modulating role on memory reconsolidation, a post-retrieval process of re-stabilization, has been investigated only recently, at times with conflicting results. The goal of this review is twofold. First, to establish the modulating role of glucocorticoids on memory reconsolidation. Second, to point the potential factors and confounds that might explain the seemingly paradoxical findings. Here we review recent pharmacological studies, conducted in rodents and humans, which suggest a critical role of glucocorticoids in this post-retrieval process. In particular, the activation of glucocorticoid receptors in the amygdala and hippocampus is suggested to be involved in emotional memories reconsolidation, pointing to a similarity between post-retrieval reconsolidation and initial memory consolidation. In addition, based on the general reconsolidation literature, we suggest several factors that might play a role in determining the direction and strength of the reconsolidation effect following glucocorticoids treatment: memory-related factors, manipulation-related factors, and individual differences. We conclude that only when taking these additional factors into account can the paradox be resolved.

Stress before extinction learning enhances and generalizes extinction memory in a predictive learning task.

In extinction learning, the individual learns that a previously acquired association (e.g. between a threat and its predictor) is no longer valid. This learning is the principle underlying many cognitive-behavioral psychotherapeutic treatments, e.g. 'exposure therapy'. However, extinction is often highly-context dependent, leading to renewal (relapse of extinguished conditioned response following context change). We have previously shown that post-extinction stress leads to a more context-dependent extinction memory in a predictive learning task. Yet as stress prior to learning can impair the integration of contextual cues, here we aim to create a more generalized extinction memory by inducing stress prior to extinction. Forty-nine men and women learned the associations between stimuli and outcomes in a predictive learning task (day 1), extinguished them shortly after an exposure to a stress/control condition (day 2), and were tested for renewal (day 3). No group differences were seen in acquisition and extinction learning, and a renewal effect was present in both groups. However, the groups differed in the strength and context-dependency of the extinction memory. Compared to the control group, the stress group showed an overall reduced recovery of responding to the extinguished stimuli, in particular in the acquisition context. These results, together with our previous findings, demonstrate that the effects of stress exposure on extinction memory depend on its timing. While post-extinction stress makes the memory more context-bound, pre-extinction stress strengthens its consolidation for the acquisition context as well, making it potentially more resistant to relapse. These results have implications for the use of glucocorticoids as extinction-enhancers in exposure therapy.

Reactivation of the Unconditioned Stimulus Inhibits the Return of Fear Independent of Cortisol.

Reconsolidation is the post-retrieval stabilization of memories, a time-limited process during which reactivated (i.e., retrieved) memories can be updated with new information, become stronger or weaker, depending on the specific treatment. We have previously shown that the stress hormone cortisol has an enhancing effect on the reconsolidation of fear memories in men. This effect was specific, i.e., limited to the conditioned stimulus (CS) that was reactivated, and did not generalize to other previously reinforced, but not reactivated CS. Based on these results, we suggested that cortisol plays a critical role in the continuous strengthening of reactivated emotional memories, contributing to their persistence and robustness. In the current study, we aimed to achieve a more generalized reconsolidation enhancement using an alternative reactivation method, i.e., by a low-intensity unconditioned stimulus (UCS) presentation instead of the more common unreinforced CS presentation. In previous studies, UCS reactivation was shown to lead to a more generalized reconsolidation effect. Therefore, we hypothesized that the combination of cortisol treatment and UCS reactivation would lead to an enhanced fear memory reconsolidation, which would generalize from previously reinforced CS to stimuli that resemble it. We tested 75 men in a 3-day fear conditioning paradigm: fear acquisition training on day 1; UCS reactivation/no reactivation and pharmacological treatment (20 mg hydrocortisone/placebo) on day 2; extinction training, reinstatement and test (of original and modified stimuli) on day 3. In contrast to our hypothesis, UCS reactivation prevented the return of fear [observed in skin conductance responses (SCR)] regardless of the pharmacological manipulation: while reinstatement to the original CS was found in the no-reactivation group, both reactivation groups (cortisol and placebo) showed no reinstatement. As the only methodological difference between our previous study and the current one was the reactivation method, we focus on UCS reactivation as the main explanation for these unexpected findings. We suggest that the robust prediction error generated by the UCS reactivation method (as opposed to CS reactivation), combined with the lower UCS intensity, has by itself weakened the emotional value of the UCS, thus preventing the return of fear to the CS that was associated with it. We call for future research to support these findings and to examine the potential of this reactivation method, or variations thereof, as a tool for therapeutic use.

How stress and glucocorticoids timing-dependently affect extinction and relapse.

In recent years, various research groups aimed to augment extinction learning (the most important underlying mechanism of exposure therapy) using glucocorticoids (GCs), in particular the stress hormone cortisol. In this review, we introduce the STaR (Stress Timing affects Relapse) model, a theoretical model of the timing-dependent effects of stress/GCs treatment on extinction and relapse. In particular, we show that (1) pre-extinction stress/GCs promote memory consolidation in a context-independent manner, making extinction memory more resistant to relapse following context change. (2) Post-extinction stress also enhances extinction consolidation, but in a context-bound manner. These differences may result from the timing-dependent effects of cortisol on emotional memory contextualization. At the neural level, extinction facilitation is reflected in alterations in the amygdala-hippocampal-prefrontal cortex network. (3) Stress/GCs before a retrieval test impair extinction retrieval and promote relapse. This may result from strengthening amygdala signaling or disruption of the inhibitory functioning of the prefrontal cortex. The STaR model can contribute to the understanding and prevention of relapse processes.

Navigating the garden of forking paths for data exclusions in fear conditioning research.

In this report, we illustrate the considerable impact of researcher degrees of freedom with respect to exclusion of participants in paradigms with a learning element. We illustrate this empirically through case examples from human fear conditioning research, in which the exclusion of 'non-learners' and 'non-responders' is common - despite a lack of consensus on how to define these groups. We illustrate the substantial heterogeneity in exclusion criteria identified in a systematic literature search and highlight the potential problems and pitfalls of different definitions through case examples based on re-analyses of existing data sets. On the basis of these studies, we propose a consensus on evidence-based rather than idiosyncratic criteria, including clear guidelines on reporting details. Taken together, we illustrate how flexibility in data collection and analysis can be avoided, which will benefit the robustness and replicability of research findings and can be expected to be applicable to other fields of research that involve a learning element.

Making translation work: Harmonizing cross-species methodology in the behavioural neuroscience of Pavlovian fear conditioning.

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.

Behavioral disruption of memory reconsolidation: From bench to bedside and back again.

During the postretrieval reconsolidation "window", memories can be disrupted, strengthened, or updated using various pharmacological and behavioral manipulations. Behavioral manipulations are more ecologically valid, thus allowing better understating of memory modification under natural conditions, but they can also be less potent compared to pharmacological interventions. In this review we present the current human and animal literature, aiming to understand the modulatory factors (i.e., task relevance, complexity, intensity) that promote reconsolidation disruption in purely behavioral means. The reviewed studies have suggested that both very simple tasks and more complex learning paradigms can be used to disrupt or update memory reconsolidation, even of stronger emotional memories. Stress exposure is a possible interference task, yet the conflicting results leave many open questions regarding its required timing and intensity. Going from bench to bedside and back again, we point to the need for more research in clinical populations to establish the therapeutic potential of reconsolidation-based treatments. Several findings from outside the laboratory offer promising leads for future research. (PsycINFO Database Record

Stress disrupts the reconsolidation of fear memories in men.

Reconsolidation is a post-retrieval process of restabilization of the memory trace. Previous findings from our group suggest that cortisol, a glucocorticoid hormone secreted in response to stress, enhances the reconsolidation of fear memories in healthy men. Cortisol effect was found to be very specific, enhancing only the fear memory that was reactivated (i.e. retrieved), but not the non-reactivated memory. In the current study we aimed to investigate the effects of psychosocial stress, a more ecologically valid intervention, on fear memory reconsolidation in men. Using a similar design, we expected stress induction to have comparable effects to those of cortisol intake. During the three testing days, the participants went through (1) fear acquisition, (2) stress induction and memory reactivation (or the corresponding control conditions), (3) fear extinction, reinstatement and reinstatement test. Salivary cortisol, blood pressure measures and subjective ratings confirmed the success of the stress induction. Skin conductance response, serving as a measure of conditioned fear, confirmed acquisition, fear retrieval, and extinction in all groups. In the three control groups (where either reactivation, stress, or both components were missing) reinstatement effects were seen as expected. Yet in contrast to the hypothesis, the target group (i.e. combining reactivation and stress) showed no reinstatement to any of the stimuli. Stress induction is thus suggested to have a general impairing effect on the reconsolidation of fear memories. The unique characteristic of the stress response and experience compared to a pharmacological intervention are proposed as possible explanations to the findings. This disruptive effect of stress on fear memory reconsolidation may have potential therapeutic implications.

Don't fear 'fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear.

The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

Cortisol effects on fear memory reconsolidation in women.

RATIONALE: Previous work from our group has shown that cortisol enhances fear reconsolidation in men. Whether similar effects can be observed in women remains an open question. OBJECTIVES: The effects of cortisol on the reconsolidation of fear memories were investigated in women. Based on results in men, we expected a specific enhancing effect of cortisol administration on the reactivated fear memory. In addition, possible interactions with oral contraceptive use were tested. METHODS: We incorporated a differential fear conditioning paradigm in a 3-day reconsolidation design. A fear memory, which was created on the first day, was reactivated on the second day following cortisol administration in the target group. One control group was given cortisol without reactivation, and the other participated in the reactivation session following placebo intake. On the third day, the return of fear for all stimuli following reinstatement was tested. Skin conductance response served as measure of conditioned response. RESULTS: In contrast to the hypothesis, cortisol in combination with reactivation did not enhance fear reconsolidation. No differences between the three experimental groups were apparent. In addition, hormonal contraceptive use had no effect on any of the learning phases and did not interact with the cortisol manipulation. CONCLUSIONS: The lack of an effect in women might be the result of alternating concentrations of sex hormones during different phases of the menstrual cycle or following oral contraceptive use. Considering the higher vulnerability of women to stress-related mental disorders, further investigations in women are of great importance for both theory and treatment.

Effects of postretrieval-extinction learning on return of contextually controlled cued fear.

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 spontaneous 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.