Context reexposure to bolster contextual dependency of emotional episodic memory.

Contextual overgeneralization of emotional memory is a core aspect of anxiety disorders. Identifying methods to enhance contextual dependency of emotional memory is therefore of significant clinical interest. Animal research points to a promising approach: reexposure to the context in which fear is acquired reduces generalization to other contexts. However, the exact conditions for this effect are unknown, complicating translation to effective interventions. Most notably, exposure to a context that resembles-but is not identical to-the learning context may diminish contextual dependency of memory by integration of additional contextual cues. Here, we therefore assessed in a large-scale study (N = 180) whether context reexposure enhances contextual dependency of emotional episodic memory whereas exposure to a similar context impairs it. We also tested whether relatively strong memory retrieval during context (re)exposure amplifies these effects. We replicated prior research showing that correct recognition depends on context and contextual dependency is lower for emotional than neutral memories. However, exposure to the encoding context or a similar context did not affect contextual dependency of memory, and retrieval strength did not interact with such effects. Thorough insight into factors underlying the effects of context (re)exposure on contextual dependency seems key to eventually attain a memory recontextualization intervention.

Renewal of conditioned fear responses using a film clip as the aversive unconditioned stimulus.

BACKGROUND AND OBJECTIVES: Pavlovian fear conditioning paradigms are valuable to investigate fear learning and the return of extinguished fear in the lab. However, their validity is limited, because the aversive stimuli (e.g., electric shocks) typically lack the modalities and complexity of real-world aversive experiences. To overcome this limitation, we examined fear acquisition, extinction and contextual renewal using an audiovisual unconditioned stimulus (US). METHOD: On day 1, 50 healthy participants completed an acquisition phase in a specific context (i.e., desk or bookcase, 'context A'). Pictures of colored lamps served as conditioned stimuli and an aversive film clip was used as US. On day 2, extinction took place in the same context ('context A') or in a different context ('context B'). Afterwards, renewal was tested in the acquisition context (AAA vs. ABA design). RESULTS: As hypothesized, fear acquisition and extinction, as measured by US expectancy ratings, fear potentiated startle (FPS), and skin conductance responses (SCRs), were successful. Most importantly, conditioned responding was renewed on all measures in the ABA condition, but not in the AAA condition. Differential renewal (i.e., larger renewal for CS + than for CS-) was only observed for US expectancy ratings. LIMITATIONS: The return of conditioned responses was non-differential for FPS and SCR. CONCLUSIONS: The current set-up enables investigation of fear renewal using an audiovisual US. Future studies can utilize this paradigm to investigate interventions that aim to reduce fear renewal by modifying the US memory, such as Eye Movement Desensitization and Reprocessing and imagery rescripting.

Noradrenergic and dopaminergic involvement in novelty modulation of aversive memory generalization of adult rats.

The generalization of aversive memory can be defined as the phenomenon in which a situation similar to (but distinctive from) a previous aversive event triggers an avoidance response. This phenomenon has been suggested to play a role in several psychological disorders. In this study, we investigate the effects of novelty on the generalization of fear memories, and the involvement of noradrenergic and dopaminergic systems in this process. For this study we used male Wistar rats (3 months old, 300-400 g). The participation of each neurotransmitter system was evaluated separately (two set of experiments). In each experimental set, the animals were divided in groups (8 animals each): (i) control, (ii) novelty, and, (iii) antagonist + novelty group (timolol, a ß-adrenergic antagonist, or SCH23390, a D1/D5 dopaminergic antagonist, in the first and in the second set of experiments, respectively). Additionaly, to investigate whether novelty exposure increases the levels of noradrenaline and/or dopamine in the hippocampus fifteen animals were divided in three groups (5 animals each).: (i) naïve, (ii) control; and, (iii) novelty. To examine aversive memory, and generalization of aversive memory, we trained adult male Wistar rats in an inhibitory avoidance (IA) memory task and after in a modified inhibitory avoidance (MIA). Before the MIA training some of the animals were exposed to environmental novelty (open field). Immediately before this novelty exposure, some animals received intrahippocampal infusion of timolol (ß-adrenergic antagonist), SCH23390 (D1/D5 antagonist) or vehicle to evaluate the involvement of noradrenergic and dopaminergic systems. Finally, to evaluate aversive memory and generalization of aversive memory respectively, half of the animals in each group were tested on IA and half on MIA. We confirmed that the exposure to novelty blocks the generalization of aversive memory, but moreover, demonstrated that this process involves activation of ß-adrenergic and dopaminergic D1/D5 pathways. We additionally observed that exposure to novelty raises hippocampal levels of noradrenaline and dopamine. This suggests that these neurotransmitters not only influence long-term memory (LTM) as such, but also aversive memory generalization.

Generalisation of threat expectancy increases with time.

Excessive fear generalisation is a feature characteristic of clinical anxiety and has been linked to its aetiology. Previous animal studies have shown that the mere passage of time increases fear generalisation and that brief exposure to training cues prior to long-term testing reverses this effect. The current study examined these phenomena in humans. Healthy participants learned the relationship between the presentation of a picture of a neutral male face and the delivery of a mild shock. One group was immediately tested with a novel picture of a somewhat different male face (generalisation test). Another group was tested one week later. A third group was also tested one week later and was additionally exposed to the training picture prior to testing. During picture presentations, shock-expectancy ratings were obtained as a measure of fear. Fear generalisation increased from the immediate test to the 1-week follow-up test. This result could not be attributed to level of neuroticism or a general increase in fear (incubation). Furthermore, the time-dependent increase in fear generalisation vanished following brief exposure to the training picture. Results indicate that human fear generalisation is a temporally dynamic process and that memory for stimulus details can be re-established following a reminder treatment.

Novelty exposure hinders aversive memory generalization and depends on hippocampal protein synthesis.

Fear generalization is defined as the transferring of fear experienced during a traumatic event to safe conditions resembling or not the traumatic event. It has been related to several psychological disorders. Here we set out to determine whether novelty exposure can be effective to avoid fear generalization. We evaluated the effect of a novelty exposure on fear memory generalization using an aversive memory task, the inhibitory avoidance (IA). Male Wistar rats were trained in IA (day 1) and 24 h after (day 2) they were exposed to a new context similar to the original (modified IA - MIA), with some rats being exposed to a novelty just before the exposure to the MIA, while others were not (controls). On day 3, retention tests for IA and MIA contexts were performed. The control rats generalized the memory, expressing aversive behavioral in both contexts whereas rats exposed to novelty only expressed aversion on IA. Furthermore, both anisomycin, an inhibitor of ribosomal protein synthesis, and rapamycin, an inhibitor of mTOR-mediated protein synthesis, injected in the CA1 region of dorsal hippocampus blocked the novelty effect, promoting memory generalization. We conclude that novelty exposure hinders aversive memory generalization depending on hippocampal protein synthesis.

A review on the effects of verbal instructions in human fear conditioning: Empirical findings, theoretical considerations, and future directions.

Fear learning reflects the adaptive ability to learn to anticipate aversive events and to display preparatory fear reactions based on prior experiences. Usually, these learning experiences are modeled in the lab with pairings between a neutral conditioned stimulus (CS) and an aversive unconditioned stimulus (US) (i.e., fear conditioning via CS-US pairings). Nevertheless, for humans, fear learning can also be based on verbal instructions. In this review, we consider the role of verbal instructions in laboratory fear learning. Specifically, we consider both the effects of verbal instructions on fear responses in the absence of CS-US pairings as well as the way in which verbal instructions moderate fear established via CS-US pairings. We first focus on the available empirical findings about both types of effects. More specifically, we consider how these effects are moderated by elements of the fear conditioning procedure (i.e., the stimuli, the outcome measures, the relationship between the stimuli, the participants, and the broader context). Thereafter, we discuss how well different mental-process models of fear learning account for these empirical findings. Finally, we conclude the review with a discussion of open questions and opportunities for future research.

A translational perspective on neural circuits of fear extinction: Current promises and challenges.

Fear extinction is the well-known process of fear reduction through repeated re-exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state-of-the-art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub-cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit are largely dependent on the methods employed, not only across species, but also across human neuroimaging studies. Directions for future research are discussed.

Prevention and treatment strategies for contextual overgeneralization.

At the core of anxiety disorders lies the tendency to generalize fear from a threatening to a safe situation. A deeper understanding of the mechanisms that facilitate and restrain generalization in humans is therefore needed. Rodent studies showed that pre-exposure to a context that is similar to the threatening context enhanced generalization to the similar context. In Experiment 1 we replicated these animal findings in humans (US-expectancy). Studies on the underlying mechanisms showed that the pre-exposure representation was recalled during conditioning (due to similarity between the contexts) and the shock also became linked to the recalled representation, resulting in greater generalization. In Experiment 2 we developed a pre-exposure procedure that increased the ability to distinguish between the conditioned and pre-exposure contexts, such that presentation of the former would no longer result in recall of the latter. We then observed that overgeneralization (US-expectancy) was prevented. Pre-exposure did not affect generalization of skin conductance response or fear potentiated startle. Finally, exploratory analyses revealed that increased generalization (US-expectancy), if not prevented, could be reduced by a reminder of the conditioned context. Hence, we developed a prevention- and a treatment-strategy for overgeneralization. These findings may guide the development of new therapeutic strategies.

Disrupting reconsolidation of fear memory in humans by a noradrenergic ß-blocker.

The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a ß-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders.

Prediction error demarcates the transition from retrieval, to reconsolidation, to new learning.

Although disrupting reconsolidation is promising in targeting emotional memories, the conditions under which memory becomes labile are still unclear. The current study showed that post-retrieval changes in expectancy as an index for prediction error may serve as a read-out for the underlying processes engaged by memory reactivation. Minor environmental changes define whether retrieval induces memory reconsolidation or the initiation of a new memory trace even before fear extinction can be observed.

Fear conditioning of SCR but not the startle reflex requires conscious discrimination of threat and safety.

There is conflicting evidence as to whether awareness is required for conditioning of the skin conductance response (SCR). Recently, Schultz and Helmstetter (2010) reported SCR conditioning in contingency unaware participants by using difficult to discriminate stimuli. These findings are in stark contrast with other observations in human fear conditioning research, showing that SCR predominantly reflects contingency learning. Therefore, we repeated the study by Schultz and Helmstetter and additionally measured conditioning of the startle response, which seems to be less sensitive to declarative knowledge than SCR. While we solely observed SCR conditioning in participants who reported awareness of the contingencies (n = 16) and not in the unaware participants (n = 18), we observed startle conditioning irrespective of awareness. We conclude that SCR but not startle conditioning depends on conscious discriminative fear learning.

Prediction error governs pharmacologically induced amnesia for learned fear.

Although reconsolidation opens up new avenues to erase excessive fear memory, subtle boundary conditions put constraints on retrieval-induced plasticity. Reconsolidation may only take place when memory reactivation involves an experience that engages new learning (prediction error). Thus far, it has not been possible to determine the optimal degree of novelty required for destabilizing the memory. The occurrence of prediction error could only be inferred from the observation of a reconsolidation process itself. Here, we provide a noninvasive index of memory destabilization that is independent from the occurrence of reconsolidation. Using this index, we show in humans that prediction error is (i) a necessary condition for reconsolidation of associative fear memory and (ii) determined by the interaction between original learning and retrieval. Insight into the process of memory updating is crucial for understanding the optimal and boundary conditions on reconsolidation and provides a clear guide for the development of reconsolidation-based treatments.

Instructed extinction differentially affects the emotional and cognitive expression of associative fear memory.

Instructed extinction after fear conditioning is relatively effective in attenuating electrodermal responding. Testing the single-process account of fear learning, we examined whether this manipulation similarly affects the startle response. Skin conductance responses (SCRs), startle responses, and online unconditioned stimulus (US) expectancy ratings were measured during fear acquisition (Day 1), extinction, and reinstatement (Day 2). Before extinction onset, half of the subjects were instructed that the conditioned stimulus would not be followed by the US (Instructed Extinction) whereas the other subjects were not instructed (Normal Extinction). This simple instruction completely abolished both differential SCR and US expectancy ratings, but not the startle fear response. Although the manipulation facilitated extinction learning, it did not prevent the recovery of the startle response. The present findings are better explained by a dual- rather than a single-process account of fear learning.

Retrieval per se is not sufficient to trigger reconsolidation of human fear memory.

Ample evidence suggests that consolidated memories, upon their retrieval, enter a labile state, in which they might be susceptible to change. It has been proposed that memory labilization allows for the integration of relevant information in the established memory trace (memory updating). Memory labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned during memory retrieval (prediction error). Thus, updating of a fear memory trace should not occur under retrieval conditions in which the outcome is fully predictable (no prediction error). Here, we addressed this issue, using a human differential fear conditioning procedure, by eliminating the very possibility of reinforcement of the reminder cue. A previously established fear memory (picture-shock pairings) was reactivated with shock-electrodes attached (Propranolol group, n=18) or unattached (Propranolol No-Shock Expectation group, n=19). We additionally tested a placebo-control group with the shock-electrodes attached (Placebo group, n=18). Reconsolidation was not triggered when nothing could be learned during the reminder trial, as noradrenergic blockade did not affect expression of the fear memory 24h later in the Propranolol No-Shock Expectation group. Only when the outcome of the retrieval cue was not fully predictable, propranolol, contrary to placebo, reduced the startle fear response and prevented the return of fear (reinstatement) the following day. In line with previous studies, skin conductance response and shock expectancies were not affected by propranolol. Remarkably, a double dissociation emerged between the emotional (startle response) and more cognitive expression (expectancies, SCR) of the fear memory. Our findings have important implications for reconsolidation blockade as treatment strategy for emotional disorders. First, fear reducing procedures that target the emotional component of fear memory do not necessarily affect the cognitive component and vice versa. Second, mere retrieval of the fear memory is not sufficient to induce its labilization and reconsolidation.