Propranolol attenuates the establishment of conditioned context aversions: differential effects compared to MK-801 in an animal model of anticipatory nausea and vomiting.

Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.

Contiguity and overshadowing interactions in the rapid-streaming procedure.

When multiple cues are associated with the same outcome, organisms tend to select between the cues, with one revealing greater behavioral control at the expense of the others (i.e., cue competition). However, non-human and human studies have not always observed this competition, creating a puzzling scenario in which the interaction between cues can result in competition, no interaction, or facilitation as a function of several learning parameters. In five experiments, we assessed whether temporal contiguity and overshadowing effects are reliably observed in the streamed-trial procedure, and whether there was an interaction between them. We anticipated that weakening temporal contiguity (ranging from 500 to 1,000 ms) should attenuate competition. Using within-subject designs, participants experienced independent series of rapid streams in which they had to learn the relationship between visual cues (presented either alone or with another cue) and an outcome, with the cue-outcome pairings being presented with either a delay or trace relationship. Across experiments, we observed overshadowing (Experiments 1, 2, 4, and 5) and temporal contiguity effects (Experiments 2, 3, and 4). Despite the frequent occurrence of both effects, we did not find that trace conditioning abolished competition between cues. Overall, these results suggest that the extent to which contiguity determines cue interactions depends on multiple variables, some of which we address in the General discussion.

A comparison of behavioral and pharmacological interventions to attenuate reactivated fear memories.

Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate reacquisition. In Experiment 2, memory reactivation was followed by extinction training or administration of midazolam (MDZ) (vs. vehicle) to reduce conditioned fear and attenuate spontaneous recovery. We found both treatments to be equally effective in both experiments. This study suggests that parameters leading to memory destabilization during reactivation are critical to observe long-lasting effects of MDZ or reactivation plus extinction.

Prediction error and trace dominance determine the fate of fear memories after post-training manipulations.

Different mnemonic outcomes have been observed when associative memories are reactivated by CS exposure and followed by amnestics. These outcomes include mere retrieval, destabilization-reconsolidation, a transitional period (which is insensitive to amnestics), and extinction learning. However, little is known about the interaction between initial learning conditions and these outcomes during a reinforced or nonreinforced reactivation. Here we systematically combined temporally specific memories with different reactivation parameters to observe whether these four outcomes are determined by the conditions established during training. First, we validated two training regimens with different temporal expectations about US arrival. Then, using Midazolam (MDZ) as an amnestic agent, fear memories in both learning conditions were submitted to retraining either under identical or different parameters to the original training. Destabilization (i.e., susceptibly to MDZ) occurred when reactivation was reinforced, provided the occurrence of a temporal prediction error about US arrival. In subsequent experiments, both treatments were systematically reactivated by nonreinforced context exposure of different lengths, which allowed to explore the interaction between training and reactivation lengths. These results suggest that temporal prediction error and trace dominance determine the extent to which reactivation produces the different outcomes.

Safety signals as instrumental reinforcers during free-operant avoidance.

Safety signals provide "relief" through predicting the absence of an aversive event. At issue is whether these signals also act as instrumental reinforcers. Four experiments were conducted using a free-operant lever-press avoidance paradigm in which each press avoided shock and was followed by the presentation of a 5-sec auditory safety signal. When given a choice between two levers in Experiment 1, both avoiding shock, rats preferentially responded on the lever that produced the safety signal as feedback, even when footshock was omitted. Following avoidance training with a single lever in Experiment 2, removal of the signal led to a decrease in avoidance responses and an increase in responses during the safety period normally denoted by the signal. These behavioral changes demonstrate the dual conditioned reinforcing and fear inhibiting properties of the safety signal. The associative processes that support the reinforcing properties of a safety signal were tested using a novel revaluation procedure. Prior experience of systemic morphine during safety signal presentations resulted in an increased rate of avoidance responses to produce the safety signal during a drug-free extinction test, a finding not seen with d-amphetamine in Experiment 3. Morphine revaluation of the safety signal was repeated in Experiment 4 followed by a drug-free extinction test in which responses did not produce the signal for the first 10 min of the session. Instrumental avoidance in the absence of the signal was shown to be insensitive to prior signal revaluation, suggesting that the signal reinforces free-operant avoidance behavior through a habit-like mechanism.

The error in total error reduction.

Most models of human and animal learning assume that learning is proportional to the discrepancy between a delivered outcome and the outcome predicted by all cues present during that trial (i.e., total error across a stimulus compound). This total error reduction (TER) view has been implemented in connectionist and artificial neural network models to describe the conditions under which weights between units change. Electrophysiological work has revealed that the activity of dopamine neurons is correlated with the total error signal in models of reward learning. Similar neural mechanisms presumably support fear conditioning, human contingency learning, and other types of learning. Using a computational modeling approach, we compared several TER models of associative learning to an alternative model that rejects the TER assumption in favor of local error reduction (LER), which assumes that learning about each cue is proportional to the discrepancy between the delivered outcome and the outcome predicted by that specific cue on that trial. The LER model provided a better fit to the reviewed data than the TER models. Given the superiority of the LER model with the present data sets, acceptance of TER should be tempered.

Memory destabilization is critical for the success of the reactivation-extinction procedure.

It has been suggested that, unlike pure extinction which typically results in the return of the fear response under a variety of circumstances, memory reactivation followed by extinction can attenuate the reemergence of conditioned fear. The reactivation-extinction procedure has attracted the attention of basic and clinical researchers due to its potential clinical value for the treatment of psychiatric conditions, such as anxiety and drug abuse disorders. However, mixed results have been achieved so far in replicating and understanding this paradigm. It has been proposed that memory destabilization could be critical in this sense. Using contextual fear conditioning in rats and midazolam as an amnesic agent, we first determined what reactivation conditions are necessary to destabilize the mnemonic trace. After establishing the conditions for memory destabilization, a series of experiments was conducted to determine if destabilization is critical for the success of the reactivation-extinction procedure. Data confirmed the importance of memory destabilization prior to extinction inside the reconsolidation window to attenuate spontaneous recovery and retard reacquisition of conditioned fear. The present report offers a candidate explanation of the discrepancy in results obtained with the reactivation-extinction procedure by different laboratories.

The impact of emotional valence on generalization gradients.

Generalization enables individuals to respond to novel stimuli based on previous experiences. The degree to which organisms respond is determined by their physical resemblance to the original conditioned stimulus (CS+), with a stronger response elicited by more similar stimuli, resulting in similarity-based generalization gradients. Recent research showed that cognitive or conceptual dimensions also result in gradients similar to those observed with manipulations of physical dimensions. Such findings suggest that attributes beyond physical similarity play a role in shaping generalization gradients. However, despite its adaptive relevance for survival, there is no study exploring the effectiveness of affective dimensions in shaping generalization gradients. In two experiments (135 Spanish and 150 English participants, respectively), we used an online predictive learning task, in which different stimuli (words and Gabor patches) were paired with the presence - or absence - of a fictitious shock. After training, we assessed whether valence (i.e., hedonic experience) conveyed by words shape generalization gradients. In Experiment 1, the outcome expectancy decreased monotonically with variations in valence of Spanish words, mirroring the gradient obtained with the physical dimension (line orientation). In Experiment 2, conducted with English words, a similar gradient was observed when non-trained (i.e., generalization) words varied along the valence dimension, but not when words were of neutral valence. The consistency of these findings across two different languages strengthens the reliability and validity of the affective dimension as a determinant of generalization gradients. Furthermore, our data highlight the importance of considering the role of affective features in generalization responses, advancing the interplay between emotion, language, and learning.

Category relevance attenuates overshadowing in human predictive learning.

In situations in which multiple predictors anticipate the presence or absence of an outcome, cues compete to anticipate the outcome, resulting in a loss of associative strength compared to control conditions without additional cues. Critically, there are multiple factors modulating the magnitude and direction of such competition, although in some scenarios the effect of these factors remains unexplored. We sought to assess whether the relative salience of the elements in a compound of cues modulates the magnitude of the overshadowing effect in human predictive learning. Two separable categories (i.e., colors and symbols) were used in a predictive learning task. In Experiment 1, different groups of participants were granted with different time of exposure to a compound of cues belonging to different categories (color and symbol) to evaluate potential differences in the magnitude of overshadowing. Furthermore, we used posttest questionnaires to assess whether participants used either only one or both categories during training, and assessed if this impacted the magnitude of overshadowing. In general, overshadowing was not modulated by the time of exposition, except in the case of very short time of exposition with prominent learning about the most salient category. In Experiment 2, the relative salience of a category was biased via prior experience either with a biconditional discrimination or attending only the relevant category (either color or symbol). The previously relevant category was less prone to overshadowing, but not the alternative one. Results are discussed in light of attentional and configural theories of associative learning. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Genetic and environmental influences on one-trial conditioned context aversion in mice.

Anticipatory nausea (AN) is caused by an association between contextual cues and the experience of nausea (the side effects of chemotherapy or radiation treatment) and it develops predominantly in female patients undergoing chemotherapy. Preclinical studies in rodents show that the administration of an illness-inducing agent in the presence of novel contextual cues can cause conditioned context aversion (CCA) and this has been proposed to model AN. The literature also suggests that brief pre-exposure to a novel context prior to shock delivery is critical in the development of contextual fear conditioning in rodents (a phenomenon known as Immediate Shock Deficit), but this has not been assessed in CCA. The aim of present study was to develop a CCA paradigm to assess this in outbred (CD1) and inbred (C57BL/6J) mice and evaluate potential sex differences. The results revealed that a single conditioning trial in which a distinctive context was paired with LiCl-induced illness was sufficient to elicit a conditioned response in both female and male CD1 outbred mice, but not in C57BL/6J inbred mice. In addition, CCA was facilitated when animals had prior experience with the context. Finally, outbred female mice showed longer and more robust retention of CCA than male mice, which parallels clinical findings. The results indicate the importance of using CD1 outbred mice as an animal model of AN as well as examining sex differences in the CCA paradigm. Similar findings in humans encourage the future use of this novel CCA preclinical mouse model.

The effects of goal-landmark distance on overshadowing: A replication in humans (Homo sapiens) of Goodyear and Kamil (2004).

Goodyear and Kamil (2004) assessed the ability of Clark's nutcrackers to find buried food based on a cross-shaped array of landmarks at different distances from the goal. Their findings suggested that proximal landmarks overshadowed learning about distal landmarks, and this was attenuated when assessing the effect of distal landmarks on learning about proximal landmarks. In this study, we aimed to replicate their findings in human spatial navigation by using a virtual environment. Three groups of participants were trained in an open environment featuring orientation cues, and they had to find a hidden goal with reference to four landmarks that were arranged in the shape of a cross and placed at different distances from the goal. Two of the four landmark distances were common across all three groups to allow a comparison of the extent of overshadowing under comparable conditions. Following training, all participants were tested with each of the four landmarks individually. Consistent with the results in birds, we observed better performance in the groups with more distal landmarks, suggesting that overshadowing was greater in the groups with closer landmarks and thus dependent on the spatial distance between the landmarks and the goal. Landmarks near the goal more effectively overshadowed landmarks far from the goal. A second experiment, in which landmarks and orientation cues were misaligned in order to prevent the use of a straightforward solution to the task, replicated the results. The results are discussed in terms of a modification of Pearce's configural model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Further evidence for the role of temporal contiguity as a determinant of overshadowing.

Three experiments explored whether weakening temporal contiguity between auditory cues and an aversive outcome attenuated cue competition in an avoidance learning task with human participants. Overall, with strong temporal contiguity between auditory cues and the outcome during training (the offset of the predictive auditory signals concurred with the onset of the outcome), the target cue trained as part of a compound yielded less avoidance behaviour than the control cue trained alone, an instance of overshadowing. However, weakening temporal contiguity during training (inserting a 5-s trace) attenuated overshadowing, resulting in similar avoidance behaviour in response to the control and target cues. These results provide evidence that, as predicted by a recent modification of Pearce's configural theory, temporal contiguity is critical for determining cue competition.

Social overshadowing: Revisiting cue-competition in social interactions.

In a large variety of contexts, it is essential to use the available information to extract patterns and behave accordingly. When it comes to social interactions for instance, the information gathered about interaction partners across multiple encounters (e.g., trustworthiness) is crucial in guiding one's own behavior (e.g., approach the trustworthy and avoid the untrustworthy), a process akin to trial-by-trial learning. Building on associative learning and social cognition literatures, the present research adopts a domain-general approach to learning and explores whether the principles underlying associative learning also govern learning in social contexts. In particular, we examined whether overshadowing, a well-established cue-competition phenomenon, impacts learning of the cooperative behaviors of unfamiliar interaction partners. Across three experiments using an adaptation of the iterated Trust Game, we consistently observed a 'social overshadowing' effect, that is, a better learning about the cooperative tendencies of partners presented alone compared to those presented in a pair. This robust effect was not modulated by gender stereotypes or beliefs about the internal communication dynamics within a pair of partners. Drawing on these results, we argue that examining domain-general learning processes in social contexts is a useful approach to understanding human social cognition.

Conditioned place avoidance in the planaria Schmidtea mediterranea: A pre-clinical invertebrate model of anxiety-related disorders.

The objective of the present study was to develop a model of avoidance learning and its extinction in planarians (Schmidtea mediterranea). Based on previous experiments showing conditioned place preference, we developed a procedure to investigate conditioned place avoidance (CPA) using shock as an unconditioned stimulus (US) and an automated tracking system to record the animals' behaviour. In Experiment 1, we assessed the unconditioned properties of different shock intensities by measuring post shock activity. In two subsequent experiments we investigated CPA using different designs, surfaces as conditioned stimuli (CSs; rough and smooth), and different US intensities (5 V and 10 V). In general, we observed the successful development of CPA. However, CPA was stronger with higher shock intensities, and we found that, in our preparation, a rough surface is best at entering into an association with the shock than a smooth surface. Finally, we also observed extinction of CPA. The evidence of CPA and its extinction in flatworms validates the planaria as a pre-clinical model for the study of avoidance learning, a hallmark of anxiety disorders.

Temporal contiguity determines overshadowing and potentiation of human Action-Outcome performance.

Three experiments (n = 81, n = 81, n = 82, respectively) explored how temporal contiguity influences Action-Outcome learning, assessing whether an intervening signal competed, facilitated, or had no effect on performance and causal attribution in undergraduate participants. Across experiments, we observed competition and facilitation as a function of the temporal contiguity between Action and Outcome. When there was a strong temporal relationship between Action and Outcome, the signal competed with the action, hindering instrumental performance but not causal attribution (Experiments 1 and 3). However, with weak temporal contiguity, the same signal facilitated both instrumental performance and causal attribution (Experiments 1 and 2). Finally, the physical intensity of the signal determined the magnitude of competition. As anticipated by associative learning models, a more salient signal attenuated to a greater extent instrumental performance (Experiment 3). These results are discussed by reference to a recent adaptation of the configural theory of learning.

The dual role of the context in postpeak performance decrements resulting from extended training.

The context's role in Pavlovian conditioning depends on the trial spacing during training, with massed trials revealing a function akin to that of discrete stimuli, and spaced trials revealing a modulatory function (Urcelay & Miller, Journal of Experimental Psychology. Animal Behavior Processes, 36, 268-280, 2010). Here we examined the contextual determinants of a common but largely ignored effect: attenuated conditioned responding with extended reinforced training (i.e., a postpeak performance deficit [PPD]). Contextual sources of PPDs were investigated in four fear-conditioning experiments with rats. In Experiment 1, as the number of reinforced trials increased, conditioned responding decreased, even when testing occurred outside the training context. Experiment 2 revealed opposing influences of context on the PPD based on trial spacing, which interacted with whether testing occurred in the training context. This finding reconciles Experiment 1's results with previous data (Bouton, Frohardt, Sunsay, Waddell, & Morris, Journal of Experimental Psychology. Animal Behavior Processes, 34, 223-236, 2008). Experiment 3 suggested that extended training with these parameters did not lead to habituation to conditioned or unconditioned stimuli. In Experiment 4, few or many massed training trials were followed orthogonally by context extinction or no context extinction. After many pairings, context extinction reduced the PPD (i.e., enhanced responding), suggesting a competitive role of the context. These results, together with prior data suggesting that context modulates expressions of the PPD, are consistent with the view that contexts can play two distinctly different roles.

Signal detection analysis of contingency assessment: Associative interference and nonreinforcement impact cue-outcome contingency sensitivity, whereas cue density affects bias.

In a signal detection theory approach to associative learning, the perceived (i.e., subjective) contingency between a cue and an outcome is a random variable drawn from a Gaussian distribution. At the end of the sequence, participants report a positive cue-outcome contingency provided the subjective contingency is above some threshold. Some researchers have suggested that the mean of the subjective contingency distributions and the threshold are controlled by different variables. The present data provide empirical support for this claim. In three experiments, participants were exposed to rapid streams of trials at the end of which they had to indicate whether a target outcome O1 was more likely following a target cue X. Interfering treatments were incorporated in some streams to impend participants' ability to identify the objective X-O1 contingency: interference trials (X was paired with an irrelevant outcome O2), nonreinforced trials (X was presented alone), plus control trials (an irrelevant cue W was paired with O2). Overall, both interference and nonreinforced trials impaired participants' sensitivity to the contingencies as measured by signal detection theory's d', but they also enhanced detection of positive contingencies through a cue density effect, with nonreinforced trials being more susceptible to this effect than interference trials. These results are explicable if one assumes interference and nonreinforced trials impact the mean of the associative strength distribution, while the cue density influences the threshold. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Fear memory modulation by incentive down and up-shifts.

Research on retrieval-induced malleability of maladaptive emotional memories has been mostly focused on the effect of drugs and extinction (i.e. post-retrieval extinction). Only a few studies addressed post-retrieval appetitive-aversive interactions. Due to the relevance that the understanding of the interactions between memory content and appetitive or aversive states under retrieval circumstances has for translational research, here we explored the relation between fear (i.e. contextual fear conditioning) and sucrose concentration down (32-4%) or up-shifts (4-32%). These have been reported as methods to induce aversive or appetitive internal states, respectively. We observed that fear expression is differentially susceptible to incentive contrast manipulations depending on the memory stage: acquisition, mere retrieval or retrieval-induced memory malleability. After fear acquisition, freezing behavior and incentive shift direction followed an inverse relation, that is: up-shift decreased fear responding and down-shift increased it. However, freezing behavior remained unaltered when incentive contrast was absent, regardless of the sucrose concentration employed (4-4% and 32-32%). When incentive shifts occurred after mere-retrieval, both negative and positive incentive shifts resulted in increased freezing behavior. Strikingly, this effect was unrelated to the nature of the incentive contrast (either positive or negative), occurring only when animals had no previous experience with the shifted solution. On the other hand, when fear retrieval led to memory malleability, up-shifts in sucrose concentration dampened freezing behavior as much as unshifted controls, whilst down-shift left freezing unaltered. Freezing facilitation was finally achieved after retrieval-induced memory malleability only after prior sampling of the down-shifted solution (i.e. 4% SUC). These results reveal a complex pattern of interactions between memory retrieval and incentive shift-induced internal states.

Temporal and spatial contiguity are necessary for competition between events.

Over the last 50 years, cue competition phenomena have shaped theoretical developments in animal and human learning. However, recent failures to observe competition effects in standard conditioning procedures, as well as the lengthy and ongoing debate surrounding cue competition in the spatial learning literature, have cast doubts on the generality of these phenomena. In the present study, we manipulated temporal contiguity between simultaneously trained predictors and outcomes (Experiments 1-4), and spatial contiguity between landmarks and goals in spatial learning (Supplemental Experiments 1 and 2; Experiment 5). Across different parametric variations, we observed overshadowing when temporal and spatial contiguity were strong, but no overshadowing when contiguity was weak. Thus, across temporal and spatial domains, we observed that contiguity is necessary for competition to occur, and that competition between cues presented simultaneously during learning is absent when these cues were either spatially or temporally discontiguous from the outcome. Consequently, we advance a model in which the contiguity between events is accounted for and which explains these results and reconciles the previously contradictory findings observed in spatial learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Nicotine chronic tolerance development and withdrawal in the planaria (Schmidtea mediterranea).

Chronic nicotine exposure reduces sensitivity to the effects of nicotine, which then results in behavioural changes and tolerance development. In the planaria, a valuable first-stage preclinical model for addictive behaviour, acute nicotine administration has been shown to steadily alter the motility of the animals, a result that has been interpreted as evidence of tolerance and withdrawal effects; however, chronic exposure - typically regarded as a condition for the development of tolerance - and the role of the contextual cues have not been systematically assessed. The present study assessed the acute and chronic effects of nicotine on the motility of planarians (Schmidtea mediterranea). The animals in the experimental groups received long chronic exposure to nicotine (ten daily 30 min exposures); a control group was exposed to water in the same context but in the absence of the drug. The motility of the animals was closely monitored on every exposure. Following this phase, all the animals were subject to three different tests: in the presence of the exposure context (without the drug, Test 1); in the presence of nicotine in the exposure context (Test 2); and in the presence of the drug in a novel context (Test 3). Exposure to nicotine consistently reduced motility; the motility in the presence of nicotine increased with repeated exposures to the drug, an instance of tolerance development. Tolerance development was dependent on nicotinic receptor activation, because it was blocked by the co-administration of mecamylamine. However, this tolerance was found to be independent of the contextual cues where the effects of the drug had been experienced. The results are discussed by reference to the existent theories of tolerance development to drugs.