Metin Uengoer

Hippocampal activation during extinction learning predicts occurrence of the renewal effect in extinction recall.

The renewal effect describes the reoccurrence of a previously extinguished response in situations where the context of extinction differs from that of acquisition, thus illustrating the context-dependency of extinction learning. A number of studies on contextual fear extinction have implicated hippocampus and vmPFC in processing and retrieval of context both during extinction learning and recall of extinction. In this functional magnetic resonance imaging (fMRI) study we explored the neural correlates of the renewal effect in associative learning, using a predictive learning task that required participants to learn relations between cues and outcomes presented in particular contexts. During extinction in a novel context, compared to extinction in a context identical to the acquisition context, participants who exhibited the renewal effect (REN) showed increased activation in brain regions including bilateral posterior hippocampus and left parahippocampal gyrus. This activation pattern was absent in participants that did not show the renewal effect (NOREN). In direct comparisons between the groups, the REN group exhibited higher activation in bilateral hippocampus, while the NOREN group showed higher activation in left dlPFC (BA 46) and right anterior cingulate (BA 32). During extinction recall, stimuli that had been extinguished in a different context were again presented in the context of acquisition. Here both groups exhibited predominantly prefrontal activation, with the REN groups focus upon bilateral OFC (BA 47) and bilateral vmPFC (BA 10), while the NOREN group showed generally more widespread activation, predominantly in large clusters of dlPFC (BA 8,9,45). In a direct comparison, the REN group showed higher activation than the NOREN group in left vmPFC (BA 10), while NOREN participants exhibited more activation in dlPFC (BA 9, 46). Activation in left vmPFC during extinction recall correlated with the number of renewal effect responses, while the dlPFC activation showed a negative correlation with renewal effect responses. These results highlight the differential activation patterns of processes that will eventually produce or not produce a renewal effect, indicating that during extinction learning hippocampus encodes the relation between context and cue-outcome, while in extinction recall vmPFC is active to retrieve this association.

The informational value of contexts affects context-dependent learning

In two predictive-learning experiments, we investigated the role of the informational value of contexts for the formation of context-dependent behavior. During Phase 1 of each experiment, participants received either a conditional discrimination in which contexts were relevant (Group Relevant) or a simple discrimination in which contexts were irrelevant (Group Irrelevant). Each experiment also included an ABA renewal procedure. Participants received Z+ in context A during Phase 1, extinction of Z in context B during Phase 2, and were tested with Z in context A during a test phase. In each experiment, extinction of Z proceeded faster and was followed by stronger response recovery in Group Relevant than in Group Irrelevant. In Experiment 2, which included recording of eye-gaze behavior, dwell times on contexts were longer in Group Relevant than in Group Irrelevant. Our results support the idea that relevant contexts receive more attention, leading to stronger context specificity of learning.

Transient inactivation of the pigeon hippocampus or the nidopallium caudolaterale during extinction learning impairs extinction retrieval in an appetitive conditioning paradigm

The majority of experiments exploring context-dependent extinction learning employ Pavlovian fear conditioning in rodents. Since mechanisms of appetitive and aversive learning are known to differ at the neuronal level, we sought to investigate extinction learning in an appetitive setting. Working with pigeons, we established a within-subject ABA renewal paradigm based on Rescorla (Q J Exp Psychol 61:1793) and combined it with pharmacological interventions during extinction. From the fear conditioning literature, it is known that both prefrontal cortex and the hippocampus are core structures for context-specific extinction learning. Accordingly, we transiently inactivated the nidopallium caudolaterale (NCL, a functional analogue of mammalian prefrontal cortex) and the hippocampus in separate experiments by intracranial infusion of the sodium-channel blocker tetrodotoxin immediately before extinction training. We find that TTX in both structures non-specifically suppresses conditioned responding, as revealed by a reduction of response rate to both the extinguished conditioned stimulus and a control stimulus which remained reinforced throughout the experiment. Furthermore, TTX during extinction training impaired later extinction retrieval assessed under drug-free conditions. This was true when responding to the extinguished stimulus was assessed in the context of extinction but not when tested in the context of acquisition, although both contexts were matched with respect to their history of conditioning. These results indicate that both NCL and hippocampus are involved in extinction learning under appetitive conditions or, more specifically, in the consolidation of extinction memory, and that their contribution to extinction is context-specific.

Modulation of attention in discrimination learning: The roles of stimulus relevance and stimulus–outcome correlation

The advantage in learning after an intradimensional shift rather than an extradimensional shift has been widely used as a behavioural marker of attentional changes during discrimination learning in different fields of neuroscientific study. However, some of the factors assumed to guide these attentional changes have not been completely disentangled by previous research. In two predictive-learning experiments, we investigated the importance of stimulus relevance and of stimulus–outcome correlation for the modulation of attention. In each experiment, participants were trained on two discrimination problems given in successive order. Each problem required participants to differentiate stimuli varying on two dimensions. We found that acquisition of the second discrimination was influenced by whether its relevant dimension (Exp. 1) or its irrelevant dimension (Exp. 2) had previously been trained as relevant and uncorrelated or as irrelevant and uncorrelated. We also observed that acquisition of the second discrimination was independent of whether its relevant dimension (Exp. 1) or its irrelevant dimension (Exp. 2) had previously been trained as relevant and uncorrelated or as relevant and correlated. Our results indicated that the modulation of attention is guided by stimulus relevance and not by stimulus–outcome correlation.

The impact of context relevance during extinction learning

In two predictive-learning experiments, we investigated the role of the informational value of contexts for the formation of context-specific extinction learning. The contexts were each composed of two elements from two dimensions, A and B. In Phase 1 of each experiment, participants received acquisition training with a target cue Z in context A1B1 (the numbers assign particular values on the context dimensions). In Phase 2, participants were trained with conditional discriminations between two other cues, X and Y, for which only one of the two context dimensions was relevant. In a third phase, participants received extinction trials with cue Z in context A2B2. During a final test phase, we observed that a partial change of the extinction context disrupted extinction performance when the extinction context was changed on the dimension that had been trained as being relevant for the conditional discrimination. However, when the extinction context was changed on the irrelevant context dimension, extinction performance was not affected. Our results are consistent with the idea that relevant contexts receive more attention than do irrelevant contexts, leading to stronger context-specific processing of information learned in the former than in the latter type of contexts.

Blocking NMDA-receptors in the pigeon's "prefrontal" caudal nidopallium impairs appetitive extinction learning in a sign-tracking paradigm.

Extinction learning provides the ability to flexibly adapt to new contingencies by learning to inhibit previously acquired associations in a context-dependent manner. The neural networks underlying extinction learning were mostly studied in rodents using fear extinction paradigms. To uncover invariant properties of the neural basis of extinction learning, we employ pigeons as a model system. Since the prefrontal cortex (PFC) of mammals is a key structure for extinction learning, we assessed the role of N-methyl-D-aspartate receptors (NMDARs) in the nidopallium caudolaterale (NCL), the avian functional equivalent of mammalian PFC. Since NMDARs in PFC have been shown to be relevant for extinction learning, we locally antagonized NMDARs through 2-Amino-5-phosphonovalerianacid (APV) during extinction learning in a within-subject sign-tracking ABA-renewal paradigm. APV-injection slowed down extinction learning and in addition also caused a disinhibition of responding to a continuously reinforced control stimulus. In subsequent retrieval sessions, spontaneous recovery was increased while ABA renewal was unaffected. The effect of APV resembles that observed in studies of fear extinction with rodents, suggesting common neural substrates of extinction under both appetitive and aversive conditions and highlighting the similarity of mammalian PFC and the avian caudal nidopallium despite 300 million years of independent evolution.

An exploration of the feature-positive effect in adult humans

Experiment 1 compared the acquisition of a feature-positive and a feature-negative discrimination in humans. In the former, an outcome was signaled by two stimuli together, but not by one of these stimuli alone. In the latter, the outcome was signaled by one stimulus alone, but not by two stimuli together. Using a within-group design, the experiment revealed that the feature-positive discrimination was acquired more readily than the feature-negative discrimination. Experiment 2 tested an explanation for these results, based on the Rescorla–Wagner theory, by examining how novel discriminations, based on a combination of a feature-positive and a feature-negative discrimination, were solved. The results did not accord with predictions from the theory. Alternative explanations for the results are considered.

A reminder of extinction reduces relapse in an animal model of voluntary behavior

One experiment with rats explored whether an extinction-cue prevents the recovery of extinguished lever-pressing responses. Initially, rats were trained to perform one instrumental response (R1) for food in Context A, and a different instrumental response (R2) in Context B. Then, responses were extinguished each in the alternate context (R1 in Context B; R2 in Context A). For one group, extinction of both responses was conducted in the presence of an extinction-cue, whereas in a second group, the extinction-cue only accompanied extinction of R1. During a final test, we observed that returning the rats to the initial acquisition context renewed performance and that response recovery was attenuated in the presence of the cue that accompanied extinction of the response. The impact of the extinction-cue, however, was not transferred to the response that has been extinguished without the cue. Our results are consistent with the idea that extinction established an inhibitory cue-response association.

Attentional Bias for Uncertain Cues of Shock in Human Fear Conditioning: Evidence for Attentional Learning Theory

We conducted a human fear conditioning experiment in which three different color cues were followed by an aversive electric shock on 0, 50, and 100% of the trials, and thus induced low (L), partial (P), and high (H) shock expectancy, respectively. The cues differed with respect to the strength of their shock association (L < P < H) and the uncertainty of their prediction (L < P > H). During conditioning we measured pupil dilation and ocular fixations to index differences in the attentional processing of the cues. After conditioning, the shock-associated colors were introduced as irrelevant distracters during visual search for a shape target while shocks were no longer administered and we analyzed the cues’ potential to capture and hold overt attention automatically. Our findings suggest that fear conditioning creates an automatic attention bias for the conditioned cues that depends on their correlation with the aversive outcome. This bias was exclusively linked to the strength of the cues’ shock association for the early attentional processing of cues in the visual periphery, but additionally was influenced by the uncertainty of the shock prediction after participants fixated on the cues. These findings are in accord with attentional learning theories that formalize how associative learning shapes automatic attention.

Extinction in multiple contexts: Effects on the rate of extinction and the strength of response recovery

In two human predictive-learning experiments, we investigated the effects of extinction in multiple contexts on the rate of extinction and the strength of response recovery. In each experiment, participants initially received acquisition training with a target cue in one context, followed by extinction either in a different context (extinction in a single context) or in three different contexts (extinction in multiple contexts). The results of both experiments showed that conducting extinction in multiple contexts led to higher levels of responding during extinction than did extinction in a single context. Additionally, Experiment 2 showed that extinction in multiple contexts prevented ABC renewal but had no detectable impact on ABA renewal. Our results are discussed within the framework of contemporary learning theories of contextual control and extinction.