Blockade of NMDA receptors in the amygdala prevents latent inhibition of fear-conditioning

The association between a conditioned stimulus (CS) and an unconditioned stimulus (US) in fear-conditioning depends on N-methyl-D-aspartate (NMDA) receptors in the basolateral amygdala complex (BLA). Latent inhibition (LI) is the retardation in learning due to nonreinforced presentation of the prospective CS before conditioning. Disruption of LI in rats is an animal model of schizophrenia, reflecting the deficits of schizophrenic patients in neglecting irrelevant information. We investigated whether the BLA is involved in LI of fear-potentiated startle. Infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5; 12.5 nmoles) into the BLA before preexposure of rats to the neutral stimulus prevent LI of fear-conditioning. We also demonstrated by the same method that a complex of thalamic nuclei, comprising the medial part of the medial geniculate nucleus, the posterior intralaminar nucleus, and the suprageniculate nucleus, is involved in fear-conditioning, but not in LI. This suggests that the presentation of an innocuous stimulus during preexposure leads to an NMDA receptor-dependent change of neurotransmission in the BLA, but not in the thalamus. Our data show that the BLA but not the thalamus regulates in LI of fear-potentiated startle. Furthermore, it supports the hypothesis that the inability of schizophrenic patients to ignore irrelevant stimuli may be caused by hypofunction of the glutamatergic transmission in the brain and suggests an involvement of the amygdala in the neuropathology of schizophrenia.     

Human latent inhibition: Problems with the stimulus exposure effect

Latent inhibition (LI) is a startlingly simple effect in which preexposure of a stimulus without consequence retards subsequent responding to a stimulus–consequence relation. The effect was first demonstrated with Pavlovian conditioning in animals and was later suggested to be a marker of human psychopathology such as schizophrenia. Individual differences in LI has supported the continued use of animal models to understand human mental health. In this review, we ask whether there is sufficient evidence to support the continued application of LI from animal models to human psychopathology because of the weak evidence for LI in humans. There is considerable variability in the methods used to assess LI, sustaining different theoretical accounts of the effects observed, which differ from the accepted accounts of LI as demonstrated in animals. The review shows that although there have been many experiments testing human LI, none provide the necessary experimental controls to support the conclusion that retarded responding is caused simply by preexposure to a stimulus, as has been demonstrated with animal models. Establishing this conflict, we set out a framework for future research.     

Contextual Control of Latent Inhibition by the Reinforcer

Three experiments examined the contextual control of latent inhibition (LI) by the unconditioned stimulus (US) using a within-subjects conditioned suppression procedure with rats. The effect of reducing the context change produced by the introduction of the shock US was investigated by presenting this US during preexposure to the conditioned stimulus (CS). Although limited CS preexposure in the absence of the US had no impact on subsequent conditioning, preexposure in the presence of the shock retarded both excitatory and inhibitory conditioning. We conclude that the introduction of the US during the conditioning phase of a normal LI experiment can produce a contextual change that reduces the observed magnitude of LI.     

A Comparison of Latent Inhibition and Learned Irrelevance Pre-Exposure Effects in Rabbit and Human Eyeblink Conditioning

The learning of an association between a CS and a US can be retarded by unreinforced presentations of the CS alone (termed latent inhibition or LI) or by un-correlated presentations of the CS and US (termed learned irrelevance or LIRR). In rabbit eyeblink conditioning, there have been some recent failures to replicate LI. LIRR has been hypothesized as producing a stronger retardation effect than LI based on both empirical studies and computational models. In the work presented here, we examined the relative strength of LI and LIRR in eyeblink conditioning in rabbits and humans. In both species, a number of preexposure trials sufficient to produce LIRR failed to produce LI (Experiments 1 & 3). Doubling the number of CS pre-exposures did produce LI in rabbits (Experiment 2), but not in humans (Experiment 4). LI was demonstrated in humans only after manipulations including an increased inter-trial interval or ITI (Experiment 5). Overall, it appears that LIRR is a more easily producible pre-exposure retardation effect than LI for eyeblink conditioning in both rabbits and humans. Several theoretical mechanisms for LI including the conditioned attention theory, stimulus compression, novelty, and the switching theory are discussed as possible explanations for the differences between LIRR and LI. Overall, future work involving testing the neural substrates of pre-exposure effects may benefit from the use of LIRR rather than LI.     

A comparison of latent inhibition and learned irrelevance pre-exposure effects in rabbit and human eyeblink conditioning

The learning of an association between a CS and a US can be retarded by unreinforced presentations of the CS alone (termed latent inhibition or LI) or by un-correlated presentations of the CS and US (termed learned irrelevance or LIRR). In rabbit eyeblink conditioning, there have been some recent failures to replicate LI. LIRR has been hypothesized as producing a stronger retardation effect than LI based on both empirical studies and computational models. In the work presented here, we examined the relative strength of LI and LIRR in eyeblink conditioning in rabbits and humans. In both species, a number of pre-exposure trials sufficient to produce LIRR failed to produce LI (Experiments 1 & 3). Doubling the number of CS pre-exposures did produce LI in rabbits (Experiment 2), but not in humans (Experiment 4). LI was demonstrated in humans only after manipulations including an increased inter-trial interval or ITI (Experiment 5). Overall, it appears that LIRR is a more easily producible pre-exposure retardation effect than LI for eyeblink conditioning in both rabbits and humans. Several theoretical mechanisms for LI including the conditioned attention theory, stimulus compression, novelty, and the switching theory are discussed as possible explanations for the differences between LIRR and LI. Overall, future work involving testing the neural substrates of pre-exposure effects may benefit from the use of LIRR rather than LI.     

The resistance of renewal to instructions that devalue the role of contextual cues in a conditioned suppression task with humans

The renewal of extinguished conditioned behaviour appears to reflect context-dependent learning. The present research used a conditioned suppression task with humans to examine whether instructions concerning the context could influence renewal. Pairings of a conditional stimulus (CS) and unconditional stimulus (US) were made in one context, followed by extinction trials of CS alone in a second context, and test trials of CS alone upon return to the original learning context. Four experiments tested whether the renewal of conditioned suppression observed during test would be attenuated if participants were instructed that the context changes were irrelevant to the predictive relationship between the CS and US. Using a differential conditioning design, no attenuation was found when the instructions were given prior to conditioning (Experiment 1) or immediately prior to the test trials (Experiment 2). The latter result was replicated with a single-cue conditioning design and further controls for exposure to the extinction contexts (Experiment 3). The collection of on-line ratings about the relationship between the contextual changes and the predictive nature of the CS indicated that participants did attend to and believe the instructions (Experiment 4). The results point to the resistance of renewal to explicit instructions that attempt to devalue the role of the contextual cues.     

Timed excitatory conditioning under zero and negative contingencies

Rats (rattus norvegicus) anticipated the arrival of a food pellet unconditioned stimulus (US) even when the conditioned stimulus (CS) signaled no overall change or a substantial decrease in the overall rate of US occurrence. Pellet USs were scheduled probabilistically in the intertrial interval at either an equivalent rate (Experiment 1) or a four times higher rate (Experiments 2 and 3) than in the CS, which included one fixed-time target US. Conditioning has been said to involve learning "whether" (contingency) the CS signals a change in the US, and if so, "when" (contiguity) the US is scheduled to arrive. Our results suggest that "when" trumps "whether," challenging the received view that a positive CS-US contingency is necessary for successful conditioning.     

A new tool for assessing context conditioning induced by US-unpredictability in humans: The Martians task restyled

Unpredictability of an unconditioned stimulus (US) typically produces context conditioning in animals and humans. We modified the Martians task - a computer game measuring learning of Pavlovian associations through conditioned suppression - for assessing context conditioning in humans. One between-subjects and one within-subjects study are reported. Both experiments comprised four conditions: a predictable (Paired) condition in which the conditioned stimulus (CS) signaled the US, a neutral condition (No-US), one unpredictable condition in which the CS did not signal the US (Unpaired) and another one in which only unsignaled, temporally unpredictable USs were presented (US-only). Results showed more contextual conditioned suppression in the unpredictable conditions compared to the predictable condition. In contrast, more cued conditioned suppression occurred in the Paired condition than in the Unpaired condition. Consistent with animal research, context conditioning was increased by unpredictability. These data support the Martians task as a promising tool to extend research on human context conditioning.     

Reinstatement of fear in humans: autonomic and experiential responses in a differential conditioning paradigm

The present study investigated reinstatement of fear in humans using an aversive differential conditioning paradigm. Two neutral human face pictures were presented during habituation, acquisition, extinction, and postreinstatement phases. One picture served as a conditioned stimulus (CS) reinforced by an unconditioned stimulus (US) in the form of electrical stimulation (CS+) and the second picture as a control stimulus that was never reinforced (CS-). The prediction that in a reinstatement manipulation a previously extinguished fear response in humans can be reinstated in a reinstatement group by the mere presentation of three unpredicted electrical stimulations (USs) was tested. Participants in the control group were not exposed to unpredicted USs and no reinstatement effect was expected. Outcome measures included subjective US expectancy ratings and skin conductance responses. Results showed non-selective return of the fear response due to fear recovery associated with both CSs (CS+/CS-) in the reinstatement group. Unexpected fear recovery was observed for both CSs (CS+/CS-) in control participants. Results are discussed with respect to context conditioning, fear generalisation, and anxiety-related cognitive mechanisms underlying fear recovery after extinction.     

The visual search analogue of latent inhibition: Implications for theories of irrelevant stimulus processing in normal and schizophrenic groups

Latent inhibition (LI) is a robust phenomenon that is demonstrated when a previously inconsequential stimulus is less effective in a new learning situation than a novel stimulus. Despite LI’s simplicity, there is considerable disagreement as to its theoretical basis. Attentional theories claim that unattended stimulus preexposures reduce stimulus associability. Alternatively, it has been asserted that associability is unaffected and that LI is a result of competition/retrieval processes. The present article reviews a series of visual search studies, some with normal subjects, both undifferentiated and divided into low and high schizotypals, and others with pathologies that entail dysfunctional attention, such as schizophrenia, Parkinson’s disease, and anxiety. The visual search conditions were designed to model those of traditional LI experiments, while tapping attentional processes independently of the learning scores that index LI. A variety of evidence from these and other studies is used to support the involvement of attentionaland retrieval processes in LI. A model of the mechanism of action of these processes in LI is presented, together with its application to schizophrenia.     

Olfactory fear conditioning paradigm in rats: Effects of midazolam,propranolol or scopolamine

In rodents, fear conditioned responses are more pronounced toward olfactory stimulus, since olfaction is a dominant sense in these subjects. The present study was outlined to investigate if the association between coffee odor (CS1) and electrical footshock (US) would be an effective model for the study of fear-induced behavior and whether compounds used in humans for emotional-related disorders such as midazolam, propranolol, or scopolamine, applied during the different stages of fear conditioning (acquisition, consolidation and expression), affect the defensive responses to both, the olfactory CS1, and the context (CS2) where the CS1 had been presented (second order conditioning). The results revealed that five pairings between coffee odor (CS1) and electrical footshock (US) were able to elicit consistent defensive responses and a second order conditioning to the context (CS2). Midazolam (0.375–0.5 mg/kg; i.p.) treatment was able to interfere with the CS1–US association and with the consolidation of the aversive information. The propranolol (5–10 mg/kg; i.p.) treatment interfered with the CS1–US association, with the retention of fear memory and with the CS1–CS2 association. Propranolol also attenuated the expression of conditioned fear responses when applied before the CS1 test session. Scopolamine (0.6–1.2 mg/kg; i.p.) treatment impaired the acquisition of CS1–US and CS1–CS2 associations, and also disrupted the expression of conditioned fear responses when injected prior to the CS1 test session. These findings have pointed out the usefulness for the olfactory fear conditioning paradigm to investigate drug effects on the acquisition, consolidation and expression of fear conditioned responses.     

Hippocampal alpha 5 subunit-containing GABA A receptors are involved in the development of the latent inhibition effect

Hippocampal GABA(A) receptors containing the alpha 5 subunit have been implicated in the modulation of hippocampal-dependent learning, presumably via their tonic inhibitory influence on hippocampal glutamatergic activity. Here, we examined the expression of latent inhibition (LI)--a form of selective learning that is sensitive to a number of manipulations targeted at the hippocampal formation, in alpha 5(H105R) mutant mice with reduced levels of hippocampal alpha 5-containing GABA(A) receptors. A single pre-exposure to the taste conditioned stimulus (CS) prior to the pairing of the same CS with LiCl-induced nausea was effective in reducing the conditioned aversion against the taste CS in wild-type mice--thus constituting the LI effect. LI was however distinctly absent in male alpha 5(H105R) mutant mice. Hence, a partial loss of hippocampal alpha 5 GABA(A) receptors is sufficient to alter one major form of selective learning, albeit this was not seen in the female. This observed phenotype suggests that specific activation of these extrasynaptic GABA(A) receptors may confer therapeutic potential against the failure to show selectivity in learning by human psychotic patients.     

The effects of context changes on the reinstatement of extinguished conditioned behavior in a conditioned suppression task with humans

Reinstatement refers to the return of previously extinguished conditioned responses to test trials of a conditional stimulus (CS) when presentations of the unconditional stimulus (US) alone are given following extinction. Four experiments were conducted to determine whether reinstatement could be found in a conditioned suppression task with humans and whether contextual changes can abolish it. Experiment 1 demonstrated the reinstatement of conditioned suppression when acquisition, extinction, US alone, and test trials were all given in the same context. Experiments 2 and 3 suggested that the reinstatement effect was still present when the US alone presentations were given in a different context to the subsequent test trials. Experiment 4 replicated this effect using additional controls over the amount of exposure to the various contexts. The results suggest that reinstatement can be robust across changing contexts. Aspects of the conditioned suppression task that promote the transfer of learning across contexts or the establishment of configural context-CS stimuli may underlie the apparent lack of contextual control over reinstatement.     

Latent inhibition: A trace conditioning phenomenon?

An informal model of latent inhibition (LI), the trace hypothesis, is described. This hypothesis holds that preexposure (PE) to the to-be-conditioned stimulus alters the salience (associability) of the CS such that only the onset and initial segments, but not the later segments, are capable of supporting conditioning when paired with a US. Thus, LI is effectively a trace conditioning phenomenon. Four experiments used rats and a one-trial fear-conditioning task to test predictions which stem from this hypothesis. Experiment 1 showed conditioning performance decreased as trace intervals increased between 0 and 12 s, thus demonstrating the sensitivity of this task to trace intervals proposed by the trace hypothesis to produce LI. Consistent with the trace hypothesis, LI was found to be an increasing function of the CS duration (Experiment 2), the number of PE trials (Experiment 3), and the US onset during a 15-s CS (Experiment 4). These data are somewhat problematic for several explanations of LI, but, in general, the trace hypothesis extends extant explanations by focusing on changes in salience within a given presentation of the CS.     

Factors regulating the effects of hippocampal inactivation on renewal of conditional fear after extinction

After extinction of fear to a Pavlovian conditional stimulus (CS), contextual stimuli come to regulate the expression of fear to that CS. There is growing evidence that the context dependence of memory retrieval after extinction involves the hippocampus. In the present experiment, we examine whether hippocampal involvement in memory retrieval after extinction is related to the history of CS presentations in the context used for retrieval testing. We used infusions of muscimol to inactivate the dorsal hippocampus (DH) during postextinction retrieval tests that were conducted in contexts that differed in their history of CS presentations in that context. We found that DH inactivation affected the context-dependent retrieval of extinction (i.e., renewal) when testing occurred in a context that had no history of CS exposure, but not in a context that reliably predicted the CS. These results are discussed in terms of theories regarding the role of the hippocampus in contextual memory retrieval.     

Contextual control of appetitive conditioning: Influence of a contextual stimulus generated by a partial reinforcement procedure

Three experiments with rat subjects examined the effects of a context switch after conditioning treatments in which the conditioned stimulus (CS) was either paired with food on every presentation (continuous reinforcement) or on some of its presentations (partial reinforcement). In each experiment, a target CS was given one of these treatments in Context A, and another CS was given a treatment during sessions that were intermixed in Context B. Final tests of the target CS in Context A and Context B often revealed no loss of responding with the switch to B. However, a loss was observed when partial reinforcement had been associated with Context A and continuous reinforcement had been associated with Context B. Those conditions caused equal decrements in responding to partially reinforced and continuously reinforced targets. The results suggest that under the present conditions partial reinforcement can generate a contextual stimulus that becomes associated with the physical context and controls responding to the CS.     

Latent inhibition and learned helplessness in children: Similarities and differences

Four experiments used a common set of procedures to investigate the occurrence and the generalization of learned helplessness (LH) and latent inhibition (LI) in 10- to 11-year-old children. In Experiment 1, preexposure to response-outcome independence impaired performance (i.e., LH) on two subsequent tests: The first was similar to the preexposure situation, the second was not. Moreover, LH occurred whether preexposure involved positive or negative feedback. On the other hand, noncontingent stimulus preexposure did not impair subsequent performance, i.e., LI was not obtained in the first experiment. Experiment 2 replicated the LH findings of Experiment 1: LH occurred following preexposure to response-independent feedback, regardless of whether that feedback was positive or negative, and LH generalized to a situation that was different from the preexposure situation. In addition, the stimulus preexposure procedures of Experiment 2 were embedded in a “masking” task and, under these conditions, LI was obtained. Nevertheless, LI did not generalize to a testing situation that was different from the preexposure situation. Experiment 3 demonstrated that noncontingent stimulus preexposure impairs performance relative to a nonpreexposed control group, that the effect is dependent upon masking, that masking alone produces no performance decrement, and that LI is, indeed, stimulus specific. In Experiment 4, preexposure to response-outcome independence impaired subsequent performance on similar and dissimilar tests whether feedback was consistently positive, consistently negative, or randomly positive and negative over trials. In addition, stimulus preexposure produced LI only under conditions of masking and even then, LI was not evident in novel test situations. The results are discussed in terms of common and different mechanisms underlying the LI and LH phenomena.     

A different recruitment of the lateral and basolateral amygdala promotes contextual or elemental conditioned association in Pavlovian fear conditioning

Convergent data suggest dissociated roles for the lateral (LA) and basolateral (BLA) amygdaloid nuclei in fear conditioning, depending on whether a discrete conditioned stimulus (CS)-unconditional stimulus (US) or context-US association is considered. Here, we show that pretraining inactivation of the BLA selectively impaired conditioning to context. In contrast, inactivation of the LA disrupted conditioning to the discrete tone CS, but also either impaired or enhanced contextual conditioning, depending on whether the context was in the foreground or in the background. Hence, these findings refine the current model of the amygdala function in emotional learning by showing that the BLA and the LA not only differentially contribute to elemental and context-US association, but also promote, through their interaction, the most relevant of these two associations.     

Preferences surf on the currents of words: Implicit verb causality influences evaluative conditioning

It is a psychological truism that thought shapes language. However, the idea that language constrains cognition is less well understood and has been debated in philosophy, linguistic, and psychology. The goal of the present research was to investigate the influence of language, as given in linguistic categories, on the formation of evaluations in an interpersonal impression formation context. Specifically, we examined the role of different verb classes in the formation of interpersonal (dis‐)likes within an evaluative conditioning (EC) paradigm. EC refers to the change in liking in a conditioned stimulus (CS) as a result of its' pairing with an unconditioned stimulus (US). In contrast to traditional EC accounts that assume the rigid and unrestricted change in valence due to CS–US co‐occurrence, we found that EC was moderated by language, that is, by the linguistic status of the US. Theoretical implications of these findings are discussed. Copyright © 2010 John Wiley & Sons, Ltd.     

Dissociating expectancy of shock and changes in skin conductance: an investigation of the Perruchet effect using an electrodermal paradigm

Is human Pavlovian conditioning driven by a unitary, propositional system (as claimed by Mitchell, De Houwer, & Lovibond, 2009) or by dual systems; one under conscious control, symbolic in nature, and requiring effort to deploy, and the other utilizing associative processes and automatic in its operation (McLaren, Green, & Mackintosh, 1994)? Past research has suggested that for electrodermal conditioning to occur in humans, conscious awareness of the contingencies is necessary to produce conditioned responding (e.g., Hinchy, Lovibond, & Ter-Horst, 1995), as predicted by single process theories that attribute the conditioned response (CR) to conscious expectancy of the shock. In this article, the authors examined the Perruchet effect (Perruchet, 1985), using an electrodermal paradigm to determine whether there is any role for associative processes in human electrodermal conditioning. The authors attempted to replicate the basic effect, whereby expectancy of an unconditioned stimulus (US) increases over a run of nonreinforced trials while the CR to the conditional stimulus (CS) declines, and the complementary pattern in which expectancy decreases over a run of reinforced trials while the CR to the CS grows in strength. In line with these patterns, the change in skin conductance response (our CR) as a function of US run length was found to follow a linear trend opposite to that of conscious expectancy of shock with respect to US run length. This dissociation supports a dual-processing system account of human Pavlovian conditioning, with conscious, controlled processes governing expectancy (and subject to the gambler's fallacy), whereas automatic, associative processes determine at least some of the strength of the CR to the CS.