Conditioned Stimulus Preexposure Research Articles

Context specificity of latent inhibition in the snail Cornu aspersum

The present study was conducted to assess the context specificity of latent inhibition (LI) in the snail Cornu aspersum, using the appetitive Pavlovian Conditioning procedure of tentacle lowering. Snails experienced an odorous conditioned stimulus (CS) without any consequence before being conditioned with food. The conditioned stimulus preexposure occurred in the same context than the conditioning and the test context or in the different context. The study was performed in two replicas in which the photoperiod was defined by level of illumination and time of day (circadian replica) or was defined only by light (light replica). Both replicas showed that the CS preexposure in the same context as conditioning produced a delay in the acquisition of the conditioned response (CR). However, when the CS preexposure took place in a different context than the conditioning context, an equivalent level of CR as that observed in controls without preexposition to CS was shown. These results are congruent with context specificity of LI and they provide the first evidence of this phenomenon in terrestrial mollusks. Learning processes and theories involved in this phenomenon are also debated in the paper.

Hippocampal Disinhibition Reduces Contextual and Elemental Fear Conditioning While Sparing the Acquisition of Latent Inhibition

Hippocampal neural disinhibition, i.e., reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signaling, which play a role in salience modulation. Consequently, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. Therefore, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response (CER) procedure. A flashing light was used as the conditioned stimulus (CS), and conditioned suppression was used to index conditioned fear. In experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin before CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls but could not be detected in picrotoxin-infused rats because of the low level of fear conditioning to the CS. In experiment 2, VH picrotoxin infusions only before CS pre-exposure did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect a disruption of neural processing both within the hippocampus and in projection sites of the hippocampus.

Stimulus preexposure speeds or slows subsequent acquisition of associative learning depending on learning test procedures and response measure.

Prior exposure to a conditioned stimulus (CS) typically results in latent inhibition-slower acquisition of associative learning about that stimulus in subsequent training. Here, we found that CS preexposure had different effects on the appetitive conditioning of rats with a sucrose unconditioned stimulus (US) depending on training test procedures, the similarity of preexposure and training procedures, and the choice of response measure. Preexposure to a visual or an auditory stimulus produced facilitation of acquisition of food-cup-directed responding when both of those cues were (separately) paired with sucrose delivery in the training test (Experiments 1 and 3). By contrast, the same preexposure procedure resulted in latent inhibition of food-cup learning if the second stimulus in the test phase was of the same modality as the preexposed stimulus (Experiment 2). In Experiment 3, latent inhibition was enhanced if both phases included a single CS or both phases included both auditory and visual CSs, compared to treatments in which only one CS was presented in one phase but two CSs were presented in the other phase. In Experiment 4, preexposure of an auditory cue slowed subsequent learning about it if the context was salient but enhanced learning if the context was of weaker salience. Finally, a measure of general activity revealed latent inhibition after preexposure in all conditions in all 4 experiments. We discuss the results within several classes of latent inhibition theories, none of which provides a comprehensive account.

Examinations of CS and US preexposure and postexposure in conditioned taste aversion: Applications in behavioral interventions for chemotherapy anticipatory nausea and vomiting

Examining CS or US preexposure and postexposure to dissociate conditioned stimulus (CS)-unconditioned stimulus (US) conditioned learning and apply these findings to alleviate anticipatory nausea and vomiting are crucial for cancer chemotherapy patients. The present study utilized a conditioned taste aversion (CTA) paradigm in rats to develop a new behavioral intervention. Experiment 1 evaluated Control, Conditioning, CS preexposure, and CS postexposure groups. Experiment 2 evaluated Control, Conditioning, US preexposure, and US postexposure groups. After conditioning in both experiments, rats were given the CS alone without the US once per day over three trials, and their conditioned taste aversion was measured. The results showed that both CS preexposure and US preexposure interfered with subsequent CS-US conditioning, indicating that both induced proactive interference. Although CS postexposure interfered with prior CS-US conditioning, which indicated extinction, US postexposure did not alter CS-US conditioning. The findings should be considered for the development of new nonpharmacological clinical interventions for cancer patients with chemotherapy-induced anticipatory nausea and vomiting.

Learning about the CS during latent inhibition: Preexposure enhances temporal control.

In 3 experiments, rats were given nonreinforced preexposure to an auditory stimulus, after which this stimulus and a second, novel cue were paired with food. Lower rates of conditioned responding were observed to the preexposed stimulus across the 3 experiments, indicative of latent inhibition. The degree to which animals used these cues to time the occurrence of food delivery was also examined. Paradoxically, the response slopes—indicating the rate of increase in responding over the course of the conditioned stimulus—were greater for the preexposed than for the novel cues, consistent with the suggestion that the preexposed stimulus exerted greater temporal control. Moreover, this was the case irrespective of whether the duration of the cue during preexposure differed from that during conditioning. These results suggest that although conditioned stimulus preexposure retards conditioning, it may enhance timing. The findings are discussed in terms of current models of conditioning and timing.

Signal transduction mechanisms within the entorhinal cortex that support latent inhibition of cued fear conditioning

Latent inhibition is a phenomenon by which pre-exposure to a conditioned-stimulus (CS), prior to subsequent pairings of that same CS with an unconditioned-stimulus (US), results in decreased conditioned responding to the CS. Previous work in our laboratory has suggested that the entorhinal cortex is critically involved in the establishment of latent inhibition of cued fear conditioning. Furthermore, utilizing systemic pharmacology, we have demonstrated a role for of NMDA receptors, protein kinase A (PKA), and mitogen activated protein kinase (MAPK, also known as ERK) in latent inhibition of cued fear conditioning, but until now, where these cell signaling cascades are critically activated during latent inhibition of cued fear was unknown. Here, we use direct drug infusion to demonstrate that cell signaling via NMDA receptors, the cAMP/PKA pathway, and the MAPK pathway within the entorhinal cortex are critically involved in latent inhibition of cued fear conditioning. In the present study, CS pre-exposed mice received 20 CS pre-exposures 24 h prior to two pairings of the same CS with a 0.53 mA foot shock US, while control animals receive no pre-exposure to the CS. The NMDA antagonist APV (0.25 or 2.5 μg/side), the cAMP inhibitor Rp-cAMP (1.8 or 18.0 μg/side), or the MAPK inhibitor U0126 (0.1 or 1.0 μg/side) were directly infused into the entorhinal cortex prior to pre-exposure. All three drugs produced dose-dependent disruptions in latent inhibition of cued fear conditioning. Importantly, none of the drugs had any effect on cued fear conditioning when administered on training day, suggesting that the effects of each of the drugs were specific to CS pre-exposure. These results are discussed in relation to the potential mechanisms of plasticity that support latent inhibition of cued fear conditioning.

Reversible inactivation of the entorhinal cortex disrupts the establishment and expression of latent inhibition of cued fear conditioning in C57BL/6 mice

For latent inhibition, preexposure to a conditioned stimulus (CS) prior to training with an unconditioned stimulus (US) results in decreased conditioned responses (CRs) to the CS at the time of testing. The mechanism by which decreased CRs occurs, however, is unknown; CS preexposure may interfere with subsequent conditioning, or modulate the expression of CRs. Previous research has suggested that the entorhinal cortex (EC) is necessary for latent inhibition of a variety of tasks. However, no studies have specifically compared the role of the EC in acquisition vs. expression of latent inhibition. The present study used reversible inactivation of the EC to address this issue. The GABA agonist muscimol (0.5 microg/side) was directly infused into the EC of mice prior to CS preexposure, training, or testing. Our results indicate that muscimol inactivation of the EC before CS preexposure disrupts latent inhibition of cued fear conditioning. Importantly, this same dose of muscimol did not disrupt cued fear conditioning, nor did it affect latent inhibition when infused into the subiculum. Furthermore, inactivation of the EC at testing disrupted the expression of latent inhibition of cued fear conditioning; that is, CS preexposed mice that received entorhinal cortical muscimol infusion at testing showed CRs compared to saline-infused CS preexposed mice. These findings suggest that repeated preexposure to the CS during latent inhibition may alter entorhinal cortical activity thereby allowing the EC to exert inhibitory control over the expression of CRs during testing of CS preexposed mice.

Theoretical note: simulating latent inhibition with selection neural networks.

The selection neural-network model proposed by Donahoe et al. [J. Exp. Anal. Behav. 60 (1993) 17] was used to simulate latent inhibition (LI). The model can simulate increases of LI by the number, intensity, and duration of preexposed conditioned stimulus (CS). It can also simulate dependence on total CS preexposure time, CS specificity, and attenuation by preexposure to a compound that includes the to-be-trained CS. It also predicts a potentially new phenomenon: acquisition facilitation by preexposure to a stimulus that is orthogonal to and synaptically competitive with the to-be-trained CS. The basic mechanism is the same through which the model simulates extinction, namely, weight decrement. The realization of this mechanism in the present simulations required two conditions. First, networks had to come to the experimental situation with substantial initial connection weights in the sensory-association subnetwork (0.15, compared to the 0.01 value we have used in all previous simulations). Second, the discrepancy threshold for deciding whether to increase or decrease weights had to be larger than zero (the value we have used in all published simulations). A value of 0.001 was sufficient to produce all the effects.

Latent inhibition and contextual associations.

Attenuated responding to a conditioned stimulus (CS) after preexposure to that CS (latent inhibition) has traditionally been attributed to reductions in CS associability. Alternatively, CS-context associations formed during CS preexposure later interfere with the acquisition or expression of CS-outcome associations. Three lick suppression experiments with rats contrasted these accounts. Presumably, exposure to the context attenuates the CS-context association without altering CS associability. With a fixed amount of CS preexposure, latent inhibition decreased with increasing context exposure during or after (but not before) CS preexposure. When the ratio of context preexposure duration to CS preexposure was fixed, latent inhibition increased with CS preexposure. These results suggest that latent inhibition is a direct function of the strength of CS-context associations formed during preexposure.

Reduction of latent inhibition by d-amphetamine in a conditioned suppression paradigm in humans

The sensitivity of latent inhibition (LI) to amphetamine has been tested in humans with a paradigm close to the conditioned emotional response suppression currently used in experimental animals. The conditioned stimulus (CS) was a tone, the unconditioned stimulus (US) a strong white noise, and the response a transient delay in a regular sequence of hand movements in the resolution of the Tower of Toronto puzzle. The aim of this study was to verify whether the previously reported, disruptive effect of CS preexposure on conditioning really represents LI, by examining its sensitivity to amphetamine. Three groups of healthy volunteers received placebo, 5 or 10 mg of dexamphetamine sulphate, respectively, in a double-blind experimental design. The preexposure, conditioning and test phases were carried out under either amphetamine or placebo. The non preexposed groups treated with amphetamine were not different from the non preexposed placebo group, indicating that amphetamine did not affect conditioning. Among the preexposed groups, those receiving 10 mg of amphetamine showed normal rates of conditioning, whereas those treated with either 5 mg of amphetamine or placebo showed LI. Similar results have been reported in experimental animals. This sensitivity to amphetamine suggests that the present paradigm may be used to study LI in humans.

Contextual control over conditioned responding in a latent inhibition paradigm.

We used 1-, 2-, and 3-context designs to study the control exerted by contexts over freezing in rats exposed to a conditioned stimulus (CS) in advance of its pairing with a shock unconditioned stimulus. The latent inhibition observed when preexposure, conditioning, and testing occurred in the same context was attenuated if preexposure occurred in a different context to conditioning and testing. Latent inhibition (i.e., attenuated performance) was restored in a CS-specific manner if preexposure and testing occurred in the same context and conditioning in a different one. Latent inhibition was also reduced by a long retention interval but remained specific for a particular context-CS relation. Finally, CS preexposure resulted in contextual control over the expression of excitatory conditioned performance. The results are discussed in terms of memory, associative, and associative-performance models of CS-preexposure effects.

Perplexing effects of hippocampal lesions on latent inhibition: a neural network solution.

Experimental data indicate that hippocampal lesions might impair, spare, or even facilitate latent inhibition (LI). Furthermore, when LI is impaired by the lesions, it might be reinstated by haloperidol administration. The present article applies a neural network model of classical conditioning (N. A. Schmajuk, Y. W. Lam, & J. A. Gray, 1996) to investigate the possible causes of these puzzling results. According to the model, LI is manifested because preexposure of the conditioned stimulus (CS) reduces Novelty, defined as proportional to the sum of the mismatches between predicted and observed events, thereby reducing attention to the CS and retarding conditioning. It is assumed that hippocampal lesions affect the prediction of events. Computer simulations reveal that, depending on the behavioral protocol (i.e., procedure and total time of CS preexposure), Novelty in hippocampal lesioned animals might be larger, equal, or smaller (corresponding to smaller, equal, or larger LI) than in normal controls. Reinstatement of LI by haloperidol administration is explained by assuming that dopaminergic antagonists decrease the value of Novelty, when Novelty increases following hippocampal lesions.

Comparator mechanisms and conditioned inhibition: Conditioned stimulus preexposure disrupts Pavlovian conditioned inhibition but not explicitly unpaired inhibition.

Three conditioned lick-suppression experiments with rats examined the effects of pretraining exposure to the conditioned stimulus (CS) on behavior indicative of conditioned inhibition. After CS-preexposure treatment, subjects received either Pavlovian conditioned inhibition training or explicitly unpaired inhibition training with the preexposed CS. The inhibitory status of the CS was then assessed with a retardation (Experiment 1) or a summation (Experiment 2) test. Experiment 3 controlled for the unconditioned stimulus-preexposure effect being a potential confound in Experiments 1 and 2. As predicted by the comparator hypothesis (R. R. Miller & L. D. Matzel, 1988), the CS-context association that developed during the CS-preexposure phase disrupted the expression of Pavlovian conditioned inhibition but not the expression of explicitly unpaired inhibition.

Comparator mechanisms and conditioned inhibition: Conditioned stimulus preexposure disrupts Pavlovian conditioned inhibition but not explicitly unpaired inhibition.

Three conditioned lick-suppression experiments with rats examined the effects of pretraining exposure to the conditioned stimulus (CS) on behavior indicative of conditioned inhibition. After CS-preexposure treatment, subjects received either Pavlovian conditioned inhibition training or explicitly unpaired inhibition training with the preexposed CS. The inhibitory status of the CS was then assessed with a retardation (Experiment 1) or a summation (Experiment 2) test. Experiment 3 controlled for the unconditioned stimulus-preexposure effect being a potential confound in Experiments 1 and 2. As predicted by the comparator hypothesis (R. R. Miller & L. D. Matzel, 1988), the CS-context association that developed during the CS-preexposure phase disrupted the expression of Pavlovian conditioned inhibition but not the expression of explicitly unpaired inhibition.

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.

Selective hippocampal lesions abolish the contextual specificity of latent inhibition and conditioning.

The contextual specificity of the conditioned response (CR) and latent inhibition (LI) was examined in rats with selective hippocampal lesions. Acquisition of the CR to a novel conditioned stimulus (CS) was equally rapid in control and hippocampal rats (Experiments 1 and 2), and CS preexposure disrupted acquisition, (i.e., produced LI) to an equal extent in both groups (Experiment 2). In control subjects, however, the CR established in one context transferred incompletely to a second context (Experiment 1), and LI was attenuated when CS preexposure and conditioning occurred in different contexts (Experiment 3). This context specificity of the CR and LI was not apparent in hippocampal rats--the CR and LI transferred readily from one context to another. In addition, hippocampal rats were impaired in a spatial learning task (Experiment 2) but were unimpaired in learning a Pavlovian contextual discrimination (Experiment 3). These results suggest that a common contextual retrieval process underlies the contextual dependence of the CR and of LI and that this process is mediated by the hippocampus.

Effects of conditioned stimulus fear-relevance and preexposure on expectancy and electrodermal measures of human Pavlovian conditioning.

The present research investigated the effects of fear-relevance of the conditioned stimulus (CS) and CS preexposure on human electrodermal conditioning and on a continuous measure of expectancy of the unconditioned stimulus (US). Both experiments employed 20 preexposure, 8 acquisition, and 8 extinction trials in a differential Pavlovian conditioning paradigm with shock as the US. In Experiment 1 (N = 48), electrodermal conditioning was retarded by CS preexposure, but was not influenced by fear-relevance of the CS. Expectancy of the US was retarded by preexposure only in the fear-relevant condition. In Experiment 2 (N = 48), the CS/US contingencies was embedded in a visual masking task. Preexposure retarded both electrodermal conditioning and US expectancy. Neither measure was influenced by fear-relevance of the CS. However, fewer subjects in the preexposure condition learned the CS/US relationship and those who did, did so on later trial than those in the no-preexposure condition. Thus, the results indicated clear retardation of conditioning as a result of preexposure, but no reliable effect of fear-relevance.

Effects of opiate manipulations on latent inhibition in rabbits: sensitivity of the medial septal region to intracranial treatments.

The effects of opiate manipulations were examined on latent inhibition of classically conditioned heart rate in rabbits. Animals were exposed to an auditory stimulus that was later used as a conditioned stimulus (CS). Administration of the agonist levorphanol into the medial septal region either preceding or immediately following CS preexposure sessions attenuated latent inhibition of the conditioned response. This effect was observed in animals that showed no change in long-term retention of habituation. Administration of levorphanol into the central nucleus of the amygdala, a sensitive site for opiate manipulations on aversive conditioning tasks, was ineffective. Further analysis of the effect obtained within the septal region revealed pharmacological specificity. The effect of posttraining levorphanol was also time dependent and exhibited neuroanatomical specificity. Posttraining opiate antagonist administration into the medial septum produced a modest augmentation of latent inhibition. The medial septal region appears to provide a site where opiate manipulations alter some aspect of retention for events that occur in the absence of reinforcement.

Effects of opiate manipulations on latent inhibition in rabbits: Sensitivity of the medial septal region to intracranial treatments.

The effects of opiate manipulations were examined on latent inhibition of classically conditioned heart rate in rabbits. Animals were exposed to an auditory stimulus that was later used as a conditioned stimulus (CS). Administration of the agonist levorphanol into the medial septal region either preceding or immediately following CS preexposure sessions attenuated latent inhibition of the conditioned response. This effect was observed in animals that showed no change in long-term retention of habituation. Administration of levorphanol into the central nucleus of the amygdala, a sensitive site for opiate manipulations on aversive conditioning tasks, was ineffective. Further analysis of the effect obtained within the septal region revealed pharmacological specificity. The effect of posttraining levorphanol was also time dependent and exhibited neuroanatomical specificity. Posttraining opiate antagonist administration into the medial septum produced a modest augmentation of latent inhibition. The medial septal region appears to provide a site where opiate manipulations alter some aspect of retention for events that occur in the absence of reinforcement.

Effects of conditioned stimulus preexposure on human electrodermal conditioning

Two experiments investigated the effects of conditioned stimulus (CS) preexposure on Pavlovian differential conditioning and extinction of the skin conductance response. In both experiments, half the subjects were exposed to 20 presentations each of the CS+ and CS-, and the other half were exposed to control stimuli. CS duration was 8 sec. The unconditioned stimulus in Experiment 1 ( N= 48) was a 1000 Hz tone of 80 dB which signalled a reaction time requirement, and in Experiment 2 ( N = 48), it was a 1 sec burst of white noise at 105 dB. The results of Experiment 1 indicated that no-preexposure groups displayed more CS+ /CS- differentiation than preexposure groups during acquisition and more resistance to extinction, at least for the first interval anticipatory response. In addition, the results of Experiment 2 indicated that no-preexposure groups displayed more differentiation than preexposure groups in terms of the second interval anticipatory response. These data constitute a demonstration of the latent inhibition effect with human subjects, and imply that there is an intrinsic relationship between the orienting response and the conditioning process.