Associability of a previously conditioned stimulus as a function of qualitative changes in the US

Hall and Pearce (1979) reported retarded manifestation of conditioned responding to repeated CS-strong shock pairings as a result of prior CS-weak shock pairings. These authors suggested that a latent inhibition (LI)-like process reduced the associability of the CS during weak shock conditioning despite excitatory associations between CS and weak shock being formed. The present experiments examined the possibility that the negative transfer from CS-weak shock conditioning in Stage 1 to CS-strong shock conditioning in Stage 2 observed by Hall and Pearce was due at least in part to the similarity between weak and strong shock rather than, or in addition to, a general loss of CS associability. Specifically, the transfer of decreased associability to conditioning with a dissimilar US was investigated. Consistent with Hall and Pearce, who gave multiple training trials in Stage 2, Experiment 1 found the development of conditioned responding owing to a single CS-strong shock pairing in Stage 2 to be retarded by prior CS-weak shock pairings and compared this effect to conventional LI. In Experiment 2, partial attenuation of the negative transfer following CS-weak shock was obtained by substituting ice water immersion for strong shock, that is, by making the strong US qualitatively dissimilar from the weak US. In contrast, conventional LI resulting from preconditioning CS-only exposures was equivalent for strong shock in Experiment 1 and ice water immersion in Experiment 2. A possible mechanism for the sensitivity to qualitative US changes of the observed negative transfer is discussed.     

Effects of the interval between exposure to a novel environment and the occurrence of shock on the freezing responses of rats

Rats were exposed to a novel environment (E1) at time T1, given a footshock at time T2, and tested for freezing in E1 or in a second environment (E2). The function relating freezing to the T1-T2 interval among rats tested in E1 was an inverted U-shape. Rats exposed to short T1-T2 intervals displayed just as much freezing in E2 as in E1, whereas rats exposed to longer intervals froze less in E2 than in E1. These differences between the freezing responses in E1 and in E2 were obtained when the T1-T2 intervals were varied, but time spent in the shocked E1 was equated. Rats given two shocks in E1 differentiated between E1 and E2 when the initial shock occurred some time after exposure to E1, but not when the initial shock was presented shortly after that exposure. Rats shocked some time after exposure to E1 on Day 1 and shortly after exposure to that environment on Day 2 differentiated between E1 and E2 more than did rats exposed to the reverse sequence of T1-T2 intervals. The results were attributed to the formation of a network of connections among the E1 cues in rats exposed to moderate or long T1-T2 intervals, and to an impairment in the formation of this network as a result of the conditioning of a subset of cues in rats exposed to short T1-T2 intervals.     

Short- and long-term decrements in toxicosis-induced odor-aversion learning: the role of duration of exposure to an odor

Six experiments employed an odor-aversion paradigm to investigate the role of the duration of exposure to an odor in determining that odor's subsequent associability with illness. Rats were exposed to an odor at times T1 and T2, and the second of these exposures was followed by toxicosis. When the initial odor exposure was brief, the odor aversion was attenuated with a moderate T1-T2 interval of 3 hr (Experiment 1) but not with long intervals of 28 hr and 76 hr (Experiment 2). In contrast, when the initial odor exposure was long, the odor aversion was attenuated at a long T1-T2 interval (Experiment 3). With a T1-T2 interval of 24 hr, a brief initial exposure did not attenuate odor aversions when the context either remained the same or was changed from T1 to T2, whereas a long initial exposure attenuated such aversions when the context remained the same but not when the context was changed (Experiment 4). With a T1-T2 interval of 3 hr, a brief initial exposure attenuated odor aversions when the context remained the same or was changed from T1 to T2, whereas a long initial exposure attenuated such aversions when the context remained the same but not when the context was changed (Experiment 5). A brief exposure at T1, either with or without a subsequent context "extinction," attenuated odor aversions when the T1-T2 interval was 3 hr but not when this interval was 24 hr; a long initial exposure at T1, without a subsequent context "extinction," attenuated odor aversions when the T1-T2 interval was 4 hr and 24 hr but with a subsequent context "extinction" did not attenuate such aversions at either 4-hr or 24-hr T1-T2 intervals (Experiment 6). The results demonstrate that the duration of exposure to an odor determined whether that odor presentation caused short- or long-term decrements in odor conditionability and are discussed in terms of the relation between self- and retrieval-generated processes.     

Short-term flavour memory in the rat

In a series of experiments, rats were exposed twice to a flavour at times T1 and T2, and the second of these exposures was followed by toxicosis. The level of the subsequent aversion was viewed as an index of whether the flavour had been recognised as familiar at T2, with a familiar flavour accruing less aversiveness than an unfamiliar one. A flavour was recognised as familiar at time T2 after a long flavour-exposure at time T1 (Experiment Ia) when moderate (3·5 h) and long (27·5 h) T1-T2 intervals were employed but was so recognised after a brief exposure at T1 (Experiment Ib) only when a moderate T1-T2 interval was employed. The memorial processes underlying flavour recognition after a brief flavour exposure were assumed, therefore, to be transient. The remaining experiments employed a brief flavour exposure at T1 and moderate T1-T2 intervals in various attempts to disrupt flavour recognition. Recognition at T2, however, was not disrupted when one (Experiment II), or three (Experiment IV) distractor flavours were interpolated between the target flavour's presentations at T1 and T2. This failure was not due to the distractor having proactively interfered with the associability of the target flavour with illness at T2 (Experiment III). Further, recognition was not disrupted when the position of the target flavour's presentation at T1 was varied across a list of distractor flavours (Experiment V), nor when the similarity of the distractor and the target flavour was varied (Experiment VI). The results indicate that the processes subserving recognition after a brief presentation of that flavour, although transient, are resistant to interference and were discussed in terms of current theories of short-term memory in animals.     

Overshadowing and blocking procedures in latent inhibition

Three experiments used rats as subjects and a flavour-aversion procedure to examine the effect of compound flavour (AB) pre-exposure on the extent of latent inhibition to an element (A) of that compound. In Experiment 1 a group of rats exposed to AB exhibited less latent inhibition to stimulus A than a group for which A was presented in isolation or than a group that received A followed by a second stimulus, B, during the pre-exposure phase. Experiment 2 and Experiment 3 showed that the effectiveness of B during compound pre-exposure depended on its novelty. Thus a group that received exposure to stimulus B prior to AB pre-exposure showed more latent inhibition than a group that did not receive prior experience of the B stimulus. Two explanations for these effects were considered: that compound pre-exposure might reduce effective processing of the elements of that compound during the pre-exposure phase; alternatively, that exposure to an element as a part of a compound may modify the way in which that element is perceived.     

Conditioned stimulus informativeness governs conditioned stimulus-unconditioned stimulus associability

In a conditioning protocol, the onset of the conditioned stimulus ([CS]) provides information about when to expect reinforcement (unconditioned stimulus [US]). There are two sources of information from the CS in a delay conditioning paradigm in which the CS-US interval is fixed. The first depends on the informativeness, the degree to which CS onset reduces the average expected time to onset of the next US. The second depends only on how precisely a subject can represent a fixed-duration interval (the temporal Weber fraction). In three experiments with mice, we tested the differential impact of these two sources of information on rate of acquisition of conditioned responding (CS-US associability). In Experiment 1, we showed that associability (the inverse of trials to acquisition) increased in proportion to informativeness. In Experiment 2, we showed that fixing the duration of the US-US interval or the CS-US interval or both had no effect on associability. In Experiment 3, we equated the increase in information produced by varying the C/T ratio with the increase produced by fixing the duration of the CS-US interval. Associability increased with increased informativeness, but, as in Experiment 2, fixing the CS-US duration had no effect on associability. These results are consistent with the view that CS-US associability depends on the increased rate of reward signaled by CS onset. The results also provide further evidence that conditioned responding is temporally controlled when it emerges.     

Attenuation of latent inhibition by post-acquisition reminder

Using lick suppression by water-deprived rats as an associative index, white noise-footshock pairings resulted in less manifest conditioning when repeated non-reinforced presentations of the white noise preceded conditioning than when no stimulus pre-exposure was given, i.e., latent inhibition was observed. However, the latent inhibition deficit was reduced in animals who received as a reminder treatment shock-alone presentations in another context during the retention interval. Animals conditioned without prior stimulus pre-exposure and those exposed to the white noise and shock unpaired during the conditioning phase of the study showed no change in lick suppression as a result of the reminder treatment. These results suggest that the behavioural deficit produced by non-reinforced pre-exposure to the to-be-conditioned stimulus arises at least in part from a reversible retrieval failure rather than a lack of acquisition.     

Effects of Retention Interval on Latent Inhibition and Perceptual Learning

Repeated, non-reinforced preexposure to a context slowed development of conditioned freezing to that context when it was subsequently paired with footshock (latent inhibition) and enhanced discriminability of that context from a similar context (perceptual learning) whether assessed by a generalization test or by explicit discrimination training. Latent inhibition was eliminated by a delay between conditioning sessions and test (Experiments 1a and 1b) and reduced by a delay between preexposure and conditioning (Experiment 2). However, perceptual learning was unaffected by either of these intervals (Experimnets 1b and 2). These results are discussed in terms their impact on theories that have latent inhibition as a possible mechanism of perceptual learning, and on theories of latent inhibition that consider the retardation of conditioned responding to be the result of an acquisition failure.     

Exposure to a stressor produces a long lasting enhancement of fear learning in rats

In contextual fear conditioning, footshock is given in a context, and re-exposure to this context elicits the conditional defensive response of freezing, a reliable behavioral index of conditional fear. Normally, the amount of contextual freezing is directly proportional to the number of shocks an animal receives in the context. However, pre-exposure to a stressor can produce an enhancement in conditional freezing. Pre-exposure to repeated footshock in one context produces an enhancement of conditional freezing to cues associated with a single shock in a second distinct context. This model of stress-enhanced fear learning (SEFL) can be utilized to study how stress affects learning of future aversive events. The experiments in this paper characterize the magnitude and longevity of SEFL. In the first experiment, the number of footshocks given during the pre-exposure session was varied and conditional fear to the single shock was assessed. Pre-exposure to 1 shock did not produce an enhancement in fear learning in the second context, but pre-exposure to 4 or 15 shocks did. The time-course of the enhancement was examined in the next two experiments. These experiments show that SEFL persists for at least 3 months.     

Effect of stimulus pre-exposure on inhibitory avoidance retrieval-associated changes in the phosphorylated form of the extracellular signal-regulated kinase-1 and -2 (pERK1/2)

One goal of the present study was to determine how pre-exposure to a set of contextual cues affected subsequent reinforced inhibitory avoidance task performance using those cues (latent inhibition model). In addition, immunohistochemical assessment of the phosphorylated (activated) form of the extracellular signal-regulated kinase-1 and -2 (pERK1/2) was examined. Adult, male Long Evans rats were randomly assigned into either pre-exposure (PE) or different pre-exposure (DPE) groups. All rats received 3 days of contextual pre-exposure (same or different context as that used for reinforced training) and were trained, 24 h later, on an inhibitory avoidance task (with or without shock). Rats were euthanized 24 h after training; half with a retention test and half without. Behaviorally, the PE group showed reduced latencies to enter the dark/shock compartment during the retention test compared to the DPE group showing the latent inhibition phenomenon. Compared to the shocked and tested DPE group, the shocked and tested PE group showed fewer pERK1/2-ir neurons in the secondary motor cortex, the anterior cingulate, the pre- and infra-limbic cortices, and the central nucleus of the amygdala. These regions showed similar numbers of pERK1/2-labeled neurons when comparing the shocked and tested PE group with the nonshocked and tested PE group. This suggests the possibility that brain regions showing decreased pERK1/2 levels in association with attenuated inhibitory avoidance performance may be involved in different aspects of the memory retrieval process.     

Effect of a retention interval between pre-exposure and conditioning on latent inhibition in humans using a blink conditioning procedure

Latent inhibition, retarded learning after pre-exposure to the to-be-conditioned stimulus, was examined using a blink conditioned procedure in humans. Experiment 1 showed that the procedure is suited to inducing the latent inhibition effect. In Experiment 2, the introduction of a 3-minute interval between pre-exposure and conditioning phases attenuated latent inhibition. These results contribute to identify the mechanisms involved in pre-exposure and subsequent conditioning of a stimulus, which is particularly important if we bear in mind that latent inhibition has been used repeatedly as an instrument to analyze the course of attentional processes in normal and pathological populations.     

Role of context in perceptual learning in maze discriminations

Three experiments with rats in a maze examined the effects of pre-exposure to the relevant discriminative stimuli (rubber and sandpaper-covered maze arms) or the extra-maze context (the maze was surrounded either by black curtains or by variety of extra-maze landmarks) on the learning of a discrimination between rubber and sandpaper arms. In Experiment 1, pre-exposure to the extra-maze context facilitated subsequent discrimination learning. Experiments 2 and 3 showed that pre-exposure to rubber and sandpaper arms facilitated subsequent discrimination learning only when these cues were presented in the same context during pre-exposure and discriminative training. Taken together, the results are consistent with the hypothesis that a major cause of perceptual learning is the latent inhibition of stimuli or features common to the two discriminative stimuli, and that such latent inhibition may be disrupted by a radical change of context.     

Effects of pre-exposure to the same or different pattern of extra-maze cues on subsequent extra-maze discrimination

In two experiments, rats learned a spatial discrimination between maze arms defined by their relationship to a variety of extra-maze cues. Prior exposure to the actual arms between which animals were required to discriminate tended to retard subsequent learning (by comparison with a control group either given no pre-exposure to the extra-maze cues or exposed only to arms pointing in the opposite direction), whereas prior exposure to arms intermediate between those used in discrimination training tended to facilitate subsequent learning. These results are consistent with the suggestion that pre-exposure will facilitate discrimination learning when it reduces the associability of features or elements common to the stimuli between which animals are required to discriminate, more than it reduces the associability of the features or elements unique to each.     

Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats

Previous research has shown that an acute, post-training injection of D-cycloserine (DCS) facilitates extinction of conditioned fear in rats; however, the effects of multiple exposures to DCS in this situation are not known. In Experiment 1, rats were conditioned (light-shock pairings) and 24 h later given six extinction (light-alone) trials followed by an injection of DCS (15 mg/kg) or saline. The next day, all rats were tested for light-elicited freezing. In Experiment 2, the effect of DCS on extinction was tested in the same manner, except that rats were pre-exposed to DCS (0, 1, or 5 injections) just prior to conditioning. In Experiment 3, rats received five pre-exposures of DCS but conditioning occurred either 2 or 28 days after the last pre-exposure. The results showed that DCS facilitated extinction of conditioned freezing to the light CS when no drug pre-exposure had occurred, but pre-exposure to DCS just prior to conditioning disrupted the facilitation of extinction effect. When 28 days were interposed between pre-exposure and conditioning, the facilitatory effects of DCS on extinction were restored. These findings suggest that DCS has significant clinical value but that behavioral desensitization may occur with multiple exposures; however, desensitization is not permanent and is reduced by the passage of time.     

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 24h 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 microg/side), the cAMP inhibitor Rp-cAMP (1.8 or 18.0 microg/side), or the MAPK inhibitor U0126 (0.1 or 1.0 microg/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.     

A search for context-stimulus associations in latent inhibition

Six experiments investigated the effects of pre-exposure to a tone on the subsequent acquisition of conditioned suppression by rats. In Experiments 1-3 the response suppressed was drinking; in Experiments 4-6 it was food-rewarded lever pressing. Repeated exposure to the tone resulted in latent inhibition, i.e., a retardation in the acquisition of suppression. The size of the latent inhibition effect was reduced when a different context was used for conditioning from that used for pre-exposure (Experiment 2). When the context remained the same throughout, a phase of exposure to the context alone, interposed between pre-exposure and conditioning, had no influence on the size of the latent inhibition effect ultimately observed. This last result casts doubt upon Wagner's (1976, 1979) theory of the role of contextual factors in latent inhibition, and alternative accounts are considered.     

Contextual Fear after Signalled versus Unsignalled Shocks: Effect of Extent of Prior Experience with Context and Signal

In the first two experiments, rats were differentially familiarized with a discrete stimulus and/ or a context prior to receiving either shocks signalled by that stimulus or unsignalled shocks in that context. As indexed by freezing, in none of the pre-exposure conditions did the signalled-shock rats consistently acquire less contextual fear than the unsignalled-shock animals. Both pre-exposure to the stimulus and relatively short pre-exposure to the future conditioning context resulted in more contextual fear in the signalled-shock than in the unsignalled-shock subjects. In a third experiment, freezing in the target conditioning context was especially enhanced in rats that had been familiarized with a stimulus, conditioned with the stimulus as a signal for shock, and subsequently further conditioned to the stimulus in a different, non-target context. The level of freezing to the stimulus in a neutral test context was positively related to the level of freezing in the target conditioning context in all experiments. These results were discussed in terms of context-shock, stimulus-shock, and context-stimulus associations.     

The temporal dynamics of retention of a context memory: something is missing

We use a variation of contextual fear conditioning, called the context pre-exposure facilitation effect (CPFE) to study the rat's memory for context. In this paradigm, the rat is pre-exposed to a conditioning context and later returned to that context, where it is immediately shocked. The memory context is revealed by the fact that pre-exposure to the conditioning context, but not to a different context, greatly enhances conditioned fear produced by immediate shock. We report that rat's retention of the context memory is a nonmonotonic U-shaped function of the interval separating pre-exposure and immediate shock. Retention performance decays rapidly so that within 2 min of pre-exposure there is no evidence that the rat was pre-exposed to the context. Within a few hours, however, a strong CPFE was observed that persisted for at least 28 d. Two hypotheses are discussed: (1) the descending arm of the U represents a retrieval failure, and (2) the U-shaped function represents two discontinuous memory processes initiated in parallel-short-term synaptic changes that are rapidly initiated, but also decay rapidly, and long-term synaptic processes that take time to generate but can endure for days.     

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.     

Context specificity of latent inhibition in taste aversion learning

In three experiments rats were given injections of LiCl after consuming distinctively flavoured water. The rats developed an aversion to the flavour and in all experiments the magnitude of the aversion was found to be reduced in subjects that had received pre-exposure to the flavour without aversive consequences. Experiment 1 demonstrated this pre-exposure effect to be a case of latent inhibition. The remaining experiments investigated the effects of pre-exposing the flavour in a context different from that used for conditioning. It was found (Experiment 2) diat latent inhibition transferred perfectly when the context change consisted of a move from one home cage to another. Context specificity of latent inhibition was found (Experiment 3) only when the subjects were given daily sessions in die experimental contexts, these being cages different from the home cage.