Preconditioning exposure to the unconditined stimulus affects the acquisition of a conditioned emotional response

Four experiments examined the UCS preexposure phenomenon using conditioned suppression of food-reinforced responding as a measure of excitatory conditioning, and electric shock as a UCS. In Experiment 1, groups of rats were preexposed to unsignaled 0.8-mA electric shocks for 0, 1, 3, 5, or 10 days, and then conditioned with a 0.8-mA electric shock. Preexposure to electric shock 1 day prior to conditioning enhanced the acquisition of a CER, whereas preexposure to electric shock for 3, 5, or 10 days prior to conditioning attenuated the acquisition of a CER as a direct function of the number of days of preexposure. In Experiments 2 and 2A, groups of rats were preexposed to unsignaled electric shocks of 0.3, 0.5, 0.8, or 1.3 mA for 10 days, and then conditioned with a 0.8-mA electric shocl. All groups preexposed to electric shock acquired the CER at a slower rate than a group not preexposed to electric shock. The greatest attenuation of CER conditioning occurred when the same intensity electric shock was used during both the preexposure and conditioning phases. In Experiment 3, groups of rats were preexposed to signaled electric shocks of either 0.5, 0.8, or 1.3 mA, and then conditioned with a 0.8-mA electric shock. All groups preexposed to electric shock acquired the CER at a slower rate than a group not preexposed to electric shock. As in Experiments 2 and 2A, the greatest attenuation of CER conditioning occurred when the same intensity electric shock was used during both the preexposure and conditioning phases. In Experiment 4, groups of rats were preexposed to series of 0.5, 0.8, or 1.3-mA electric shocks which they could escape by performing a chain-pull response. Rats in each of these groups had yoked partners which received the same number, intensity, and temporal pattern of electric shocks, but could not perform a response to escape shock. All groups were then conditioned with a 0.8-mA electric shock. Rats preexposed to escapable electric shocks showed equal or greater attenuation of CER conditioning than rats which could not escape shock during the preexposure phase. These results are discussed in terms of nonassociative and associative explanations of the UCS preexposure phenomenon.     

The Influence of Retention Interval on the US Preexposure Effect: Changes in Contextual Blocking over Time

A number of studies manipulating the length of the interval between conditioning and testing indicate spontaneous recovery from overshadowing, suggesting that certain instances of overshadowing represent a deficit in memory retrieval rather than a failure of animals to form an association between the overshadowed stimulus and the US. The present series of experiments examined the influence of lengthening the retention interval on blocking, another stimulus selection phenomenon that is typically interpreted as an acquisition deficit. The results indicated that when subjects were tested shortly (3 days) after training conditioning to a taste blocked subsequent conditioning to an odor conditioned in compound with that taste (Experiment 1), whereas prior conditioning to an odor did not block subsequent conditioning to a taste conditioned in compound with that odor (Experiment 2). This pattern of results was essentially unchanged when testing occurred at a longer (21-day) retention interval. However, there was evidence of a US preexposure effect in Experiment 2 when subjects in the US ONLY control condition were tested at the 3-day retention interval, but not when testing occurred 21 days after conditioning. Experiments 3 and 4 examined whether this loss of the US preexposure effect over time might actually represent a change in the degree of contextual blocking as the retention interval is lengthened. Exposure to the conditioning context either during the interval between Phase 1 and Phase 2 of conditioning (Experiment 3) or prior to Phase 1 of conditioning (Experiment 4) alleviated this US preexposure effect suggesting that the loss of the US preexposure effect as the retention interval is lengthened observed in Experiment 2 is due to changes in the degree of blocking by contextual stimuli over time. The results are discussed in terms of differential susceptibility of forgetting of two functional roles played by a contextual stimuli in the current situation-context as a CS and context as a retrieval cue for other CS-US associations.     

Latent inhibition and conditioning after preexposure to the training context

Experiment 1, using the conditioned suppression technique with rats, showed that the retardation of learning produced by prior exposure to a stimulus (latent inhibition) was more marked in subjects given an initial phase of preexposure to the training context. This effect was confirmed and extended in Experiment 2 in which an appetitive conditioning procedure was used. Experiments 3 and 4, again using conditioned suppression, found no effect of preexposure to the context on the acquisition of suppression when training was given with a novel stimulus, either immediately after preexposure or after a delay; but context preexposure was again found to be effective when exposure to the to-be-conditioned stimulus was given in the delay interval between context preexposure and conditioning. The implications of these findings for accounts of the role of contextual factors in latent inhibition are discussed.     

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

The present study investigated whether the selective nociceptin opioid peptide (NOP) receptor agonist, Ro64-6198, impairs acquisition of fear conditioning through glutamatergic mechanisms. Systemic administration of Ro64-6198 (0.3 and 1 mg/kg) or the non-competitive NMDA receptor antagonist, MK-801 (0.03 and 0.1 mg/kg) prior to conditioning severely impaired contextual but not cued fear learning in C57BL/6N mice. When administered together at sub-effective doses, Ro64-6198 (0.5 mg/kg) and MK-801 (0.05 mg/kg), synergistically impaired contextual fear learning, but left cued fear learning intact. We next used the immediate shock deficit paradigm (ISD) to examine the effects of Ro64-6198 and MK-801 on contextual memory formation in the absence of the foot-shock. As expected, naive mice that were shocked briefly after being placed in the training chamber displayed no contextual fear conditioning. This learning deficit was elevated by prior exposure of mice to the training context. Furthermore, administration of Ro64-6198 and MK-801, either separately at amnesic doses (1 mg/kg and 0.1 mg/kg, respectively) or concomitantly at sub-effective doses (0.5 mg/kg and 0.05 mg/kg, respectively) significantly reduced the facilitating effects of context preexposure. These findings demonstrate the existence of functional antagonism between NOP and NMDA receptors that predominantly contributes to modulation of conditioned fear learning which involves spatial-processing demands.     

Infusion of lidocaine into the dorsal hippocampus before or after the shock training phase impaired conditioned freezing in a two-phase training task of contextual fear conditioning

Learning in a contextual fear conditioning task involves forming a context representation and associating it with a shock. The dorsal hippocampus (DH) is implicated in representing the context, but whether it also has a role in associating the context and shock is unclear. To address this issue, male Wistar rats were trained on the task by a two-phase training paradigm, in which rats learned the context representation on day 1 and then reactivated it to associate with the shock on day 2; conditioned freezing was tested on day 3. Lidocaine was infused into the DH at various times in each of the two training sessions. Results showed that intra-DH infusion of lidocaine shortly before or after the context training session on day 1 impaired conditioned freezing, attesting to the DH involvement in context representation. Intra-DH infusion of lidocaine shortly before or after the shock training session on day 2 also impaired conditioned freezing. This deficit was reproduced by infusing lidocaine or APV (alpha-amino-5-phosphonovaleric acid) into the DH after activation of the context memory but before shock administration. The deficit was not due to drug-induced state-dependency, decreased shock sensitivity or reconsolidation failure of the contextual memory. These results suggest that in contextual fear conditioning integrity of the DH is required for memory processing of not only context representation but also context-shock association.     

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.     

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.     

Temporally graded,context-specific retrograde amnesia and its alleviation by context preexposure: effects of postconditioning exposures to morphine in the rat

Five experiments studied retrograde impairments in Pavlovian fear conditioning following prolonged exposure to the opioid receptor agonist morphine. Injections of morphine commencing 1-7 days but not 14 days after conditioning produced amnesia for that conditioning episode. This amnesia was (a) selective such that morphine impaired freezing to the conditioning context but not to the auditory conditioned stimulus, (b) independent of the interval between the last injection of morphine and test, and (c) accompanied by a failure of contextual discrimination. Context preexposure protected context conditioning and discrimination from the amnestic effects of morphine. These results show that retrograde deficits in contextual fear conditioning are mediated by failures to consolidate a contextual representation.     

The US preexposure phenomenon in the conditioned suppression paradigm: A role for conditioned situational stimuli

Four experiments evaluated possible associative and nonassociative accounts of the retardation in the acquisition of conditioned suppression produced by repeated prior exposure to an electric shock US. Associative interference resulting from conditioning of situational stimuli during preexposure to shock was suggested by the findings that signaling the occurrence of high-intensity shock with a discrete nontarget CS during the preexposure phase reduced the magnitude of the retardation effect compared to an unsignaled shock preexposure treatment (Experiments 1 and 4), nonreinforced presentations of putatively conditioned situational stimuli prior to conditioned suppression training reduced the magnitude of the retardation effect (Experiment 2), and the magnitude of the retardation effect was directly related to the intensity of preexposure shock (Experiment 3). Nonassociative interference was suggested by the finding that signaling the occurrence of low-intensity shock with a discrete nontarget CS during the preexposure phase did not reduce the magnitude of the retardation effect compared to an unsignaled shock preexposure treatment (Experiment 4). It was suggested that associative and nonassociative mechanisms govern the US preexposure phenomenon obtained in the conditioned suppression paradigm, and their relative contribution depends upon the intensity of shock.     

Latent inhibition experiments with goldfish (Carassius auratus)

Evidence of latent inhibition was sought in a series of experiments with goldfish. In Experiment 1, goldfish were given nonreinforced preexposure to a color that subsequently predicted shock in an activity conditioning situation; their performance did not differ from that of control animals preexposed to a markedly different color. In Experiment 2, a group of goldfish given nonreinforced preexposure to a tone and an unstimulated control group were trained in an appetitive situation, with the tone serving either as a conditioned excitor or as a conditioned inhibitor. Preexposure had no significant effect in the conditioned excitation training, but it reduced the level of responding both to the positive stimulus and to the negative compound in the conditioned inhibition training. In Experiments 3 and 4, classical aversive conditioning was studied in the shuttle box. In Experiment 3, excitatory conditioning to a color was found to be impaired (relative to the performance of nonpreexposed control animals) as much by nonreinforced preexposure to the training color as by nonreinforced preexposure to a markedly different color; substantial variation in amount of preexposure was without significant effect. In the conditioned inhibition training of Experiment 4, animals with nonreinforced preexposure responded less than did unstimulated control animals both to the positive stimulus and to the negative compound. The results for goldfish can be understood on the assumption that the effect of preexposure in these animals is simply to reduce general responsiveness or level of arousal.     

Naloxone and Pavlovian fear conditioning

Previous research has shown that pretreating rats with the opiate antagonist naloxone increases the freezing that follows painful electric shock. Three experiments, using freezing behavior as a dependent variable, were carried out to determine whether the drug might cause this effect by enhancing fear conditioning. Two of the studies employed a differential context fear-conditioning paradigm. Naloxone did not affect freezing behavior during the preshock adaptation period. In Experiment 1, naloxone was found to increase resistance to extinction in the S+ context. In Experiment 2, naloxone was found to increase freezing in the S+ context. This effect was dependent upon administering naloxone during training but not dependent on administering it during testing. The third study employed a generalization paradigm. It was found that naloxone's effect on postshock freezing was dependent on the place of testing; as the contextual cues of the test chamber were changed from those of the conditioning chamber, the effect of naloxone on freezing was reduced. The results of these experiments lend strong support to the hypothesis that naloxone increases freezing by enhancing the conditioning of fear to contextual stimuli associated with shock.     

Naloxone and shock-elicited freezing in the rat.

The freezing behavior of the rat that occurs following painful electric shock was found to increase when the animal was pretreated with the opiate antagonist naloxone. Freezing was a positive linear function of drug dose and shock intensity (Experiment 2). Naloxone pretreatment enhanced freezing only when the animal was given two or three shocks but did not affect freezing when the animal was given only one shock or not shocked at all (Experiments 3, 4, and 5). Naloxone must be present during shock, nor just during the observation period, in order to increase freezing (Experiment 6). These results suggest that when an animal is shocked, it releases endogenous analgesics (endorphins) that make a subsequent shock less aversive. Naloxone, by blocking the endorphin system, makes the shock more aversive than it would normally be.     

Ventral and dorsolateral regions of the midbrain periaqueductal gray (PAG) control different stages of defensive behavior: Dorsolateral PAG lesions enhance the defensive freezing produced by massed and immediate shock

Rats that receive nociceptive electric shock in an environment normally show the conditional fear-induced defensive response of freezing when returned to that environment. If several electric shocks are given in a massed manner they will condition less freezing than the same shocks given in a distributed manner. If a single shock is given immediately after placement in the chamber it does not support any conditioning, although the same shock given after a brief delay does. Electrolytic lesions of the dorsolateral periaqueductal gray (PAG), which damaged dorsomedial, dorsolateral, and lateral PAG, enhanced freezing under these conditions. Lesions of the ventral PAG, which caused extensive damage to the central gray below the aqueduct, reduced conditioning under the more optimal parameters (distributed or delayed shock). This was taken to indicate that both of these regions support different modes of defensive behavior and that when activated, the dorsolateral PAG inbits conditional fear-induced defensive behavior. © 1995 Wiley-Liss, Inc.     

Associative effects of US preexposure: modulation of conditioned responding by an excitatory training context

In two experiments we examined factors that contribute to retarded emergence of conditioned responding to a conditioned stimulus (CS) trained in a context in which unsignaled unconditioned stimuli (USs) had previously been administered. In both experiments water-deprived rats were used in a conditioned lick suppression task to measure the conditioned response elicitation potential of the CS and the training context. From Experiment 1 we determined that nonreinforced exposure to the excitatory context after US preexposure and prior to CS-US pairings in that context eliminated the conditioned response deficit observed on a subsequent test of the CS. The recovery from the US preexposure deficit was nearly as great in animals that received nonreinforced exposure to the excitatory training context after the CS-US pairings but prior to the ultimate test of the CS. From Experiment 2 we determined that the recovery induced by contextual deflation after CS training was specific to deflation of the context in which the CS was trained as opposed to another excitatory context. In total, these experiments suggest that context-US associations partially mask the expression of a learned CS-US association. These results are discussed in terms of recent models of conditioned response generation.     

Influence of dorsolateral periaqueductal grey (dlPAG) lesions on contextual conditioning with massed and distributed shock

Three experiments investigated the conditions under which electrolytic lesions of the dorsolateral periaqueductal grey (dlPAG) facilitate conditioned defensive freezing in the rat ( Rattus norvegicus ). Experiment 1 found that dlPAG lesions placed before context-shock pairings facilitated conditioned defensive freezing with massed but not distributed shock. No such effect was found in Experiment 2, when the lesions were placed after context-shock pairings. Experiment 3 found that dlPAG lesions facilitated subsequent conditioning with massed but not a single shock. In addition, no differences in sensitivity to thermal or shock pain were evident in lesioned and unlesioned rats. Taken together, these results are consistent with the suggestion that dlPAG activation interferes with the processing of contextual cues during association formation.     

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.     

Disrupting the conditioned stimulus preexposure effect in flavor-aversion learning: effects of interoceptive distractor manipulations

Rats exposed to a flavor prior to a conditioning trial involving that stimulus learn a significantly diminished flavor aversion relative to nonpreexposed control animals. A series of four experiments investigated the ability of the conditioned stimulus (CS) preexposure effect to be disrupted by the introduction of a distractor flavor stimulus between the preexposure and conditioning episodes. Experiment 1 demonstrated that the preexposure effect could be reduced by a distractor presented immediately following the preexposure. In Experiment 2, it was discovered that a novel distractor was more effective than a familiar distractor, even though both stimuli were sensorily equivalent. Experiment 3 further analyzed the distractor effect and demonstrated that the magnitude of disruption was more pronounced with immediate than with delayed (3 hr) distractor manipulations. Finally, Experiment 4 assessed the effects of the distractor in the absence of CS preexposure. The relation of the results from these experiments to general information theory is discussed.     

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.     

Analysis of the learned irrelevance effect in appetitive Pavlovian conditioning

In Experiments 1 and 2 rats received uncorrelated presentations of a light conditioned stimulus (CS) and a food unconditioned stimulus (US) on each day of a preexposure phase. Control subjects received the same number of USs during the first half of preexposure and the same number of CSs during the second. Uncorrelated preexposure retarded inhibitory conditioning. Experiment 3 showed, however, that the different patterns of US preexposure experienced by the two groups could in itself influence the course of subsequent inhibitory conditioning. When this factor was equated by restricting the uncorrelated treatment to the first half of the pre-exposure phase (Experiment 2) or by extending the control treatment throughout the phase (Experiment 4) it was found that uncorrelated preexposure retarded excitatory conditioning, but facilitated inhibitory conditioning. This outcome challenges an interpretation in terms of the concept of learned irrelevance, which predicts that uncorrelated preexposure should retard both forms of conditioning.     

Nicotine enhances contextual fear conditioning in C57BL/6J mice at 1 and 7 days post-training

Nicotine has been demonstrated to enhance learning processes. The present experiments extend these results to examine the effects of nicotine on acquisition and consolidation of contextual and cued fear conditioning, and the duration of nicotine's enhancement of conditioned fear. C57BL/6 mice were trained with two pairings of an auditory CS and a foot shock US. Multiple doses of nicotine were given before or immediately after training and on testing day (0.0, 0.050, 0.125, 0.250, and 0.375 mg/kg, i.p). Freezing to both the context and auditory CS was measured 24h after training and again 1 week after training. Mice did not receive nicotine for the 1-week retest. Nicotine (0.125 and 0.250 mg/kg) given on both training and testing days enhanced freezing to the context at 24h. In addition, elevated freezing to the context was seen 1 week post-training in mice previously treated with 0.125 and 0.250 mg/kg nicotine. Thus, nicotine-treated mice did show elevated levels of freezing when retested 1 week later, even though no nicotine was administered at the 1-week retest. Mice that received nicotine on training day or testing day only and mice that received nicotine with mecamylamine, a nicotinic receptor antagonist, were not different from saline-treated mice. In addition, post-training administration of nicotine did not enhance fear conditioning. The present results indicate that nicotine enhancement of contextual fear conditioning depends on administration of nicotine on training and test days but results in a long-lasting enhancement of memories of contextual fear conditioning that remains in the absence of nicotine.