Selective impairment of long-term but not short-term conditional fear by the N-methyl-D-aspartate antagonist APV.

Previous research has indicated that the competitive N-methyl-D-aspartate (NMDA) antagonist APV ({dl}-2-amino-5-phosphonovalerate) prevents the Pavlovian conditioning of fear to contextual stimuli when tested 24 hrs, but not immediately, after training. The present study investigated this differential time-dependent effect of APV on fear conditioning. Rats were given either APV or saline and presented with 3 footshocks in a distinctive chamber. Promptly after the shock, rats that had received APV exhibited a species-typical fear response: freezing. However, the freezing lasted for only a short period of time (     

Factors governing single-trial contextual fear conditioning in the weanling rat.

Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The authors adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that N-methyl-D-aspartate (NMDA) receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial exploration is required for the formation of contextual fear memory.

The acquisition of contextual fear in mice is thought to require the formation of a conjunctive representation of the conditioning chamber. This can be achieved during a minimum of 20 to 40 s of exploration immediately prior to the shock or during preexposure to the context at an earlier time. An animal receiving less time in the chamber will show reduced freezing 24 hr later, a condition termed the immediate shock deficit (ISD). In this study, the authors have attempted to uncouple the formation of a contextual representation, based on the conjunction of a defined set of cues, from the establishment of a spatial representation, which requires active exploration, by inserting a transparent plastic partition in the center of the chamber. Taking advantage of the ISD and the context preexposure effect, the authors found that animals preexposed to one side of the chamber on Day 1, but shocked on the other side on Day 2, show significantly less fear than animals exposed to and shocked on the same side. Our results indicate that spatial exploration is necessary for mice to benefit from contextual preexposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of the N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonovalerate on acquisition of fear of auditory and contextual cues.

Intracerebroventricular (icv) administration of the N-methyl-D-aspartate (NMDA) antagonist {dl}-2-amino-5-phosphonovalerate (APV) before tone-shock pairings caused a dose-dependent suppression of acquisition of fear of contextual cues associated with shock in 3 experiments involving 110 rats. Acquisition of fear of the tone was not impaired. Exp 2 showed that the fear of the tone was associative and that this tone-shock association was less affected by APV than was a context-shock association. Rats receiving APV before context-shock pairings showed an equivalent loss of fear regardless of whether testing occurred 1 or 28 days after training. It appears that icv administration of APV blocks acquisition of context conditioning by affecting NMDA receptors in the hippocampus. Activity at these receptors at the time of acquisition seems critical for later expression of both intermediate (1 day to 2 wks) and remote (4 wks) fear memories. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories.

The authors used 3-phase context preexposure facilitation methodology to study the contribution of N-methyl-D-aspartate (NMDA) receptors in dorsal hippocampus (DH) and the basal lateral region of the amygdala (BLA) to (a) acquisition of the context memory, (b) retrieval of the context memory, (c) acquisition of context-shock association, and (d) retrieval of the context-shock association. The NMDA receptor antagonist D-2-amino-5 phosphonopentanoic acid (D-AP5) was injected into either the DH or BLA prior to (a) the context preexposure phase, (b) the immediate shock phase, or (c) the test for contextual fear. Antagonizing NMDA receptors in the DH impaired the acquisition of the context memory but did not affect its retrieval or retrieval of the fear memory. Antagonizing NMDA receptors with D-AP5 in the BLA impaired acquisition of the context-shock association but had no effect on the expression of fear. However, both DL-AP5 and L-AP5 reduced the expression of fear when they were injected into the amygdala prior to testing for contextual fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Preexposure effects in the spatial domain: Dissociation between latent inhibition and perceptual learning.

In 4 experiments, rats were given intermixed or blocked preexposure to an array of landmarks that subsequently defined the location of a hidden goal in a Morris pool task. Previous research has shown that intermixed preexposure to pairs of adjacent landmarks retards learning whereas preexposure to individual landmarks facilitates subsequent learning (J. Prados, V. D. Chamizo, & N. J. Mackintosh, 1999). Accordingly, in Experiment 1, intermixed and blocked preexposure to pairs of adjacent landmarks was found to retard learning. In Experiment 2, however, a scheduling effect was found: Rats given intermixed preexposure to the individual landmarks learned faster than rats given blocked or no preexposure. Experiment 3 showed that intermixed (but not blocked) preexposure to pairs of landmarks resulted in a facilitatory effect when preexposure and test were carried out in different contexts. Experiment 4 replicated within a single experiment the main results observed in Experiments 1 and 3. This pattern of results suggests that intermixed preexposure engages learning processes other than latent inhibition that facilitate subsequent learning of the navigation task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats

NMDA receptors in the amygdala seem to be critical for fear conditioning in naive rats. Recent spatial-learning studies suggest that previous learning protected animals from the amnesic effect of NMDA antagonists on new learning (of a similar behavioral task). Therefore, the present study examined whether blocking of NMDA receptors in the basolateral nucleus of the amygdala (BLA) prevents new fear learning in previously fear-conditioned rats, as measured by freezing behavior. Intra-BLA infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) completely blocked fear conditioning to a tone stimulus in animals that had previously been fear-conditioned to a light stimulus. Similar results were obtained with intra-BLA infusions of APV before contextual fear conditioning in rats that had been fear-conditioned to a different context. Additional experiments showed that intra-BLA APV infusions substantially interfere with the expression and extinction of conditioned fear to tone, light, and context stimuli. Together, these results indicate that NMDA receptors in the BLA are crucial for the encoding of new fear memories (i.e., the formation of specific conditioned stimulus-unconditioned stimulus association), the expression of conditioned fear responses, and the extinction of acquired fear.     

Nicotine enhances context learning but not context-shock associative learning.

Nicotine has been found to enhance learning in a variety of tasks, including contextual fear conditioning. During contextual fear conditioning animals have to learn the context and associate the context with an unconditioned stimulus (footshock). As both of these types of learning co-occur during fear conditioning, it is not clear whether nicotine enhances one or both of these types of learning. To tease these two forms of learning apart, the authors made use of the context preexposure facilitation effect (CPFE). Acquisition of the CPFE requires that contextual and context-shock learning occurs on separate days, allowing for their individual manipulation. Nicotine (0.09 mg/kg) administered prior to contextual learning and retrieval enhanced the CPFE whereas administration prior to context-shock learning and retrieval had no effect. Thus, nicotine enhances contextual learning but not context-shock associative learning. Finally, the results are discussed in terms of a theory of how nicotine could alter hippocampal-cortical-amygdala interactions to facilitate contextual learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Latent inhibition and contextual associations.

Attenuated responding to a 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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex differences, context preexposure, and the immediate shock deficit in Pavlovian context conditioning with mice.

The acquisition of context fear in rats is affected by variables such as the sex of the animal, the placement to shock interval (PSI), and preexposure to the context. The current experiments assessed the effects of these variables on context conditioning in mice (C57BL/6). In Experiment 1, mice were placed in a chamber and received a single shock 5 s, 20 s, 40 s, 60 s, 180 s, or 720 s later. Increasing the PSI produced corresponding increases in conditional freezing during the context test. In addition, male mice acquired more context conditioning than female mice did but only at intermediate PSIs. In Experiment 2, preexposure to the context before training alleviated the sex difference found with an intermediate PSI. The results are discussed in terms of configural learning theory and are argued to be contrary to the predictions of scalar expectancy theory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An immediate-shock freezing deficit with discrete cues: A possible role for unconditioned stimulus processing mechanisms.

Five experiments with C57BL/6 mice (Mus musculus) investigated whether failures in shock processing might contribute to deficits in freezing that occur after an animal receives a shock immediately on exposure to a conditioning context. Experiment 1 found that more contextual freezing resulted from delayed shocks than from immediate shocks across 4 shock intensities. Experiment 2 extended the immediate-shock freezing deficit to discrete stimuli. Experiment 3 found that preexposure to the to-be-conditioned cue did not facilitate immediate cued conditioning. Experiment 4 found that context preexposure enhanced context-evoked fear after an immediate shock. Experiment 5 found that context preexposure also enhanced immediate cued conditioning. These findings are problematic for current theories of the immediate-shock freezing deficit that focus exclusively on processing of the conditioned stimulus, and they suggest that failures in shock processing may contribute to the deficit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Exercise on Pavlovian Fear Conditioning.

Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

State-dependent fear extinction with two benzodiazepine tranquilizers.

Investigated whether fear extinction conducted under the influence of a benzodiazepine transfers to the undrugged state in rats. Fear was conditioned by pairing an experimental chamber with footshock and was assessed by observing freezing, a characteristic response of the rat to stimuli associated with shock. In Exp 1, both chlordiazepoxide (librium) and diazepam (valium) interfered wih extinction in a dose-dependent manner as indicated by freezing during an undrugged test. Further results with chlordiazepoxide suggested that the effect depended on the drug's specific combination with extinction and that it occurred even though the extinction procedure otherwise eliminated fear completely (Exp 2). Repeated preexposure to the drug, and the development of partial tolerance to its sedative effects, did not weaken the interference effect (Exp 3). Other evidence suggested that the drug signaled or retrieved extinction instead of disrupting learning or consolidation (Exp 4). The results are consistent with research suggesting that extinguished fear can be "renewed" if the exteroceptive contextual stimuli are changed after extinction. Extinction combined with either unique exteroceptive or interoceptive cues may be specific to its context. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of the conditional fear.

The acquisition of conditional freezing is abolished by N-methyl-D-aspartate (NMDA) receptor antagonism in the basolateral complex of the amygdala (BLA) during fear conditioning, suggesting that memory formation is prevented. The present study examined whether there is residual memory, or "savings," for fear conditioning in rats trained under amygdaloid NMDA receptor blockade. Rats infused with D,L-2-amino-5-phosphonovalerate (APV) into the BLA or central nucleus of the amygdala (CEA) during fear conditioning did not acquire either auditory or contextual fear conditioning. However, savings of conditional fear was exhibited by rats infused with APV into the CEA but not the BLA. These results suggest that both the BLA and CEA play a critical role in the acquisition of conditional fear but that the BLA is able to process and retain some aspects of aversive memories in the absence of the CEA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potentiation of latent inhibition.

Rats were given exposure either to an odor (almond) or a compound of odor plus taste (almond plus saline), prior to training in which the odor served as the conditioned stimulus. It was found, for both appetitive and aversive procedures, that conditioning was retarded by preexposure (a latent inhibition effect), and the extent of the retardation was greater in rats preexposed to the compound (i.e., latent inhibition to the odor was potentiated by the presence of the taste). In contrast, the presence of the taste during conditioning itself overshadowed learning about the odor. We argue that the presence of the salient taste in compound with the odor enhances the rate of associative learning, producing a rapid loss in the associability of the odor. This loss of associability will generate both overshadowing and the potentiation of latent inhibition that is observed after preexposure to the compound. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microinjection of morphine into the nucleus accumbens impairs contextual learning in rats.

A unilateral microinjection of morphine into the amygdala impaired fear conditioning to both a conditioned stimulus (CS) paired with shock and the context where shock occurred, whereas a microinjection of morphine into the nucleus accumbens (NA) spared fear conditioning to the CS but impaired, in a dose-dependent and receptor-specific manner, fear conditioning to the context. Morphine in the NA also spared extinction and latent inhibition of a CS but abolished the context specificity of these effects and eliminated the increase in discriminability that results from preexposure to a to-be-shocked context. The results identify a role for the NA in the processes by which rats learn about a context and are discussed in terms of an opioid disruption of either within-context associations or of attentional processes that contribute to such associations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala.

24 female rats, with chronic cannula placed bilaterally in the amygdala, received infusions of the N-methyl-{d}-aspartate (NMDA) receptor antagonist {d},{l}-2-amino-5-phosphonovaleric acid (APV) before contextual Pavlovian fear conditioning. Administration of APV to the basolateral nucleus prevented acquisition of fear. Central nucleus infusions had no effect. It is concluded that an NMDA-mediated process near the basolateral region of the amygdala (e.g., lateral or basolateral nucleus) is essential for the learning of fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Immediate shock deficit in fear conditioning: Effects of shock manipulations.

Pavlovian contextual fear conditioning occurs when an aversive unconditional stimulus (US), such as a footshock, is presented to a rat shortly after it is placed in an experimental context. Contextual fear conditioning does not occur when the shock is presented immediately upon placement of the rat in the novel chamber. In the present study, the authors report that increasing either the number of immediate shock sessions (Experiment 1) or the immediate shock duration (Experiment 2) did not reverse this deficit. However, immediate shock seems to sensitize subsequent context conditioning (Experiment 3). These findings suggest that the associative deficit produced by immediate shock is not related to the rat's ability to process the footshock US. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Temporal-difference prediction errors and Pavlovian fear conditioning: Role of NMDA and opioid receptors.

Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear conditioning. In Stage I, rats received conditioned stimulus A (CSA) paired with shock. In Stage II, they received pairings of CSA and CSB with shock that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB 3 CSA, was followed by shock. The change in intratrial durations supported fear learning to CSB but reduced fear of CSA, revealing the operation of TD prediction errors. N-methyl- D-aspartate (NMDA) receptor antagonism prior to Stage III prevented learning, whereas opioid receptor antagonism selectively affected predictive learning. These findings support a role for TD prediction errors in fear conditioning. They suggest that NMDA receptors contribute to fear learning by acting on the product of predictive error, whereas opioid receptors contribute to predictive error. (PsycINFO Database Record (c) 2010 APA, all rights reserved)