Ontogeny of contextual fear conditioning in rats: Implications for consolidation, infantile amnesia, and hippocampal system function.

Presents developmental evidence that contextual fear conditioning is supported by a short-term memory system that supports conditioning immediately after a shock and by a long-term memory system that supports contextual conditioning 24 hrs after training. This is based on the finding that after 1 conditioning trial, rats 18–32 days old show the same amount of conditioned freezing when tested immediately after conditioning but 18-day-old rats show much less conditioned freezing than the older rats when the retention interval is 24 hrs. The data also suggest that the long-term memory representation of context that mediates conditioned fear is not available until several hours after the conditioning trial. Implications of these findings for memory consolidation processes, infantile amnesia, and hippocampal formation development are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A comparison of contextual and generalized auditory-cue fear conditioning: evidence for similar memory processes

A number of variables influence contextual, but not auditory-cue, fear conditioning. However, several of these variables (isolation, stimulus preexposure, retention interval, and age) affect generalized auditory-cue fear. More generalized fear was found when (a) rats were isolated in a novel environment than when returned to their home cages, (b) the retention interval was 3 hr rather than 24 hr, and (c) in 18-day-old compared with 25-day-old rats. Moreover, preexposure to the auditory cue eliminated the isolation effect. At a behavioral-psychological level, these variables may exert their effects by influencing the processes that construct a memory representation of the stimulus. At a neural systems level, they may influence processing carried out in the thalamo-corticoamygdaloid auditory pathway.     

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)     

Eyeblink conditioning in the developing rat.

Long-Evans rat pups, 17–18 or 24 days of age, were trained with an eyeblink conditioning (EBC) procedure that was used previously with adult rats (R. W. Skelton, 1988). Pups received 3 sessions of delay conditioning in a single day at about 4-hr intervals (100 trials/session). Trials involved pairings of an auditory CS (2.8-kHz, 82-db tone) and a periocular-shock unconditioned stimulus (UCS; 100 msec, 2mA), which were presented 280 msec apart. EBC was observed at both ages, but older pups learned much more rapidly. Subsequent experiments established that this effect is associative (Exp 2), that age differences in EBC cannot be attributed to differences in ability to respond or in sensitivity to the UCS (Exp 3), and that EBC rate can be modulated by motivational state (Exp 4). This preparation may help elucidate the relation between neural development and the ontogeny of learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behaviorally functional opioid systems in infant rats: I. Evidence for olfactory and gustatory classical conditioning.

Conducted 2 series of experiments to characterize the behavioral function of opioid systems in neonatal rats. In the 1st series, the reinforcing properties of exogenous opioids were investigated in 112 5-day-old pups. Ss' ability to associate the novel taste of saccharin, received while suckling, with intraperitoneal morphine injections was assessed. Results show that Ss that received 0.5 ml of saccharin prior to morphine administration ingested considerably more saccharin on Day 10 than did control rats. The 2nd set of experiments was conducted to determine whether 144 rat pups could associate a novel odor with morphine administration. Five days after conditioning, that stimulus was highly preferred by morphine-treated Ss compared with saline control Ss. Thus positive associations were formed with either a novel taste stimulus experienced while suckling or with an odor experienced during social isolation. Conditioning was cue specific and was retained for at least 5 days. The formation of these associations was blocked with opioid antagonists given prior to conditioning. Data suggest behaviorally functional opioid receptors and raise the possibility of a functional role of the endogenous opioids in motivational processes in infant rats. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Identification of quantitative trait loci involved in contextual and auditory-cued fear conditioning in BXD recombinant inbred strains.

Fear conditioning shows associations formed between contextual or auditory stimuli with an unconditioned stimulus. Inbred mouse strains differ in their ability to demonstrate fear conditioning, suggesting at least a partial genetic influence. The present study identified the possible chromosomal loci regulating fear conditioning in BXD recombinant inbred strains using quantitative trait loci (QTL) analysis. Estimates of heritability for all 3 measures of conditioning were about .28. Correlational analyses between genetic markers and strain means identified multiple putative QTLs. The strongest associations were on Chromosomes 1 and 17 for freezing to the context, Chromosome 12 for freezing to an altered context, and Chromosome 1 for freezing to the auditory stimulus. Overlapping QTLs may indicate some common genes that underlie aspects of this learning task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conserved regulatory element involved in the early onset of Hoxb6 gene expression

When administered before training to 23-day-old Long-Evans rats, scopolamine hydrobromide significantly impaired both contextual and auditory-cue fear conditioning in a dose-dependent manner. Methylscopolamine which does not cross the blood-brain barrier, however, had no effect on either form of conditioned fear. Scopolamine administered up to 3 h after training also impaired both forms of fear conditioning when administered following a single pairing of the auditory cue and shock. When rats received three pairings, however, a posttraining treatment with scopolamine only impaired contextual fear conditioning. These results suggest that central cholinergic systems are involved in the posttrial processes that establish the memory trace for the conditioning experience.     

Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.

The contribution of the amygdala and hippocampus to the acquisition of conditioned fear responses to a cue (a tone paired with footshock) and to context (background stimuli continuously present in the apparatus in which tone–shock pairings occurred) was examined in rats. In unoperated controls, responses to the cue conditioned faster and were more resistant to extinction than were responses to contextual stimuli. Lesions of the amygdala interfered with the conditioning of fear responses to both the cue and the context, whereas lesions of the hippocampus interfered with conditioning to the context but not to the cue. The amygdala is thus involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli (CS) as well as to complex, polymodal stimuli, whereas the hippocampus is only involved in fear conditioning situations involving complex, polymodal events. Findings suggest an associative role for the amygdala and a sensory relay role for the hippocampus in fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Backward conditioning: Mediation by the context.

The information acquired in backward conditioning (i.e., outcome→cue) was assessed in 3 Pavlovian lick-suppression experiments with water-deprived rats as subjects. Experiment 1 confirmed previous research that few outcome→cue pairings made the cue into a conditioned excitor and additionally showed that massive posttraining extinction of the training context attenuated a backward-trained cue's excitatory value. Experiment 2 found that many outcome→cue pairings made the cue into a conditioned inhibitor and that the same context manipulation attenuated this inhibitory value. Experiment 3 confirmed the observations of Experiments 1 and 2 and demonstrated that these effects of context extinction were specific to backward-trained cues conditioned in the extinguished context. These results are interpreted in terms of cue→context and context→outcome associations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Regulation of contextual conditioning by the median raphe nucleus

The median raphe nucleus (MRN) has been suggested as the origin of a behavioral inhibition system that projects to the septum and hippocampus. Electrical stimulation of this mesencephalic area causes behavioral and autonomic manifestations characteristic of fear such as, freezing, defecation and micturition. In this study we extend these observations by analyzing the behavioral and autonomic responses of rats with lesions in the MRN submitted to a contextual conditioning paradigm. The animals underwent electrolytic or sham lesions of the median raphe nucleus. One day (acute) or 7 days (chronic) later they were tested in an experimental chamber where they received 10 foot-shocks (0.7 mA, 1 s with 20-s interval). The next day, sham and MRN-lesioned animals were tested again either in the same or in a different experimental chamber. During this, the duration of freezing, rearings, bouts of micturition and number of fecal boli were recorded. Sham-operated rats placed in the same chamber showed more freezing than rats exposed to a different context. This freezing behavior was clearly suppressed in rats with acute or chronic lesions in the MRN. MRN lesions also reduced the bouts of micturition and number of fecal boli. These rats showed a reduced number of rearings than sham-lesioned rats. This effect is probably the result of the displacement effect provoked by freezing since no significant differences in the number of rearings could be observed between these animals and the NMR-lesioned rats tested in an open field. This lesion produced higher horizontal locomotor activity in this test than the controls (sham-lesioned rats). These results point to the importance of the median raphe nucleus in the processing of fear conditioning with freezing being the most salient feature of it. Behavioral inhibition is also under control of MRN but its neural substrate seems to be dissociated from that of contextual fear.     

Differential effects of training intertrial interval on acquisition of trace and long-delay fear conditioning in rats.

Many factors govern conditioning effectiveness, including the intertrial interval (ITI) used during training. The present study systematically varied the training ITI during both trace and long-delay fear conditioning. Rats were trained using one of six different ITIs and subsequently tested for conditioning to the white noise conditioned stimulus (CS) and the training context. After trace conditioning, percent freezing to the CS was positively correlated with training ITI, whereas percent freezing to the context was negatively correlated with training ITI. In contrast, when rats were trained using a long-delay paradigm, freezing during the CS test session did not vary as a function of training ITI; rats exhibited robust freezing at all ITIs. The long-delay conditioned rats exhibited relatively low levels of freezing during the context test. Thus, trace is more sensitive than long-delay fear conditioning to variations in the training ITI. These data suggest that training ITI is an important variable to consider when evaluating age or treatment effects, where the optimal ITI may vary with advancing age or pharmacological treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli.

The GABAa agonist, muscimol (0.5 μg in 0.5 μl saline), or vehicle was infused into the lateral and basal amygdala nuclei prior to fear conditioning or testing in rats. Rats given muscimol before conditioning and saline before testing showed much less freezing to the conditioned stimulus (CS) and the context than did controls given saline before training and testing. Rats given saline before training and muscimol prior to testing also showed low levels of freezing to the CS and the context. In follow-up procedures, rats with acquisition initially blocked by pretraining muscimol infusions froze in a manner similar to that of controls when retrained and retested with saline infusions. Rats trained with saline but tested with muscimol presumably became conditioned but could express the learning. When retested with saline, they froze in the same manner as controls. Thus, activity in the lateral and basal amygdala appears to play an essential role in the acquisition and expression of fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ontogenetic differences in the expression of conditioned stimulus conditioning: effects of retention interval

Preweanling 17-day-old rats were tested for retention of the conditioned emotional response after a 5-min or 24-hr retention interval. For a variety of conditioning parameters (i.e., variation in conditioned stimulus modality, unconditioned stimulus intensity, number of training trials), conditioned responding was consistently weaker after 5 min than after 24 hr. This apparent "incubation," or "hypermnesic," effect was not found in adult rats, even when comparable conditioning levels were indicated on the 24-hr test. The transient short-term retention deficit observed in 17-day-old preweanlings was alleviated by placing the pup in its home cage during the 5-min retention interval or by extending the conditioning session. Fifteen-day-old rat pups did not benefit from home cage exposure or extended training and displayed the transient short-term retention deficit regardless. The results are discussed in terms of age-related effects on time-dependent memory consolidation.     

DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning.

It has been proposed that DBA/2 and C57BL/6 mice perform differently on some learning and memory tasks because of functional differences in the hippocampal formation. To evaluate this hypothesis, DBA/2 and C57BL/6 male mice were tested on 2 forms of conditioned fear: contextual fear conditioning, which depends on the integrity of the hippocampal formation, and auditory cue conditioning, which does not. Both mouse strains displayed equivalent conditioning when the auditory cue was paired with shock, but DBA/2 mice showed significantly less conditioning to the context in which shock was experienced. These results are consistent with the hypothesis that the pattern of spared and impaired performance, which DBA/2 mice display on a variety of learning and memory tasks, is related to impaired hippocampal formation function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal lesions impair contextual fear conditioning in two strains of mice.

Two different strains of mice, C57BL/6J and BALB/c, with hippocampal, cortical, or sham lesions, underwent contextual fear conditioning. In both strains, contextual fear, as measured by the freezing response, was significantly impaired in hippocampus-lesioned animals compared with sham control animals. Fear conditioning was not affected in the cortical-lesioned group. Moreover, there was a strain difference in fear conditioning: The C57BL/6J mice exhibited freezing more frequently than the BALB/c mice. Consistent with previous hippocampal lesion studies in rats, these results indicate that contextual fear conditioning in mice also requires the intact hippocampus. This study provides a basis for evaluating hippocampal synaptic mechanisms in relation to contextual fear conditioning in widely available gene knockout or transgenic mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticosteroid induction of threat-induced behavioral inhibition in preweanling rats.

Termination of ongoing behavior and assumption of defensive postures when threatened are adaptive characteristics of vertebrates. Altricial rat pups develop these characteristics by 14 days of age. At this time, pups inhibit their ultrasonic vocalizations and freeze when threatened. This emergence of behavioral inhibition is impaired when rats are adrenalectomized (ADX) at 10 days of age. That is, 14-day-old ADX pups exhibit deficits in freezing and continue to emit ultrasounds when confronted by an adult male rat. Studies also showed that removal of adrenal hormones does not potentiate vocalizations or render pups incapable of reducing their ultrasounds. More important, 3.0 mg/kg of corticosterone (CORT), but not lower doses, administered daily to ADX pups restored freezing, with lesser effects on ultrasound inhibition. Disrupting the developmental action of endogenous CORT appears to impair the ontogenic expression of behavioral inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Partial disruption of fear conditioning in rats with unilateral amygdala damage: correspondence with unilateral temporal lobectomy in humans

Conditioned fear in rats was assessed for the effects of pretraining amygdala lesions (unilateral vs. bilateral) across unconditioned stimulus (US) modalities (white noise vs. shock). In contrast to sham controls, unilateral amygdala lesions significantly reduced conditioned freezing responses, whereas bilateral amygdala lesions resulted in a nearly complete lack of freezing to both the conditioned stimulus (CS) and the context. The lesion effects were more pronounced for CS conditioning but were consistent across US modalities. It was concluded that white noise can serve as an effective US and that unilateral amygdala lesions attenuate but do not eliminate conditioned fear in rats. The results support our interpretation of a recent fear conditioning study in humans (K. S. LaBar, J. E. LeDoux, D. D. Spencer, & E. A. Phelps, 1995).     

Effects of lesions to the hippocampus on contextual fear: Evidence for a disruption of freezing and avoidance behavior but not context conditioning.

The effects of ibotenic lesions of the hippocampus on conditioning to contextual cues during classical fear conditioning in rats were evaluated by (a) the amount of freezing elicited by contextual cues and (b) the relative avoidance of a shock compartment. In Experiment 1, lesions to the hippocampus had no effect on contextual freezing and marginally affected avoidance after repeated sessions. Experiment 2 showed that lesions to the hippocampus disrupted avoidance when tested after a single conditioning session, while leaving unaffected the acquisition of contextual freezing. Experiment 3 indicated that these lesions decreased the acquisition of contextual freezing when higher footshock intensity was used but had no effect on avoidance after repeated conditioning sessions. These results show that freezing and avoidance do not quantify context conditioning similarly. They further indicate that lesions to the hippocampus may disrupt the expression of these behaviors used as measures of context conditioning but not the acquisition of context conditioning per se. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contextual and cued fear conditioning in C57BL/6J and DBA/2J mice: Context discrimination and the effects of retention interval.

Context discrimination and time course studies of contextual fear conditioning revealed strain differences between C57BL/6J (B6) and DBA/2J (D2) mice. Both strains discriminated contexts, but D2 mice exhibited less freezing in a shock-paired context. The strains did not differ immediately, or at 2 and 3 hr after contextual fear conditioning training. D2 mice showed less freezing at 15 min, 30 min, and 24 hr after training. B6 mice exhibited exaggerated generalized freezing and poor discrimination between the context and altered context 7-30 days after training. The acoustic startle response in B6 mice was also enhanced at 14 days after training. D2 mice did not show this pattern of generalized freezing. B6, but not D2, mice retained contextual memories for at least 60 days. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interpreting the effects of exercise on fear conditioning: The influence of time of day.

Previous studies indicate that physical exercise improves contextual fear memory, as evidenced by increased freezing behavior when rats are returned to a training environment that was initially paired with footshock. However, freezing behavior could also be affected by fatigue, especially because rats were tested shortly after the end of the dark cycle, which is when most wheel running was likely to occur. In addition, exercise has been shown to have anxiolytic effects, further confounding interpretation of the effects of exercise on cognition when using aversive conditioning tasks. These factors were examined in the present study by comparing freezing behavior in exercising and nonexercising rats that were tested at different times in the light cycle. In addition, all rats were tested on an elevated plus maze to assess anxiety-like behavior and in an open-field apparatus to measure locomotor activity in order to directly examine interactions between freezing, anxiety-like behavior, and locomotion. Consistent with prior studies, exercising rats exhibited more context freezing than did sedentary rats when tested early in the light cycle. However, the opposite pattern of results was obtained when testing occurred late in the light cycle, an effect driven by a difference in the amount of freezing exhibited by the sedentary control groups. Indeed, the levels of context freezing exhibited by exercising rats were comparable regardless of when the rats were tested during the light cycle. These data have implications for interpreting the effects of exercise on aversive conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)