MK-801 induced retrieval, but not acquisition, deficits for passive avoidance conditioning.

Two experiments using a state-dependent retention (SDR) design determined whether MK-801 blocked the acquisition and retention of an avoidance response. In Experiments 1 and 2, rats were trained and tested 30 min after injections of either saline or MK-801 (0.05 and 0.10 mg/kg, respectively). Two minutes after training, subjects were immediately tested, and in both experiments, the avoidance response was acquired. The 24-h retention tests for Experiment 1 revealed that the data marginally supported a SDR interpretation. In Experiment 2, the dose of MK-801 was increased to 0.10 mg/kg, and the results showed that MK-801 rendered passive avoidance (PA) state-dependent. These experiments indicate that neither the 0.05 nor 0.10 mg/kg doses of MK-801 prevented acquisition of the avoidance response and that the latter dose rendered memory for PA training state-dependent. It is suggested that doses of MK-801 that did not impair PA learning can function as a cue state and influence expression of memory for PA.

Interpretations of retrograde amnesia: old problems redux.

Recent evidence indicates that an old memory reactivated by cueing becomes labile and vulnerable to an amnesic treatment. Although the 'reconsolidation' concept derived from these findings challenges the traditional consolidation theory, here we argue that the new concept suffers from some of the same limitations as the earlier model. We propose an alternative retrieval-based theory that accommodates the recent data, as well as other puzzling related observations.

d-Cycloserine: effects on long-term retention of a conditioned response and on memory for contextual attributes.

d-Cycloserine (DCS), a partial agonist of the glycine recognition site of the N-methyl d-aspartate receptor, has beneficial effects on learning and memory. In order to investigate its potential to influence learning and memory of both the response and the stimulus attributes of training, male Sprague-Dawley albino rats were trained in a one-trial inhibitory avoidance task following an acute intraperitoneal injection of DCS (3 mg/kg) or an equal volume of saline. In order to measure memory for stimulus attributes, testing involved a context shift paradigm, in which subjects are tested in either the environment of training or a different one. Good memory for the contextual attributes of training is indicated by poor performance in the alternate context. Retention was assessed either 1, 7, or 14 days after training. At 1 day, Saline subjects were affected by a change in context, while DCS subjects were not. In subjects tested 1 week following training, Saline subjects were no longer affected by a change in context, in that they performed the avoidance response in both contexts. This indicates the forgetting of stimulus attributes in Saline subjects. DCS subjects did show the context shift effect at 1 week, indicating the retention of stimulus attributes. Finally, Saline subjects demonstrated the context shift rebound at 14 days, while DCS subjects performed equivalently in both contexts. Taken together, these data suggest that DCS may enhance retention of fear and slow the forgetting of stimulus attributes.

Ketaset-Rompun extends the temporal gradient for hypothermia-induced retrograde amnesia.

In studies of experimentally induced retrograde amnesia (RA), as the interval between training and the amnestic treatment is lengthened, amnesia decreases (4). This temporal gradient for RA has been reported with a wide variety of amnestic agents, including RA produced by thermoregulatory disturbances (8). This temporal gradient for RA is not unlike certain characteristics of classical conditioning, where weaker conditioned responding occurs when the interval between the conditioned stimulus (CS) and unconditioned stimulus (US) is lengthened. Furthermore, there is evidence that administration of anesthetics can lengthen the "effective conditioning" interval between the CS and US, as demonstrated in a conditioned taste-aversion (CTA) procedure (10). In that study, little conditioning was observed when a 3-h delay (or more) was incorporated between presentations of the CS (flavor) and the US (toxin). However, if subjects were anesthetized immediately after the CS was delivered and remained anesthetized during the CS-US interval, strong conditioning was observed with CS-US intervals of up to 9 h. The aim of the present experiment was to determine if the temporal gradient for hypothermia-induced RA could also be lengthened. That is, we tested whether the interval between training and hypothermia treatment could be lengthened by anesthetizing subjects with Ketaset-Rompun. The results indicate that the training-to-amnestic agent interval could be lengthened within moderate limits. The implications for hypothermia-induced RA is further discussed.

Post-training glucose administration attenuates forgetting of passive-avoidance conditioning in 18-day-old rats.

The study of memory modulation in infant rats has typically focused on reminder/retrieval treatments involving reexposure to components of the internal or external training context. Rarely have studies employed pharmacological treatments to investigate the neurochemical substrates of memory storage in preweanling rats. The present study investigated the effect of 100 mg/kg of glucose, a common memory modulator in adult mammals, on memory for passive-avoidance conditioning in 18-day-old Sprague-Dawley rats. Subjects that were administered an immediate post-training injection of glucose performed significantly better, on a retention test 24 h following training, than those animals that received saline. The glucose group also performed comparably to a control group that was tested 10 min following training. These results are consistent with those of the memory modulation literature in adults and suggest that the rapid rate of forgetting in immature organisms may be the result of a deficiency in a general memory modulatory system.

The contextual change paradox is still unresolved: comment on Bouton, Nelson, and Rosas (1999)

According to the contextual change theory of memory loss, spontaneous forgetting reflects a retrieval impairment due to subtle and unprogrammed shifts in environmental cues over a retention interval. However, Riccio, Richardson, and Ebner (1984) noted an apparent paradox in this model; specifically, laboratory studies inducing explicit shifts in contextual cues found less disruption of performance as retention intervals increased. Bouton, Nelson, and Rosas (1999) critiqued several of the claims made by Riccio et al. and concluded that the contextual cue theory is still a valid account of spontaneous forgetting. In this comment, the authors address the 3 major criticisms offered by Bouton et al., point out an inconsistency in their argument, and conclude that the original paradox still poses problems for the contextual change theory of forgetting.

Pretest administration of glucose attenuates infantile amnesia for passive avoidance conditioning in rats.

Infantile amnesia in rats may be attenuated by a wide variety of retrieval cues which reactivate memory for the training episode. The present study investigated the effects of glucose on memory retrieval in infant rats. In Experiment 1, 17-day-old preweanling rats were trained to criterion on passive avoidance conditioning. Twenty-four hours later, each subject received a subcutaneous injection of either saline, 100 mg/kg, or 250 mg/kg of glucose just prior to testing. Saline animals displayed poor retention scores, suggesting infantile amnesia; however, glucose significantly attenuated the 24-hr retention loss. Experiment 2 attempted to replicate the previous experiment, control for age and general drug effects, and extend the dose of glucose to 400 mg/kg. The results of Experiment 2 were consistent with Experiment 1 and also indicated that infant subjects performed significantly worse than adults. Both 100 and 250 mg/kg of glucose significantly attenuated infantile amnesia; however, 400 mg/kg had no effect. These results support a retrieval failure view of infantile amnesia and extend the memory-influencing properties of glucose to infants. Context and neuroendocrine views of memory retrieval are discussed.

Does induced recovery from amnesia represent a disinhibition effect?

Induced recovery from amnesia appears similar to disinhibition effects obtained when response strength is weakened in various ways. Therefore, the possibility that reexposure to the amnestic treatment acts as a "disinhibitor" is problematic for a retrieval interpretation of recovery following amnesia. Two experiments examined the question of whether or not hypothermia treatment (i.e., deep body cooling) acts as a disinhibitor for an extinguished fear response in Sprague-Dawley rats. The results of Experiment 1 indicate that deep body cooling did not significantly disinhibit a passive-avoidance response that had previously been extinguished with a 4-min nonreinforced exposure to the shock chamber of the apparatus. Experiment 2 further examined this negative effect by using a modified passive-avoidance procedure and lengthening the extinction session from 4 to 12 min. Similar to Experiment 1, the results of the second experiment also suggested that if the subject's body temperatures were reduced prior to the retention test, no disinhibitory effect of fear conditioning was manifested. These findings support the notion that memory retrieval (i.e., the contextual cue explanation) is the basis for the alleviation of amnesia by reexposure to the amnestic agent.

Differential effects of Ketaset/Rompun anesthesia on hypothermia-induced retrograde amnesia and its recovery.

A nonbarbiturate anesthetic consisting of ketamine HCl (Ketaset) and xlyazine (Rompun) was administered to assess the effects of anesthesia on hypothermia-induced retrograde amnesia in Long Evans hooded and Sprague-Dawley albino rats. Results from Experiment 1a indicate that this anesthetic does not attenuate retrograde amnesia, and the findings from Experiment 1b suggest that awakening from Ketaset/Rompun anesthesia at normal body temperature (following administration of deep body cooling) does not attenuate the resulting hypothermia-induced retrograde amnesia. Experiment 2 demonstrated that various delays between training and hypothermia resulted in a temporal gradient that was the same for animals cooled while either conscious or under anesthesia. The results of Experiment 3 showed that rats made amnesic while under anesthesia did not recover the target memory if given a recooling treatment, but rats that were made amnesic while conscious did recover the memory with the same reminder treatment. These findings indicate that the conscious processing of stimuli associated with hypothermia treatment is not necessary in inducing hypothermia-induced retrograde amnesia, but that conscious processing is an important factor if the amnesia is to be recovered with a recooling treatment.

Concussion-induced retrograde amnesia in rats.

Three experiments were conducted to investigate the characteristics of retrograde amnesia (RA) induced by concussion in rats. In Experiment 1, rats receiving experimental concussion shortly after training in a single punishment trial exhibited severe forgetting on a retention test 48 h later. In the second experiment, rats receiving a concussion within 6 h after training showed severe RA, while those receiving concussion one day to five days after training exhibited progressively weaker amnesia. In Experiment 3, amnesic animals in one group received pretest noncontingent foot shock as a reminder treatment. This pretest cue significantly increased the cross-through latency, thus indicating a reduction in the memory deficit resulting from concussion. These results suggest that experimental concussion can be an effective method to induce retrograde memory loss in rats; that the RA caused by concussion is time-dependent; and that concussion-induced RA can be alleviated by a pretest cue indicating that the underlying mechanism of concussion-induced RA is more likely to be a retrieval deficit than a consolidation failure.

State-dependent retention produced with estrus in rats.

State-dependent retention (SDR) has frequently been demonstrated with drug-induced physiological changes which apparently serve as contextual cues for memory. These support the assumption that commonly occurring endogenous dispositions play a role in memory, yet there are few reports showing SDR with states that are likely to be part of an organism's natural experiences. To determine if behavioral estrus could produce SDR, ovariectomized female rats were rendered estrus via hormone injections or remained anestrus via placebo injections, trained with quinine-laced apple juice, and later tested while in the same or different state for reactions towards pure juice. SDR was not evident in the amount of juice consumed; however, those tested in the same state as the initial experience were slower to initiate drinking than those tested in a different state revealing a state-dependent influence on memory related to phases of the ovarian cycle.

Memory. When less is more.

Loss of memory for the characteristics of stimuli (i.e., forgetting of stimulus attributes) can lead to increases in behavior, a consequence quite different from the impairments associated with the forgetting of responses. Evidence from animal and human research for the forgetting of stimuli as a distinct memory principle is presented, and the methodological and conceptual implications of this pervasive type of memory loss are considered. Malleability of eyewitness memory, cognitive confusions, sleeper and familiarity effects, and temporal distortions in inferences and attributions are among the varied behavioral phenomena that can be accounted for in terms of forgetting of stimulus attributes.

The effect of US preexposure on conditioned taste aversion: lack of postconditioning recovery of the aversion.

Although the CS preexposure effect in CTA was once viewed exclusively as an acquisition failure, recent studies have suggested that the latent inhibition phenomenon is the result of retrieval impairment. This interpretive challenge is based on the unexpected finding that recovery of the aversion occurs over a long retention interval following conditioning (Kraemer, Lariviere, & Spear, Animal Learning and Behavior, 16, 185-190, 1988; Bakner, Strohen, Nordeen, & Riccio, Physiology & Behavior, 50, 1269-1272, 1991). This study examined whether a similar recovery occurs after US preexposure. Following preexposure to the US (LiCl), rats received a sucrose-illness pairing and were subsequently tested after either short or long training-to-test intervals. In contrast to the findings with the CS preexposure effect, US-preexposed subjects did not show a spontaneous increase in CTA following the long retention interval.

Forgetting of stimulus attributes: methodological implications for assessing associative phenomena.

Differential responding to changes in the stimulus situation, long central to the concept of stimulus control, also provides the implicit conceptual basis for assessing the nature of a variety of associative relationships. However, there is substantial evidence that the perception of stimulus similarity is not a static property. Generalization gradients to contextual as well as discriminative stimuli flatten over time, and this increase in perceived similarity presumably reflects forgetting of the detailed characteristics or attributes of stimuli. Methodologically, the flattening of the gradient imposes an important constraint: The effect of a stimulus shift will be highly sensitive to the length of the delay interval between training and testing. Conceptually, the loss of memory for stimulus attributes also implies that the sources of interference in retention can increase over time.

Reinstatement of latent inhibition following a reminder treatment in a conditioned taste aversion paradigm.

Reminder treatments have been shown to facilitate the retrieval of a variety of conditioned responses. Whether or not similar results would occur with an experimental paradigm which involves primarily memory for a stimulus, i.e., where no particular response is specified, is unclear. Accordingly, using Sprague-Dawley rats, we employed a latent inhibition paradigm with a long (10 days) retention interval between sucrose (CS) preexposure and sucrose-illness pairing (training). The results demonstrated a loss of latent inhibition following the 10-day retention interval suggesting "forgetting" of the CS preexposure. However, placing a single reminder exposure to the CS within the preexposure-to-training interval reinstated the preexposure effect. Controls indicated that in the absence of the initial preexposure the reminder per se did not produce latent inhibition. Thus, a reminder can reinstate a stimulus attribute (flavor representation) and explicit conditioned responses.

Postconditioning recovery from the latent inhibition effect in conditioned taste aversion.

Two experiments were conducted examining the effects of flavor (CS) preexposure on the retention of conditioned taste aversion. In Experiment 1, rats received preexposure to sucrose solution followed by a sucrose-illness pairing. The expected "latent inhibition" effect was obtained when testing occurred after a two-day but not an eleven-day training-to-test interval. Experiment 2 extended these results by employing five- and twenty-one-day training-to-test interval parameters and provided evidence that the stronger taste aversion displayed by preexposed subjects following long retention intervals is not attributable to differences in training consumption of sucrose solution. This posttraining increase in conditioned taste aversion (CTA) suggests that preexposure blocks expression of memory.

Increased generalization between drug-related interoceptive stimuli with delayed testing.

Although the flattening of generalization gradients over time has been widely investigated using exteroceptive stimuli, little attention has been given to generalization involving interoceptive stimuli. To investigate generalization between internal states, Sprague-Dawley rats were given either 0.835 ml/kg chloropent or 15 mg/kg sodium pentobarbital. Both drugs produced asymmetrical state-dependent retention of a passive avoidance response, that is, good retention in the "same state" conditions (i.e., the drug-drug and no drug-no drug conditions) as well as in the no drug-drug conditions but poor retention in the drug-no drug conditions, at both 1- and 7-day retention intervals. Furthermore, subjects trained in one drug state (pentobarbital or chloropent) demonstrated disrupted performance when tested 1 day later in another drug state, but good performance when tested 7 days later in the other drug state, indicating a decrement in the discriminability of the two drug states after 7 days. This outcome demonstrates that generalization gradients between drug states flatten over time. Moreover, these results suggest that memory for attributes of internal stimuli undergoes changes similar to those found for exteroceptive stimuli. Implications for contextual cues models of forgetting are considered.

Associative processes in adaptation to repeated cold exposure in rats.

Learning processes have been implicated in drug tolerance, but the role of associative mechanisms in adaptation to stressors has not previously been determined. Rats that received daily brief cold exposures demonstrated adaptation to the cold as measured by an attenuation of hypothermia. Tolerance to the cold was disrupted by changing the context in which the subject experienced the cold. These findings provide evidence of associative processes in adaptation to cold exposure and illustrate that these processes are not limited to drug tolerance.

The effects of preexposure to the drug on state dependent retention.

The present experiment examined whether previous experience with a drug would decrease the potential of the drug to produce state dependent retention (SDR) for a passive avoidance response in rats. In the first experiment, a single injection of sodium pentobarbital (20 mg/kg) given on six consecutive days before the training day slightly reduced, but did not block, pentobarbital-induced SDR. In Experiment Two, four preexposure injections of 5 IU/kg insulin reduced the magnitude of memory loss produced by administration of the hormone prior to training. As with pentobarbital, however, preexposure to insulin did not completely block the amnestic effect of the hormone. A subsequent experiment demonstrated that the decrease in the strength of insulin-induced SDR in insulin preexposed rats was not the result of enhanced acquisition. Collectively, these data indicate that noncontingent preexposure to an amnestic treatment may decrease the magnitude of memory loss that would normally result from the administration of that treatment during training.

Homeostatic disruption and memory: effect of insulin administration in rats.

The present study examined the effect of insulin-induced hypoglycemia on 24-h retention of passive avoidance in rats. In the initial experiment, rats received either insulin (50 U/kg) or saline injections 30 min prior to training and testing. Impairments in retention were observed when animals were trained with insulin and tested with saline. This anterograde memory loss was attenuated, however, when insulin was administered prior to both training and testing. A subsequent experiment further explored the disruptive effect of hypoglycemia on memory. Data from this study indicated that lower doses of insulin at training (5 and 10 U/rat) yielded impairments in 24-h retention of passive avoidance. It is concluded that disruption of glucoregulation can produce state-dependent anterograde memory losses in rats. Possible implications for the effects of hypoglycemia on cognitive functioning in humans are discussed.