Long-Term Memory and Extinction of Rabbit Nictitating Membrane Trace Conditioning

LEARNING AND MOTIVATION ARTICLE NO.

29, 68–82 (1998)

LM970990

Long-Term Memory and Extinction of Rabbit Nictitating Membrane Trace Conditioning Bernard G. Schreurs Behavioral Neuroscience Unit, Laboratory of Adaptive Systems, National Institute of Neurological Disorders And Stroke, National Institutes of Health Long-term memory for and extinction of trace conditioning were examined using the rabbit nictitating membrane response (NMR) preparation. Rabbits were trained on four consecutive days with 80 trials of a 100-ms tone followed 500 ms later by a 100-ms periorbital electrical pulse. After a period of 1, 2, 3, or 6 months in their home cages, rabbits were given four consecutive days of 80 tone-alone extinction trials followed by a single day of 80 reacquisition trials. The results showed the following: (1) rabbit NMR conditioned responses following trace conditioning were reduced to approximately 55% of acquisition levels after an interval as short as a month between acquisition and extinction. All but one rabbit responded at baseline levels (,2% CRs) 6 months following trace conditioning. In other words, there was a significant amount of forgetting of the association acquired during trace conditioning. (2) Conditioned responses that occurred 1, 2, or 3 months following acquisition were extinguished whereas responses that were absent following an interval of 6 months tended to reemerge over the course of extinction trials. (3) Reacquisition of the classically conditioned NMR in rabbits that had returned to baseline after extinction was significantly faster than initial acquisition levels in all groups and suggested a substantial level of savings. 1998 Academic Press

Although it has been reported that laboratory animals have long memories for simple associations (e.g., Hilgard & Marquis, 1940; Schreurs, 1993; Skinner, 1950; Spear, 1978), there is also strong evidence that animals can forget these associations over time (e.g., Schreurs, 1993; Spear, 1978). Spear (1978) has documented that in many cases subjects performed at levels substantially below those attained during initial training. When animals did perform at high levels, they had been given ‘‘reminder trials’’ before conditioned responses could be observed (Spear, 1978). Schreurs (1993) has shown that following delay conditioning of the NMR, the performance of rabbits was inversely proportional to the length of the interval between acquisition and The author thanks Drs. John H. Freeman, Jr. and Daniel Tomsic for their critical reading of the manuscript and Matt Oh for help with data collection. Address reprint requests to Dr. Bernard G. Schreurs, BNU, LAS, NINDS, Building 36, Room B205, National Institutes of Health, Bethesda, MD 20892. 68 0023-9690/98 $25.00 Copyright  1998 by Academic Press All rights of reproduction in any form reserved.

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testing. Nevertheless, subsequent reminder trials produced extremely rapid reacquisition (e.g., Napier, Macrae, & Kehoe, 1992). A number of factors have been invoked to account for the forgetting that occurs in laboratory animals. First, at a physiological level, the notion of decay has been used to refer to a process of degradation of the biological substrates that might underlie an association (see Spear, 1978). For example, the storage of an association may involve a series of different biochemical processes such as elevation of intracellular calcium concentration, modification of potassium channels, and changes in membrane proteins (e.g., Schreurs & Alkon, 1992). A cascade of these biochemical processes could permit the association to be stored first for seconds and minutes, then for hours, and eventually for days and months (Alkon & Rasmussen, 1988). The lack or degradation of any of the constituent elements of a particular biochemical step would mean that an association would not exist beyond the point of degradation. The use of protein synthesis inhibitors following training is an example of an experimental disruption in the biochemical cascade (for review see Davis & Squire, 1984). At a psychological level, interference has been suggested as a factor that contributes to forgetting. It has been proposed that the events and associations that occur between training and testing interfere with recall (e.g., McGeoch, 1942; Spear, 1973, 1978). It has also been suggested that a change in the context between the training and testing situations may interfere with recall (e.g., Bouton, 1991; Spear, 1978; Tulving, 1974; but see Gisquet-Verrier & Alexinsky, 1986; Riccio & Ebner, 1981). During a classical conditioning experiment, the conditioned stimulus (CS, e.g., tone) is always followed by the unconditioned stimulus (US, e.g., air puff to the eye) during acquisition and the CS is presented alone during extinction. In this case, the US may give rise to stimuli that become part of the context and those stimuli are not present during CS alone extinction. Extinction of a conditioned response (CR) as a function of presentations of the CS alone has been argued to involve either the unlearning of the original association (e.g., Rescorla & Wagner, 1972) or the modification of that association (e.g., Baeyens, Eelen, & Crombez, 1995; Bouton, 1991, 1993; Pavlov, 1927). Evidence from classical conditioning studies using the rabbit suggests that during extinction, the acquisition process is at least partially reversed because CRs decrease in frequency and amplitude and increase in latency (e.g., Moyer, Deyo, & Disterhoft, 1990; see Pavlov, 1927, p. 49). However, the occurrence of rapid reacquisition is a clear indication that the association is not completely unlearned (e.g., Napier et al., 1992; Pavlov, 1927; Schreurs, 1993). Other evidence that an association remains intact after an extinction procedure includes the observation of spontaneous recovery (e.g., Bouton, 1993; Napier et al., 1992; Pavlov, 1927; Schneiderman & Gormezano, 1964; Schreurs, 1993). A further indication that associations remain intact comes from experiments that show substantial transfer of an association from one CS to a second CS even after conditioning to the first CS has

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been extinguished (e.g., Kehoe, Morrow, & Holt, 1984). A final piece of evidence for the persistence of an association is the context specificity of extinction (e.g., Bouton, 1991, 1993). Given the considerable behavioral and physiological interest in trace conditioning and the relative lack of information on long-term memory for the trace conditioned response, the purpose of the present experiment was to examine the nature of retention and extinction of trace conditioning using the rabbit nictitating membrane preparation (e.g., Gormezano, 1966). METHODS

The subjects were 37 adult, male, albino rabbits (Oryctolagus cuniculus) weighing approximately 1.5–2.0 kg at the beginning of the experiment. Rabbits were individually housed, given access to food and water, and maintained on a 12 : 12 light/dark cycle. Animals were allocated randomly to one of four groups that corresponded to one of the four intervals that were scheduled to occur between acquisition and extinction (1, 2, 3, or 6 months). Subjects received one day of preparation, four consecutive days of acquisition, a period of 1, 2, 3, or 6 months in their home cages followed by four days of extinction, and one day of reacquisition. On adaptation day, the rabbits were prepared for periorbital electrical stimulation and recording of nictitating membrane movement and then adapted to the training chambers for length of time of subsequent training sessions (Schreurs, 1993). Each acquisition and reacquisition session consisted of 80 presentations of a 100-ms, 1000-Hz, 82-dB tone CS followed by a 500-ms trace and a 100-ms, 60-Hz, 2-mA electrical pulse US. Each extinction session consisted of 80 CS-alone presentations. The paired stimulus presentations of acquisition and reacquisition, and the CS-alone presentations of extinction were delivered, on average, every 60 s (range 50 to 70 s). Consequently, all sessions lasted approximately 80 min. A response was scored as a conditioned response if it exceeded a criterion amplitude of 0.5 mm between CS onset and the point of US onset. Onset latency was determined to be the point at which the response exceeded two A/D units (0.11 mm) above a 200-ms baseline period that occurred prior to the onset of the CS. Due to the occurrence of an unconditioned response (UR) to the US on paired trials, peak latency and amplitude of conditioned responses were biased by the UR during acquisition and reacquisition and were not submitted to statistical analysis. Stimulus delivery and data collection were accomplished using a Compaq/ASYST system previously described (Schreurs & Alkon, 1990). RESULTS

Conditioned Response Frequency A total of 28 animals reached a criterion of 90% CRs and were included in the analysis. Figure 1 depicts the mean percent conditioned responses for

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FIG. 1. Mean percent conditioned responses during the four days of acquisition, extinction, and one day of reacquisition for subjects in the 1-, 2-, 3-, and 6-month groups.

the four groups (1 month, n 5 6; 2 months, n 5 7; 3 months, n 5 7; 6 months, n 5 8) during the four days of acquisition, four days of extinction and one day of reacquisition. Inspection of the left side of Fig. 1 shows that rabbits reached asymptotic levels of 90% CRs by the end of acquisition with no between-groups differences in the rate or level of conditioning. An analysis of variance with Group and Days as factors confirmed these observations with a significant effect for Days (F(3, 72) 5 142.72, p , .001) but yielded no other significant effects or interactions (F’s , 1). The right side of Fig. 1 shows that all groups responded at substantially lower levels during extinction than on the last day of acquisition (95.9 versus 29.2%). In fact, rabbits in the 1-, 2-, and 3-month groups all began responding at a mean level of approximately 50% CRs and, with the exception of only one animal that responded an initial level of 74% CRs, rabbits in the 6-month group responded at baseline levels (1.1% CRs). Thereafter, rabbits in the 1-, 2-, and 3-month groups extinguished to levels of between 20 and 30% CRs. Rabbits in the 6-month group showed some increase in the level of responding as a function of the four days of extinction to levels comparable to the other three groups. Indeed, one rabbit in the 6-month group increased responding from 4% to 98% CRs over the course of extinction and another rabbit increased its level of responding from 0% to 47% CRs. Similar, but less dramatic increases in responding during extinction were observed in at least two of the animals in each of the other three groups. The net result of the observed differences in CR frequency during extinction was that there were initial differences between the 6-month group and the 1-, 2-, and 3-month groups which disappeared toward the end of the extinction phase.

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A repeated measures analysis of variance verified the observed differences between the terminal acquisition level and the average level of responding during extinction (F(1, 24) 5 340.93, p , .001). An analysis of responding during extinction revealed a significant effect of Days (F(3, 72) 5 5.72, p , .01) which was comprised of significant linear (F(1, 24) 5 8.24, p , .01) and cubic (F(1, 24) 5 4.41, p , .05) trends. As Fig. 1 suggests, because CRs for all groups were extinguished to comparable terminal levels, any differences between groups appeared to be restricted to the first two days of extinction. An analysis of the first two days of extinction did yield a significant main effect of Group (F(3, 24) 5 3.15, p , .05) which follow-up post hoc comparisons (Keppel, 1973) comfirmed to result from the 6-month group responding at significantly lower levels than the other three groups ( p’s , .01). Finally, Fig. 1 illustrates that reacquisition for all subjects was extremely rapid with responding reaching a mean value of 92.6% CRs. To avoid the potential inflation of reacquisition levels by the occurrence of spontaneous recovery (Napier et al., 1992; Schreurs, 1993), data from the 8 rabbits that showed no spontaneous recovery by the last day of extinction were examined and it was found that these subjects reached a mean level of 90% CRs. A repeated measures comparison of those rabbits revealed a highly significant difference between the level of acquisition on Day 1 (4.85% CRs) and the level of reacquisition (90.2% CRs, F(1, 7) 5 603.62, p , .001). The first CR for these rabbits occurred, on average, after the fourth CS–US pairing providing clear evidence of extremely rapid reacquisition in the absence of spontaneous recovery (e.g., Napier et al. 1992; Schreurs, 1993). Conditioned Response Topographies Figure 2 shows sample response topographies during the last day of acquisition (Fig. 2A) and the first day of extinction (Fig. 2B). Responses at the end of acquisition tended to have relatively short onset latencies, multiple peaks, and a maximal peak latency that coincided with the occurrence of the US. In fact, during acquisition, responses had a mean peak latency of 660 ms and mean amplitude of 5.87 mm. It seems clear from Fig. 2A that the relatively long mean peak latency is attributable to the occurrence of the UR. During extinction, responses continued to have a short onset latency but fewer peaks and a peak latency that occurred much sooner than during acquisition. In the absence of the US/UR, the mean peak latency of CRs occurred closer to the CS (386 ms) and the amplitude of CRs was reduced (3.25 mm). Conditioned Response Onset Latency Figure 3 shows the mean onset latency of conditioned responses for the four groups during the four days of acquisition, four days of extinction, and one day of reacquisition. The figure illustrates the clear decrease in the latency of CRs for each of the groups during the course of acquisition from

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FIG. 3. Mean conditioned response onset latency during the four days of acquisition, extinction, and one day of reacquisition for subjects in the 1-, 2-, 3-, and 6-month groups.

a mean of 580 ms on Day 1 to a mean of 292 ms on Day 4. In marked contrast to the decreasing latencies during acquisition, the latency of CRs for each of the groups was relatively short across all four days of extinction (231 ms; range 250–214 ms) as well as during reacquisition (210 ms). Statistical analysis of CR onset latency during acquisition showed a highly significant effect of Days (F(3, 72) 5 84.75, p , .001) attributable to linear and quadratic trends (F’s(1, 24) 5 271.21, p , .001 and 33.44, p , .001, respectively). There were no further significant main effects or interactions during acquisition. A comparsion of CR latency on the last day of acquisition with CR latency during extinction and on reacquisition showed a significant difference between acquisition and extinction (F(1, 24) 5 8.62, p , .01) and a significant difference between acquisition and reacquisition (F(1, 21) 5 14.23, p , .001). Separate analyses of CR latency during extinction and reacquisition showed no significant main effects or interaction (F’s , 2.1). Conditioned Response Peak Latency Figure 4 illustrates the mean peak latency of conditioned responses for the four groups during acquisition, extinction, and reacquisition. The figure

FIG. 2. Sample response topographies during the last day of acquisition (Fig. 2A) and the first day of extinction (Fig. 2B). Responses at the end of acquisition tended to have relatively short onset latencies, multiple peaks, and a maximal peak latency that coincided with the occurrence of the US. The arrows on the second and fourth responses show peaks that are correlated with CS onset and CS offset (see Desmond & Moore, 1991). During extinction, responses continued to have a short onset latency but with fewer peaks and a maximal peak latency that appeared to be much shorter.

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FIG. 4. Mean conditioned response peak latency during the four days of acquisition, extinction, and one day of reacquisition for subjects in the 1-, 2-, 3-, and 6-month groups. Note that the long response peak latency during acquisition coincides with the occurrence of the UR.

indicates that during acquisition mean response peak latency occurred at 660 ms after tone onset, a point which coincided with the peak of the UR to the electrical stimulation US (see Fig. 2). On the first day of extinction, peak latencies had dropped to 439 ms in the absence of the UR and by the last day of extinction peak latencies had decreased even further to 350 ms. An analysis of CR peak latencies during extinction revealed a main effect of Days (F(3, 72) 5 5.78, p ,.01) which was accounted for by a linear decrease across the extinction phase (F(1, 24) 5 8.20, p , .01). With the reintroduction of the US during reacquisition, CR peak latencies returned to a mean level of 636 ms. Conditioned Response Amplitude Figure 5 shows mean CR amplitude during acquisition, extinction, and reacquisition. As with CR peak latencies, CR amplitudes were biased by the occurrence of the UR during acquisition and reacquisition. However, during extinction, CR amplitudes decreased from an initial value of 4.23 mm to a terminal value of only 2.76 mm. A repeated measures analysis of the CR amplitude extinction data showed that there was a significant effect Days (F(3, 72) 5 8.56, p , .001) which was comprised of significant linear (F(1, 24) 5 17.24, p , .001) and cubic trends (F(1, 24) 5 4.69, p , .05). DISCUSSION

The major findings of the present experiment were the following: (1) rabbit NMR conditioned responses to CS-alone extinction trials following trace

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FIG. 5. Mean conditioned response amplitude during the four days of acquisition, extinction, and one day of reacquisition for subjects in the 1-, 2-, 3-, and 6-month groups.

conditioning were reduced to approximately 55% of acquisition levels after a retention interval as short as 1 month. In fact, a comparable decrease in the level of responding occurred at retention intervals of 1, 2, and 3 months. However, with the exception of one rabbit, conditioned responses returned to baseline levels after a retention interval of 6 months. In other words, if compared to extinction data collected one day after acquisition (e.g., Moyer et al., 1990), the present data suggest that there was significant forgetting across all of the retention intervals studied in the present experiment with most of the forgetting occurring after 6 months (e.g., Schreurs, 1993; Spear, 1978). (2) The conditioned responses that occurred 1, 2, or 3 months following acquisition were extinguished during CS-alone extinction trials. In contrast, responses tended to reemerge over the course of extinction trials following an interval of 6 months (e.g., James, 1890; Schreurs, 1993). (3) Response topographies during extinction were substantially different from responses topographies during acquisition. In particular, the response, although smaller during extinction, occurred and peaked much earlier than during acquisition. (4) Reacquisition of the classically conditioned NMR in rabbits that had returned to baseline after extinction was significantly faster than initial acquisition levels and suggested a substantial level of savings in all groups. The present data provide some of the first systematic evidence for longterm memory of trace conditioning in the rabbit NMR preparation. The experiment shows that, following trace conditioning, subjects retain moderate levels of conditioned responses for at least 3 months after training. In fact,

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the same moderate level of responding was obtained regardless of whether 1, 2, or 3 months elapsed between training and testing. After a 6-month interval all but one of the rabbits were responding at baseline levels. The present data also provide some insights into the extinction of longterm memories. For example, conditioned responses observed during extinction following an interval as short as 1 month were quantitatively and qualitatively different from responses observed when extinction took place without an extended retention interval (e.g., Moyer et al., 1990). In particular, extinction of CRs 1 month after acquisition yielded response levels of only 50% CRs whereas levels of 80% CRs have been observed 1 day following acquisition of trace conditioning (Moyer et al., 1990). Furthermore, although responses in the present experiment did show low amplitudes during extinction, they occurred with relatively short onset and peak latencies. Responses during extinction without an extended retention period increased in onset latency and decreased in amplitude (e.g., Moyer et al., 1990). Moreover, the peak amplitude of responses normally coincides with the point at which the US would have occurred (e.g., Gormezano & Kehoe, 1981; Millenson, Kehoe, & Gormezano, 1974). A comparison of responding during acquisition and extinction also shows some differences in topography. Desmond and Moore (1991) have shown that on CS-alone test trials following trace conditioning, a CR may have two peaks—one correlated with the onset of the CS and another correlated with the offset of that CS. Although the first two peaks that occurred during acquisition did appear to be correlated with CS onset and CS offset (arrows in the second and fourth responses of Fig. 2A; see Desmond & Moore, 1991), this multiple peak timing was absent or degraded during extinction. There are some significant differences as well as interesting similarities between the long-term memory of trace conditioning observed in the present experiment and the previously reported long-term memory of delay conditioning (Schreurs, 1993). For example, the present data show that even if high levels of trace conditioning were obtained during acquisition, the conditioned responses were forgotten more rapidly than those acquired during delay conditioning. As already noted, 1 month following trace conditioning to 90% CRs, rabbits were only responding at a level of 50% CRs. Schreurs (1993) showed that 1 month following delay conditioning to a level of 90% CRs, rabbits were still responding at a level of 80% CRs. On the other hand, at longer retention intervals such as 3 months and 6 months, the level of responding was almost identical for rabbits given trace or delay conditioning. Moreover, over the course of repeated CS-alone extinction trials, rabbits appeared to ‘‘recall’’ conditioned responses after long retention intervals following both trace and delay conditioning (Schreurs, 1993). An apparent difference between the present trace conditioning retention data and another set of retention data in the literature (Moyer, Thompson, & Disterhoft, 1996) raises the issue of how retention is measured. In the present

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experiment as well as in those of Solomon and colleagues (e.g., Solomon, Barth, Wood, Velazquez, Groccia-Ellison, & Yang, 1995; Solomon, Wood, Groccia-Ellison, Yang, Fanelli, & Mervis, 1995), retention of the conditioned response is measured using CS-alone trials (see also Kehoe & McCrae, 1997; Schreurs, 1993; Napier et al., 1992). In these experiments, rabbits responded at a level of approximately 50–60% CRs even if extended training with an air puff US were used (100 trials per day for 18 days, Solomon et al., 1995) rather than relatively brief training (80 trials per day for 4 days) with an electrical stimulation US. When retention is measured using CS–US trials, animals have been reported to respond at levels of 80% 3 months following training (e.g., Moyer et al., 1996). Using the latter definition of retention, the reacquisition phase of the present experiment shows that rabbits ‘‘retained’’ a level of 90% CRs even after a 6-month retention interval (but see Coffin & Woodruff-Pak, 1993, for longer intervals). There is considerable evidence that trace conditioning is more difficult to acquire than delay conditioning (e.g., Hilgard & Marquis, 1940; Flaherty, 1985; Pavlov, 1927; Schneiderman, 1966). For example, Schneiderman (1966) found that trace conditioning produced lower levels of responding than delay conditioning at every CS–US interval that he tested. Indeed, in the present experiment not all animals reached the criterion of 90% CRs even after 4 days of training. In contrast, all animals in the Schreurs (1993) study reached 90% CRs following 3 days of delay conditioning. Trace conditioning has also been shown to be different from delay conditioning from a physiological point of view. For example, trace conditioning has been shown to be hippocampally dependent whereas delay conditioning is not (e.g., Kim, Clark, & Thompson, 1995; Moyer et al., 1990). However, as little as 2 weeks after trace conditioning, changes in hippocampal pyramidal cell excitability which occur as a function of training are no longer detectable (Moyer, Thompson, & Disterhoft, 1996; Thompson, Moyer, & Disterhoft, 1996). Similarly, 1 month after trace conditioning, hippocampal lesions which normally interfere with responding immediately after training, no longer interfere with retention of the conditioned response (Kim, Clark, & Thompson, 1995). Consequently, although the hippocampus was presumably necessary for the acquisition of trace conditioning in the present experiment, it might not have been responsible for the drop in the level of responding 1 month later. One intriguing aspect of the present data is the replication of the increase in responding during extinction that occurred in a number of rabbits, particularly those tested at the longest retention interval (Schreurs, 1993). This increase in responding supports concepts such as redintegration (James, 1890) and reactivation (Spear, 1981) and the idea that exposure to some of the stimuli in a situation (i.e., context) may activate the entire stimulus sequence (Bouton, 1991, 1993; but see Riccio & Ebner, 1981). The increase in re-

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sponding during extinction is in strong contrast to the extinction of responding normally observed if extinction trials are presented immediately following acquisition (e.g., Gabriel, 1968; Gabriel & Vogt, 1972; Napier et al., 1993; Schneiderman & Gormezano, 1964; Schreurs, 1993). To some extent, these findings also address the notion of ‘‘reinstatement’’ (e.g., Bouton, 1993) but in this case the reinstatement results from the presence of stimuli other than the US. In other words, the occurrence of the CS in the context in which acquisition took place was enough to restore the conditioned response (e.g., Gabriel 1968; Gabriel & Vogt, 1972). Reinstatement was obviously complete following several CS–US pairings during reacquisition. Taken together, the current results address several issues raised by accounts of retention and forgetting. Hilgard and Marquis (1940) claimed that in laboratory animals there is little spontaneous decay in CRs even over a period of months. They suggested that forgetting is interference by competing responses and that the resistance of laboratory animals to forgetting is the result of artificial laboratory circumstances where there are few stimuli that could interfere with the CR (Spear, 1978). The decrease in responding from a level of 90 to 50% CRs as soon as 1 month following acquisition suggests that rabbits began to forget the trace CR relatively quickly although not completely (cf. Schreurs, 1993). Nevertheless, it seems highly unlikely that during confinement to the home cage, associations involving the CS and/or US interfered with the association formed during acquisition (Spear, 1978). In fact, the original association appeared to be perfectly intact following as few as two CS–US reminder trials even after extensive extinction. However, the change in context from CS–US pairings to CS-alone presentations may have diminished responding to the CS (Bouton, 1991; Spear, 1978). In particular, the presentation of the CS in delay conditioning occurs in a complex which includes the CS, the US, and the context. In other words, the sequence of a brief CS followed by the context and then the US may be less discriminable from the context than an overlapping CS–US complex. Thus, the change in context between training and testing may have been responsible for the comparable levels of diminished responding across the 1-, 2-, and 3-month groups. However, the change in context was the same for all of the groups in the present experiment and so does not explain the significantly lower level of responding in rabbits in the 6-month group. Consequently, under conditions in which the potential for interference from other associations and from the change in context were both relatively constant, decay may account for the lower level of responding at the longest retention interval. Given the present results and the current advances in understanding the neural substrates of classical conditioning of the rabbit NMR (e.g., Alkon, 1989; Schreurs, 1989; Schreurs & Alkon, 1992; Thompson, 1986), the rabbit NMR appears to be an ideal model for examining the role of context and decay that appear to underlie forgetting of a classically conditioned response.

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