The Contextual Modulation of Conditioned Taste Aversions by the Physical Environment

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1 Brief Communication The Contextual Modulation of Conditioned Taste Aversions by the Physical Environment and Time of Day Is Similar Ignacio Morón, 1 Tatiana Manrique, 1 Andrés Molero, 1 M a Angeles Ballesteros, 1 Milagros Gallo, 1,2,5 and Andre Fenton 3,4 1 Department of Experimental Psychology and Physiology of Behavior, University of Granada, Campus Cartuja, Granada 18071, Spain; 2 Institute of Neurosciences F. Oloriz, University of Granada, Spain; 3 Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic; 4 Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York 11203, USA In a pair of experiments, we have compared the ability of changes of place (Exp. 1) and changes of time of day (Exp. 2) to separately modulate learned saline-aversion memory phenomena in rats. Neither a spatial nor a temporal change disrupted latent inhibition using the present behavioral procedure. However, pre-exposure to the taste increased the contextual control of the learned aversion expression. The aversion reappeared in the place or at the time of conditioning after extinction in a different context. The results indicate that environmental and temporal contexts can independently, but similarly modulate taste aversion learning. Context is an often loosely defined term, which in neuroscience is becoming more common, especially with the current interest to investigate the neural bases of episodic memory in humans (Nadel et al 1985; Schacter and Tulving 1994) and to search for equivalent memory phenomena in nonhuman animals (Clayton and Dickinson 1998; Aggleton and Brown 1999). Whereas rats readily associate tastes of substances with their visceral consequences (García and Koelling 1966; García et al. 1968; Bures et al. 1998; Bernstein 1999), contextual cues also modulate conditioned taste aversions (CTA), because the context specificity, both of the expression (Boakes et al. 1997; Archer et al. 1979, 1980; Jarbe et al. 1986; Puente et al. 1988; Bonardi et al. 1990; Loy et al. 1993) and extinction (Rosas and Bouton 1997; Archer et al. 1979) of a learned aversion, and of the latent inhibition (LI) of CTA (Rudy et al. 1977; Hall and Channell 1986) has been reported. In CTA studies, context frequently refers to a particular place that may combine a variety of external environmental cues. However, a broad definition of context may include not only external, but also internal, background cues and a sense of time (Bouton 1993; Pearce and Bouton 2001). Very few of the above-cited studies reporting context modulation of CTA have included the time of day as part of the context, either purposely (Rosas and Bouton 1997) or as the outcome of applying two daily drinking sessions (Hall and Channell 1986; Bonardi et al. 1990). Moreover, although the possibility that the time of 5 Corresponding author. mgallo@ugr.es; FAX Article and publication are at /lm day may itself form a context is supported by a recent report showing a time-of-day-dependent expression of the behavioral sensitization to amphetamine (Arvanitogiannis et al. 2000), to our knowledge, no study has explored the ability of the time of day to modulate CTA independently of the spatial context. In the present experiments, we specifically examine whether spatial (Exp. 1) and temporal (Exp. 2) contextual cues separately modulate learned saline-aversion memory phenomema. In Experiment 1, two different sized and shaped cages were used as contexts (Fig. 1). The environments differed in location, geometry, visual, auditory, and tactile cues. In Experiment 2, two different times during the illumination cycle were used as temporal contexts. To differentiate them as much as possible, morning (10:00) and evening (20:00) drinking sessions were used. Except for the details concerning the specific contexts used (Fig. 1), both experiments were similarly designed and allowed us to measure the context dependency of LI, the extinction, and the context-specific expression of extinguished learned saline aversions. Four groups of rats were used in a 2X2 design (Table 1). Pre-exposed groups (Pre), but not control groups (Ctrl), received two nonreinforced saline pre-exposures before conditioning. Animals in each group were further assigned to one of two groups, a group (Same), were preexposed, aversively conditioned to saline, and tested in the same place or at the same time of day. Another group (Different) were aversively conditioned to saline in a different context of the pre-exposure and testing. After the saline aversions had extinguished in all groups, a context-specific extinction test was given. The context of this test was the LEARNING & MEMORY 9: by Cold SpringHarbor Laboratory Press ISSN /02 $

2 Physical and Temporal Context Modulation of Learning Figure 1 Depiction of the experimental conditions. Experiment 1(A,B). Photographs from the side of Context A (e.g., A: Pre-exposure) and from overhead of Context B (e.g., A: Conditioning). Experiment 2 (C,D) had a similar design. The physical conditions were identical for each drinkingsession, only the time of day (phase of the light/dark cycle) differed. context in which the saline aversion had been conditioned. This design allowed us to measure (1) the expression of a learned taste aversion after a change of physical or temporal context between the conditioning and testing sessions, (2) the effect of taste familiarity on the magnitude of any context-specific modulation, and (3) whether extinction was specific to the context. The volume of consumed saline was compared across groups and across days. The average values ± SEM are reported. No differences were found among the groups in the water intake, either during the habituation or before testing. There were no differences between water intake in both contexts at the end of the context habituation phase. Prior to conditioning, the only differences between the groups in both experiments was the expected preference for saline in the rats of the pre-exposed groups compared with the water intake by the control nonpre-exposed groups. Figure 2A summarizes the results of the conditioning, testing, and renewal phases in Experiment 1. All of the groups drank the same amount of saline in the conditioning session. A 2X2 ANOVA (Pre-exposure X Group) analysis of the different groups saline intake during the conditioning session showed no significant effect of pre-exposure (F 1,36 = 0.85; P >0.36), group (F 1,36 = 1.34; P <0.25), nor the interaction pre-exposure X group (F 1,36 = 0.11; P >0.74). The analysis of saline intake during the testing using a 2X2X3 (Pre-exposure X Group X Days) mixed ANOVA analysis revealed significant main effects of Group (F 1,36 = 6.24; P <0.02), Days (F 1,36 = 112.9; P <0.001), and the interaction Pre-exposure X Days (F 1,36 = 6.03; P <0.01). The rats that were tested in a different environment than the one in which they were conditioned, had lower saline aversions (14.1 ± 0.78) than those tested in the context that the aversion was conditioned (11.7 ± 0.87). The saline intake increased on each of the three extinction tests (each P <0.01). The Pre-exposure X Days interaction was analyzed by independent 2X2 (Pre-exposure X Group) ANOVAs of each test. In the first test, there was a significant effect of Preexposure (F 1,36 = 3.31; P = 0.05) and Group (F 1,36 = 6.92; P <0.02), but no effect of the interaction Pre-exposure X Group (F 1,36 = 0.27; P >0.6). Latent inhibition of the 219

3 Morón et al. Table 1. Behavioral Procedures for the Different Groups in Experiment 1 (A) and Experiment 2 (B) A Pre-1 & 2 ConditioningRecovery Extinction 1 3 Context-specific retention Pre-Different Sal (A) Sal-LiCl (B) W (HC) Sal (A) Sal (B) Ctrl-Different W (A) Sal-LiCl (B) W (HC) Sal (A) Sal (B) Pre-Same Sal (A) Sal-LiCl (A) W (HC) Sal (A) Sal (A) Ctrl-Same W (A) Sal-LiCl (A) W (HC) Sal (A) Sal (A) B Pre-1 & 2 ConditioningRecovery Extinction 1 5 Context-specific retention Pre-Different Sal (pm) Sal-LiCl (am) W (am/pm) Sal (pm) Sal (am) Ctrl-Different W (pm) Sal-LiCl (am) W (am/pm) Sal (pm) Sal (am) Pre-Same Sal (pm) Sal-LiCl (pm) W (am/pm) Sal (pm) Sal (am) Ctrl-Same W (pm) Sal-LiCl (pm) W (am/pm) Sal (pm) Sal (am) For brevity counterbalancingis not represented. (A/B) Contexts; (HC) Home cage; (LiCl) Lithium Chloride; (Pre-1 and Pre-2) Pre-exposure 1 and 2; (Sal) Isotonic saline; (W) Water. learned saline aversion occurred, because the Pre-exposed groups had a reduced saline aversion (8.78 ± 1.03) compared with the nonpre-exposed control groups (6.45 ± 0.83). The modulation of the learned aversion by context was also evident, as the animals that were tested in a different context from where they were conditioned had a weaker saline aversion (9.3 ± 0.89) than the animals that were tested in the same context as where they were conditioned (5.93 ± 0.91). No effect reached significance in Test 2 and Test 3, due to the extinction of the learned aversions in all of the groups. The renewal of the extinguished saline aversion in the context that the aversion was learned was examined in the Context-specific test. The data were analyzed by a 2X2 (Preexposure X Group) ANOVA. There was a significant main effect of group (F 1,36 = 6.43; P <0.02), confirming the lower saline intake in those groups, which has extinguished the saline aversion in a different context. No other effect was significant. A mixed 2X2 (Test-Context X Days) ANOVA of the saline intake of the different groups on both the last test and the Context-specific test showed no effect of group (F 1,36 = 0.63; P >0.42) and no effect of Days (F 1,36 = 1.9;P >0.17), but a significant Group X Days (F 1,36 = 9.28; P >0.01) interaction. A repeated measures ANOVA indicated a reduced saline intake in the renewal test compared with the last test only in the groups that had extinguished the aversion in a different context than they had been conditioned in P <0.02. Figure 2B summarizes the results of the conditioning, testing, and renewal phases in Experiment 2. A 2X2 (Preexposure X Group) ANOVA analysis of the different groups saline intake in the conditioning session showed no significant effect of Pre-exposure (F[1,31] = 0.94; P >0.3), Group (F[1,31] = 0.94; P >0.3) or the interaction Pre-exposure X Group (F[1,31] = 0.94; P >0.3). The evening saline intake over five extinction tests was analyzed using a 2X2X5 (Pre-exposure X Group X Days) ANOVA. There were significant main effects of Pre-exposure (F[1,31] = 10.43; P <0.01) and Days (F[4,124] = 72.82; P <0.01). No other effect approached significance, except the interaction Preexposure x Days (F[4,124] = 2.29; P <0.07). There was a clear latent inhibition effect, as the Pre-exposed groups had a reduced saline aversion (6.58 ± 0.69) compared with the nonpre-exposed control groups (3.92 ± 0.68). Saline intake increased through the first four extinction tests (P <0.01). The extinction of the aversion stabilized after Day 4, as there were no differences in saline intake between Test 4 and Test 5 (P >0.36). As the interaction Pre-exposure X Days approached significance, independent 2 X 2(Pre-exposure xgroup) ANOVAs were performed for each extinction test. In the first test, there was only a significant effect of Pre-exposure (F[1,31] = 6.55; P = 0.01). In Test 2, there were significant effects of Pre-exposure (F[1,31] = 23.95; P <0.01) and the Pre-exposure X Group (F[1,31] = 7.99; P <0.01), but the main effect of Group did not reach significance (F[1,31] = 3.81; P = 0.06). Post-hoc Newman- Keuls comparisons indicated a higher saline intake in the group Pre-Different compared with the rest of the groups (P <0.01), indicating contextual control of the saline-aversion expression only in the pre-exposed groups. In Test 3, there was only a significant main effect of Pre-exposure (F[1,31] = 14.23; P <0.01). No effect approached significance in Tests 4 and 5, due to the extinction of the learned aversions in all of the groups. The analysis of the morning renewal test using a 2X2 (Pre-exposure X Group) ANOVA showed a significant main 220

4 Physical and Temporal Context Modulation of Learning Figure 2 Mean (± SEM) saline intake of the different groups during the conditioning, extinction, and the Context-specific retention phases in Experiment 1 (A) and Experiment 2 (B). (Cond) Conditioning; (D) different Groups; (S) same Groups; (E1 E5) extinction tests 1 to 5; (Ret) Context-specific retention test. effect of Group (F[1,31] = 3.87; P = 0.05). No other effect approached significance. To test whether the change to saline in the morning altered the amount to saline intake compared with the previous day s intake in the evening, a repeated measure ANOVA was performed on the Test 5 and Renewal data. There was a relative increase in saline intake during the morning renewal test (P <0.01) only in those groups that had been conditioned and given extinction sessions during the same evening period. There was no such increase in those groups that were conditioned during the morning drinking session and extinguished in the evening (Pre-Different, P >0.56; Ctrl-Different, P >0.16). Taken together, the results of Experiments 1 and 2 indicate that both a change in the physical context and a change in the temporal context have similar effects on CTA learning phenomena. After learning a saline taste aversion in a particular physical context or at a particular time of day, the extinction of the taste aversion was context specific. Renewal of taste aversions extinguished in a different context has been reported upon returning to the conditioning context using both singlebottle tests (Rosas and Bouton 1997) and two bottle tests (Archer et al. 1979). Consistent with previous work (Bonardi et al. 1990; Rosas and Bouton 1997), the present results do not indicate that either the physical or temporal context has a relevant influence on the expression of a learned taste aversion after one conditioning trial in the nonpreexposed groups. The previous experience with the taste seemed, however, to increase the ability to express lower aversions when the conditioning and testing were in different contexts. This effect was clear when the physical context was examined and it reached significance in the second test after changing the time of day. An increase of the contextual control of CTA induced by taste familiarity has been reported (Puente et al. 1988; Boakes et al. 1997). Consistent with this finding, the bulk of the studies reporting context dependency of CTA expression have applied several conditioning trials (Archer et al. 1979, 1980; Jarbe et al. 1986; Puente et al. 1988; Loy et al. 1993; Boakes et al. 1997). Latent inhibition of CTA was not affected by changing the physical or temporal context. Although a context change between preexposure and conditioning eliminates latent inhibition (LI) in a variety of learning tasks (Lubow 1989), evidence is not so clear using CTA. Some studies have found LI independent of the context (Kurz and Levitsk 1982; Best and Meachum 1986) and others have reported context-dependent LI (Rudy et al. 1977; Hall and Channell 1986). To our knowledge, this is the first definitive evidence that rats use the time of day as a context to modulate the expression and extinction of a learned taste-aversion memory that was acquired in one conditioning trial. Although further research on the relevance of procedural features that may be critical for time-dependent latent inhibition is required, the phenomenon opens the door for research into 221

5 Morón et al. the neural mechanisms that underlie how memories are stored and modulated by a sense of extended time. Forty naïve male Long-Evans rats ( g) provided by the breeding colony of the Institute of Physiology (Prague) were used in Experiment 1 (n = 10 per group). The animals were housed four per cage in a 22 C temperature and 12:12 light:dark cycle controlled vivarium. Thirty-five naïve male Wistar rats ( g) from the breeding colony of the University of Granada were used in Experiment 2 (n = 9 per group except Ctrl-Different n = 8). They were housed individually in a room with constant temperature and a 12:12 h. light-dark cycle, with lights on at 9:00 and off at 21:00. Food was available ad libitum, but water availability depended on the behavioral procedure. In the first experiment, the animals had a daily 15-min drinking session, and in the second experiment, two daily 15-min drinking sessions. The procedures were approved by the Institute of Physiology and the University of Granada Ethics Committees, and were in accordance with both the NIH of the United States guidelines for the ethical treatment of animals, and the European Communities Council Directive of 24 November 1986 (86/609/ EEC). The behavioral procedure had five phases as follows: Context Habituation, Taste Pre-exposure, Conditioning, Extinction, and Context-specific Extinction (Fig. 1). The amount of fluid ingested was recorded to the nearest 0.1 ml in all phases. During the Context Habituation phase, all of the animals drank water during the daily 15-min drinking period until the water intake in each context was similar. In Experiment 2, morning and evening intake was equated by limiting morning water ingestion to 6 ml. The Pre-exposure phase lasted for 2 d. The pre-exposed groups (Pre-Same and Pre-Different) were allowed to drink saline (1%) for 15 min, whereas the control nonpreexposed groups (Ctrl-Same and Ctrl-Different) were allowed to drink water instead. The spatial contexts were counterbalanced in Experiment 1, but saline pre-exposures always took place during the evening drinking session in Experiment 2. During the conditioning session, the animals were allowed to drink the saline solution either in the same context as during the pre-exposure sessions (Pre-Same) or in the other context (Pre-Different). The nonpre-exposed (Ctrl) groups drank in the same contexts as their corresponding pre-exposed group. Immediately after the 15 min of saline drinking, all of the animals were poisoned with an i.p. injection of lithium chloride (0.15 M; 2% body weight) and returned to the home cage. The next day, they were allowed to recover from the poisoning with access to water in the home cage during the daily drinking period. The extinction phase began the day after recovery. The rats were allowed to drink the saline solution in the context they had pre-exposure drinking sessions. The extinction phase lasted 3 d in Experiment 1 and 5 d in Experiment 2. After the learned taste aversion was extinguished, the Context-specific saline aversion was tested. The rats were allowed to drink the saline solution in the context in which the Different groups had the conditioning session. ACKNOWLEDGMENTS This research was supported by the CICYT grants PB (Spain). Ignacio Morón and Andrés Molero were recipients of a predoctoral grant of the Junta de Andalucía (Spain). We thank Geoffrey Hall for an informative discussion on this topic and related data. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 USC section 1734 solely to indicate this fact. 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