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Age and Stress History Effects on Spatial Performance in a Swim Task in Fischer-344 Rats
NEUROBIOLOGY OF LEARNING AND MEMORY ARTICLE NO.
66, 1–10 (1996)
0038
Age and Stress History Effects on Spatial Performance in a Swim Task in Fischer-344 Rats T. R. MABRY,1 R. MCCARTY, P. E. GOLD,
AND
T. C. FOSTER2
Department of Psychology, Gilmer Hall, University of Virginia, Charlottesville, Virginia 22903
Palmer, Ziegler, & Lake, 1978; Young, Rowe, Pallotta, Sparrow, & Landsberg, 1980; Sapolsky, Krey, & McEwen, 1984; Fleg, Tzankoff, Lakatta, & Lakatta, 1985; McCarty, 1985; Lorens, Hata, Van De Kar, Guschwan, Goral, Lee, Hamilton, Bethea, & Clancy, 1990; Mabry, Gold, & McCarty, 1995a,b,c). For example, compared to young adult rats, aged rats exhibit potentiated plasma catecholamine responses, especially increases in plasma epinephrine levels, after placement in water at temperatures routinely employed for swim task training (McCarty 1985, 1986; Mabry et al., 1995a). With the considerable evidence that the plasma level of stress-related hormones near the time of training can regulate learning and memory (Bohus, Grubits, Kovacs, & Lissak, 1970; McGaugh, 1989; De Wied & Croiset, 1991; Gold, 1992), the possibility arises that agerelated changes in learning and memory may reflect alterations not only in memory storage mechanisms per se, but also in neuroendocrine responses known to modulate memory storage processes (Gold & Stone, 1988; Issa, Rowe, Gauthier, & Meaney, 1990; Gold, 1992). An important feature of the stress response is that habituation of the response is seen with repeated exposure to a stressful experience. For example, when compared to rats experiencing water immersion for the first time, plasma catecholamine levels show diminished responses to water immersion in rats that had received daily exposure to the same stressor over several weeks (Konarska, Stewart, & McCarty, 1989, 1990a,b). Swim tasks are widely used to examine age-related deficits in spatial memory (e.g., Gallagher & Pelleymounter, 1988; Brandeis, Brandys, & Yehuda, 1989; Foster, Barnes, Rao, & McNaughton, 1991; Lindner, Balch, & VanderMaelen, 1992; McNamara & Skelton, 1993). In some cases (e.g., Rapp,
This study determined whether prior habituation to water immersion would ameliorate age-related deficits in learning and memory in a swim task. Aged (22 months) and young adult (3 months) rats were immersed in water (307C) for 15 min on each of 28 consecutive days before training in the swim task. Additional groups of agematched animals served as handled controls. Training on a spatial discrimination version of the water task was conducted over 5 days with two trials per day (1-h intertrial interval). A probe trial was substituted for the last trial on the fifth day to assess the rats’ use of spatial information. Three days later, rats received cue discrimination training to find a visible platform. In the spatial task, prior habituation to water immersion ameliorated deficits in acquisition within each day (i.e., at a 1-h intertrial interval) but not across days (at 24 h). The results obtained with the 24-h interval confirm the rapid forgetting characteristic of aged rats in many tasks. The stress-habituation procedures reduced age-related deficits seen on the probe trial and on cue discrimination training. These findings indicate that several aspects of age-related impairments in the swim task, often attributed to primary age-related deficits in learning and memory processes per se, may instead be secondary to age-related differences in stress responses to water immersion. q 1996 Academic Press, Inc.
Aged animals exhibit enhanced plasma catecholamine and corticosterone responses to acute stress (Riegle & Hess, 1972; Ziegler, Lake, & Kopin, 1976; 1 Present address: Department of Behavior Science and Leadership, U.S. Air Force Academy, CO 80840. 2 This research was supported in part by U.S. Public Health Service Grants AG07648, NS32914, and NS31830 and by a grant from the American Federation for Aging Research. Address correspondence and reprint requests to Dr. Thomas Foster, Department of Psychology, 102 Gilmer Hall, University of Virginia, Charlottesville, Virginia 22903-2477. Fax: (804) 982-4785. Email: [email protected].
1 1074-7427/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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Rosenberg, & Gallagher, 1987; Clark, Magnusson, & Cotman, 1992; Gage, Dunnett, & Bjorklund, 1984; Tandon, Mundy, Ali, Nanry, Rogers, & Tilson, 1991; Lindner et al., 1992), acquisition trials presented across many days reveal age-related deficits early in training but aged rats eventually approach the performance of young rats. Moreover, aged rats exhibit no deficits on later training on the cue version of the task, with the findings generally interpreted to reveal age-related impairments in spatial learning coupled with relative preservation of cued learning (e.g., Rapp et al., 1987). However, the extensive training (up to 30 days), together with available information about stress responses and adaptation of those responses, suggests a quite different view. This alternative view is that the absence of deficits late in training, i.e., after many days of immersion in water, may reflect habituation of stress responses, thereby attenuating an impairing impact of stress hormone responses on learning. According to this view, performance of aged rats would eventually approach that of young rats and later tests on cued learning would reveal no deficits; these are findings reported previously (Rapp et al., 1987). Assuming that repeated exposure to water immersion results in a diminished stress response in both young adult and aged rats, repeated exposure to immersion in water provides a possible manipulation with which to decrease the otherwise exaggerated stress responses in aged rats and, thereby, to examine the contribution of these responses to age-related memory deficits. The present experiment tested the hypothesis that prior exposure to water immersion would improve the acquisition and retention of spatial information in the swim task. The performance of both young adult and aged rats that had been exposed to water immersion on each of 28 consecutive days prior to training was compared to that of age-matched rats with no prior water exposure. METHOD Animals Young adult (3 months, N Å 32) and aged (22 months, N Å 32) male Fischer-344 rats were obtained from the National Institute on Aging colonies maintained by Harlan Sprague–Dawley, Inc. (Indianapolis, IN). Upon arrival in our vivarium, rats were housed individually in suspended metal cages with ad libitum access to food and water. The vivarium rooms were maintained on a 12-h light–dark cycle (lights on 0700–1900 h) at an ambient temperature of 22 { 17C.
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Stress Habituation Procedures Animals were randomly assigned to one of two conditions within each age group. Chronically stressed animals (CS) were weighed and then immersed in 307C water for 15 min each day for 28 consecutive days. The apparatus was a standard 20gallon aquarium that was subdivided into four compartments (15 1 36 1 30 cm) and fitted with a plexiglass top. A small hole was cut in the plexiglass top above each compartment. The diameter of the hole did not allow escape from the water, but did provide a place for each rat to grasp with its mouth and/ or paws. Within 3-4 sessions, rats learned to swim directly to the hole and remain there for the entire session and therefore expended minimal effort to stay afloat. Of relevance to the outcomes of this manipulation, exercise per se apparently does not modify spatial memory in aged Fischer-344 rats (Barnes, Forster, Fleshner, Ahanacu, Laudenslager, Mazzeo, Maier, & Lal, 1991). Age-matched handled controls (HC) were weighed and returned to their home cages each day. All manipulations occurred between 0830 and 1130 h each day. Swim Task Protocol All rats were tested on both spatial and nonspatial versions of the swim task starting the day after the 28th water immersion session. The apparatus was an all-black circular pool (164 cm diameter and 45 cm depth). The pool was filled with water maintained at 30 { 17C and was located in a room that had colored paper and cardboard of various shapes on the walls. Several pieces of laboratory equipment, a wall clock, and a stepladder were also located near the pool as additional spatial cues. The escape platform for the spatial version of the task was circular (12 cm in diameter) and black in color. The top of the platform was positioned approximately 1 cm below the surface of the water. The platform used in the cue discrimination version of the task had similar dimensions, but a white band was painted on its sides to increase contrast between it and the black areas of the pool. The visible platform was positioned approximately 2 cm above the water level and was topped by wire mesh to facilitate climbing onto the platform surface. Spatial discrimination procedures. Prior to spatial discrimination training, each rat was given an adaptation session in the pool. Each rat was (1) placed on the platform for 30 s; (2) allowed to swim without the platform present for 30 s; (3) placed onto
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the platform for an additional 10 s; and (4) allowed to practice climbing onto the platform from three different directions after its forepaws were placed on the platform. Each rat was then placed under a heat lamp for several minutes. One hour after the adaptation session, training began on the spatial task. The platform was placed in one of the four quadrants. This location was fixed for each rat throughout the training period, but the goal location was equally distributed across all quadrants for the experiment. Each rat was placed into the water, facing the wall, at one of eight starting locations. The starting location was randomly selected for each trial. All starting locations were equally used across the experiment. Path length and latency to find the platform were recorded by a computer-based video camera tracking system (Videomex - V, Columbus Instruments, Columbus, OH). Maximum trial length was 60 s. If a rat found the platform, it was allowed to remain there for 30 s prior to being returned to its home cage. If a rat did not locate the platform within the 60-s time limit, it was placed onto the platform for 30 s by the experimenter. After removal from the pool, each rat was warmed under a heat lamp for a short period between trials. The intertrial interval was 1 h. Two trials per day were conducted over 4 consecutive days. On the fifth day, an additional spatial training trial was conducted during the first trial of the day. The second trial consisted of a probe trial during which the platform was removed and each rat was allowed to swim freely for 60 s. Total time spent in each quadrant was recorded to assess retention of the platform location. All trials took place between 1030 and 1345 h. Cue discrimination procedures. Three days after completion of the spatial task, all rats were tested on a cue discrimination task to assess visual acuity and motor ability. Generally, cued training is conducted first to eliminate impaired animals prior to spatial task testing (Foster et al., 1991). However, we conducted the cue discrimination task last in order to avoid the possibility of masking the effect of differential stress history on spatial performance by subjecting all animals to water immersion. In this task, rats had to find the location of the visible platform when both the starting location and the platform location were varied from trial to trial. If the rat did not find the platform within 60 s, it was placed onto the platform by the experimenter and was allowed to remain there for 30 s. The in-
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TABLE 1 Changes in Body Weight (g, Day 28–Day 1) after 28 Days of Chronic Intermittent Swim Stress at 307C for 15 min per Day for Young Adult and Aged F-344 Male Rats Stress History
Age
Handled controls
Chronic stress
Young Aged
36 { 5 (16) 05 { 4 (11)
5 { 5 (16) 032 { 4 (13)
Note. Values are means { SEM. Numbers in parentheses indicate number of animals in each group. The effects of both stress history and age were statistically significant (see text).
tertrial interval was approximately 30 s. Rats received five blocks of 3 trials over 1 day. The interblock interval was approximately 15 min. Path length and latency were recorded using the same video tracking system. All testing was conducted between 1000 and 1645 h. Statistical Analysis Behavioral data were analyzed using a repeatedmeasures analysis of variance (ANOVA). The repeated measures were the different days, blocks of training, and pool quadrants for each rat on the spatial and cue discrimination tasks and probe trial, respectively. Repeated-measures ANOVA post hoc comparisons within age or stress history factors were performed to examine the specificity of main effects interactions. Post hoc comparisons of age effects on individual trial blocks were analyzed using factorial ANOVAs. RESULTS Five aged rats (three HC and two CS) were unable to complete the swim trials in either the spatial or cue discrimination tasks and were not included in the analyses. A two-way ANOVA revealed significant effects of age and stress history on changes in body weight (g, Day 28–Day 1) over the water immersion preexposure period (Table 1). In general, aged rats lost body weight, while young adult rats gained body weight during the preexposure period, F(1, 55) Å 75.57, p £ .0001. In addition, the habituation procedure had a significant effect on body weight such that aged CS rats lost more body weight and young adult CS rats gained less body weight
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training was confirmed by post hoc analyses for simple effects which indicated a significant decrease in escape latency across days only for young adult animals [F(3, 90) Å 11.54, p £ .0001]. A stress history influence on escape latency was detected as an age X stress history interaction [F(1, 159) Å 4.88, p £ .05]. Post hoc comparisons of the age and stress interaction indicated no age difference for the CS animals; however, aged HC rats had significantly higher escape latencies than did young HC rats [F(1, 78) Å 22.48, p £ .0001].
FIG. 1. Effects of age on acquisition of spatial discrimination in the Morris swim task. Mean latency (A) and mean path length (B) to locate the escape platform are shown as a function of training over 4 days for chronic stress (circles) and handled control animals (squares) for both young adult (filled symbols) and aged rats (open symbols). Error bars equal SEM.
than did age-matched HC rats, F(1, 55) Å 41.56, p £ .0001. Spatial Discrimination Latency. Figure 1 illustrates the change in performance parameters for the four groups across the first 4 days of training on the spatial discrimination task. Only young rats exhibited an obvious reduction in latency over the 4 days of training. Overall, latency measures were highest in aged HC animals, followed by the age-matched CS group (Fig. 1A). A repeated-measures ANOVA indicated significant interaction of day 1 age [F(3, 159) Å 5.50, p £ .005]. The age-related difference in latency over days of
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Path length. The pattern of results obtained for mean path length was somewhat different than that for mean latency. While the general shape of the line graph for each group was maintained, the relationship between groups was altered (Fig. 1B). For the last 2 days of training, discernibly higher values were observed in the aged HC group than in the other three groups. Repeated-measures analysis of escape path length did not indicate significant main effects for age, stress history, or training across days. However, there were significant interactions for age X stress history [F(1, 159) Å 4.12, p £ .05] and age X day [F(1, 159) Å 7.87, p £ .0001]. Simple effects post hoc comparisons indicated that the path length decreased over the days of training for the young rats [F(3, 90) Å 5.18, p £ .005] and increased for aged rats [F(3, 69) Å 4.96, p £ .005] (Fig. 1B). A significant effect of stress history on path length was observed for aged animals [F(1, 69) Å 5.39, p £ .05]. The greater path length for the aged animals during the last 2 training days and the influence of stress on this group was largely due to poor performance by aged HC rats on trial 2 of each day of training. Figure 2 illustrates the escape path lengths on trials 1 and 2 for the four groups of rats on the last 2 full days of training. Aged HC rats exhibited equally poor performance across trials within a day, while aged CS rats, like younger animals, exhibited a tendency for reduced path length on the second trial of each day. A comparison of the average difference in path length (trial 2–trial 1) across the 4 days of training indicated no effect of stress history and a significant effect of age [F(1, 53) Å 4.64, p £ .05]. Post hoc comparisons indicated a significant age effect for the HC animals [F(1, 26) Å 4.69, p £ .05], while no difference was observed between young adult and aged animals in the CS condition. Thus, prior exposure to water immersion attenuated the age-related deficit in acquisition within a day (i.e., with a 1-h intertrial interval) but not across days (24-h interval).
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trial indicated a significant stress history effect only for aged animals [F(1, 23) Å 8.66, p £ .001] and a significant age difference only for the HC animals [F(1, 26) Å 11.15, p £ .005]. Thus, the age-related difference was not evident in those rats with prior water immersion histories. Individual ANOVAs examining differential quadrant search for each group revealed that for chronically stressed animals, both young [F(3, 63) Å 4.54, p £ .0073] and old [F(3, 51) Å 6.75, p £ .001] rats spent significantly more time searching the goal quadrant. For handled controls, only the young group spent significantly more time in the goal quadrant [F(3, 63) Å 9.52, p £ .0001]. Cue Discrimination Mean escape latencies on the cued discrimination task were higher for aged compared to young adult animals from the first to the last block of training and initial latencies were notably higher for aged HC rats (Fig. 4A). Unlike the results obtained in the spatial discrimination task, all groups exhibited learning over the course of training. A repeated-measures ANOVA indicated a significant age X trial block interaction [F(4, 212) Å 3.62, p £ .01). Post hoc comparisons revealed a significant difference between the two age groups on each trial block. While the influence of stress history approached signifi-
FIG. 2. Stress history of aged animals influenced the improvement in performance of spatial discrimination normally observed across training trials. Mean path length (cm) to escape is illustrated for trials one (filled) and two (open) on the last 2 days of training [Days 3(A) and 4(B)]. In contrast to young adult rats and aged CS rats, aged HC rats failed to exhibit reduced escape path length over the 1-h intertrial interval. Error bars equal SEM.
Probe trial. To determine whether animals had learned the spatial location of the platform and to test for retention across the 1-h intertrial interval, a 60-s probe trial was presented as the second trial on Day 5. Animals that learn and retain the spatial location of the escape platform spend more time in the goal quadrant. As illustrated in Fig. 3, aged handled control animals did not exhibit a differential search pattern, spending approximately an equal portion of their time in each quadrant. An ANOVA on the percentage of time animals spent searching the goal quadrant indicated a significant age X stress history interaction [F(1, 53) Å 5.16, p £ .05]. Post hoc analyses of performance on the probe
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FIG. 3. Percentage of time spent searching each quadrant during the spatial task probe trial on Day 5. Significantly more time was spent searching the goal (Goal) rather than the opposite quadrant (Opp) by young adult rats in the chronic stress (filled) and handled control groups (diagonal lines), as well as aged chronic stress animals (open). The differential search pattern indicates use of a spatial search strategy. Only the aged handled control animals (vertical lines) did not exhibit a differential search pattern. Values are means and SEMs are indicated.
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a large age effect for the HC group [F(1, 100) Å 35.75, p £ .0001) as well as an age X block interaction for HC animals [F(4, 100) Å 5.36, p £ .001]. Thus, prior water immersion history diminished the age-related differences on acquisition of the cue task as that history had done on the spatial task. Examination of the escape path length revealed a stress history influence on the initial performance of aged rats; however, with continued training all animals acquired the task to about the same extent. A repeated-measures ANOVA of escape path length indicated significant interactions of age X stress history [F(1, 212) Å 15.37, p £ .0005], block X age [F(4, 212) Å 4.28, p £ .005), and block X age X stress history [F(4, 212) Å 3.59, p £ .01). Similar to latency measures, both age groups exhibited a decreased path length across trial blocks [young: F(4, 120) Å 7.90, p £ .0001; aged: F(4, 92) Å 4.91, p £ .005] and aged rats exhibited a significant stress history effect [F(1, 92) Å 15.23, p £ .001]. However, while young adult rats exhibited overall shorter path lengths compared to aged rats, post hoc comparisons for each stress history group indicated an age effect only for the HC animals [F(1, 100) Å 34.82, p £ .0001] and an age X block interaction [F(4, 100) Å 6.32, p £ .0001]. Post hoc analysis for each trial block indicated that significant differences between age groups were observed only on trial blocks 1 through 3, and by the end of training, older animals traversed the same distance as young animals to reach the escape platform (Fig. 4B). FIG. 4. Effects of age on acquisition of cue discrimination in the Morris swim task. Mean latency (A) and mean path length (B) to locate the escape platform are shown as a function of training over blocks of trials (three trials per block) for chronic stress (circles) and handled control animals (squares) for both young adult (filled symbols) and aged rats (open symbols). Error bars equal SEM.
cance [F(1, 212) Å 3.27, p Å .07], a significant age X stress history X block interaction was observed [F(4, 212) Å 3.52, p £ .01]. The interactions were due, in large part, to longer escape latencies for the aged HC animals early in training. Simple effects analyses indicated that both age groups exhibited decreased latencies across blocks of training [young: F(4, 120) Å 10.13, p £ .0001; old: F(4, 92) Å 3.43, p £ .05], and a significant stress history effect was observed for the aged animals [F(1, 92) Å 7.29, p £ .05]. In addition, simple effects analyses for each stress history group indicated a small but significant age effect for CS animals [F(1, 112) Å 5.67, p £ .05] and
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DISCUSSION By using procedures shown in other studies to result in habituation of stress responses to water immersion in laboratory rats, the present study was designed to determine whether the performance of aged animals in a swim task would be improved. The results indicate that age-related learning deficits are reduced by stress habituation procedures. Furthermore, under the conditions employed, the habituation procedure appears to benefit only aged animals; stress history influences on the performance of young adult animals were not observed. Because of the stressful nature of the swim task, as defined by very large increases in circulating catecholamine levels after immersion in water, and the age-related differences in the catecholamine response (Mabry et al., 1995a), interpretation of age-related deficits in learning and memory in this task are likely to be complicated by age-related differences in stress responses. Stress effects were evidenced by the ability of aged
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CS but not HC rats to exhibit savings across the 1h retention period (Fig. 2). In addition, the results obtained with probe trials provide a clear indication that stress habituation procedures can augment the use of spatial information in aged rats; aged CS but not HC animals exhibited spatial search bias during the probe trial. The ability of aged CS rats to retain information within a day of training is remarkable considering the difficulty of the task employed here, i.e., only two trials each day with a 1-h intertrial interval. The ability of aged animals to learn and to retain information over short intertrial intervals, and yet forget this same information when tested over longer time periods, is consistent with findings of many previous studies using a wide range of tasks (e.g., Gage et al., 1984; Rapp et al., 1987; Foster et al., 1991; Gold, McGaugh, Hankins, Rose, & Vasquez, 1981; Lindner et al., 1992; Winocur, 1988). In the case of the spatial version of the swim tasks employing short (60–90 s) intertrial intervals, aged rats exhibit improvement in performance across trials within a day and age-related differences emerge as poor performance on the first trial examined across days of training (Foster et al., 1991; Gage et al., 1984; Rapp et al., 1987). This pattern of performance results in a ‘‘saw toothed’’ appearance of behavioral measures which is conspicuously absent for aged HC rats exposed to a 1-h intertrial interval, due mainly to a failure of aged HC animals to improve within a day. Panakhova, Buresova, and Bures (1984) have shown that the 1-h intertrial interval is taxing for memory processes of young adult rats and Lindner et al. (1992), using a similar testing procedure, have demonstrated large and reliable age-related deficits. Taken together, the results suggest that memory deficits observed at a 1-h intertrial interval may be augmented in aged animals due to the stress of the testing procedure. Importantly, stress habituation did not alleviate all age-related deficits in the swim task. Compared to young adult rats, impairments in 24-h retention (spatial task) were evident in aged rats with and without prior water immersion histories. Thus, the habituation procedures did not ameliorate age-related memory deficits on the spatial task over a 24h retention interval. A more rapid rate of forgetting of newly acquired spatial information has been noted by several researchers (Barnes & McNaughton 1985; Foster et al., 1991; Tandon et al., 1991; Zornetzer, Thompson, & Rogers, 1982). Thus, while improved utilization or acquisition of information can be fostered in aged animals by the water immersion procedure, serious memory deficits remain.
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The influence of stress history on learning was not limited to the spatial task. On the cued discrimination task, aged HC animals initially exhibited an acquisition deficit but their performance improved with training. As a result, the escape path length was comparable between all groups by trial blocks 4 and 5 of cue discrimination training. It is important to note that training on the cue task was conducted following spatial training, and all trials were massed into a single day with relatively short intertrial intervals. Our previous work using a similar training procedure indicates that, when animals are trained using massed trials and short intertrial intervals, age-related differences in performance are evident during the initial training trials on both cue and spatial tasks, but these differences rapidly disappear (Foster et al., 1991). Consistent with the idea that differences are due to the initial response to the swim procedure, the results of the current study indicate that age-differences observed early in training are absent in animals previously exposed to water immersion. Using a two trial per day training procedure, Rapp et al. (1987) examined age-related acquisition deficits of spatial and cue discrimination. When naive rats were initially trained on the spatial or cued version, an age-related acquisition deficit was observed. Interestingly, no acquisition deficits were observed for transfer training on the spatial task after 20 days of swim experience or when animals were switched to cue training after 29 days of spatial training in the pool. Taken together, the results suggest that rather than an aging effect specific to spatial learning, the ability of aged animals to perform in the swim task may involve an interaction of age and stress level. While improvement was observed for escape latency during cue discrimination, aged rats did not reach final latencies as low as those of young adult rats. Results from both the cue and spatial discrimination tasks confirm previous findings that aged male Fischer-344 rats exhibit slower swim speeds and longer escape latencies. Therefore, as noted in several past experiments (Foster et al., 1991; Lindner & Gribkoff 1991; Lindner et al., 1992), latency itself is not a good measure with which to differentiate cognitive function between ages. In addition, measures of path length alone can be misleading (Gallagher, Burwell, & Burchinal, 1993). For example, path length measures suggest that the performance of aged animals deteriorated across days on the spatial task (Fig. 1). However, the shorter mean path length on the first day of training is due to a tendency of animals to paw the walls of the pool,
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resulting in vigorous activity in the absence of translation through space. As such, escape path length appears to increase in the absence of a change in latency as animals change their strategy from searching the pool wall to searching the pool. Regardless, the probe trial measures indicate that when the experimental situation is arranged to minimize stress responses, aged animals can exploit information required for performance of swim tasks and could learn the tasks to approximately the same extent as do young adult animals. While plasma catecholamine and corticosterone levels were not specifically measured during training in the present experiment, a reduction in responsiveness to chronic intermittent stress has been observed for young adult and aged rats (Riegle, 1973; Konarska et al., 1989, 1990a,b). The significant changes in body weight between the aged-matched CS and HC groups over the preexposure phase of this experiment are consistent with findings reported by Konarska et al. (1990a) for young adult Sprague–Dawley rats. In their study, young adult CS rats had significantly smaller gains in body weights compared to HC rats over 26 days of chronic intermittent exposure to water immersion. The CS rats in that study also exhibited attenuated plasma norepinephrine and epinephrine responses compared to the responses of young adult rats exposed to water immersion for the first time. Taken together, the results indicate that stress responses are modified by stress history procedures as employed in the present experiment and that such procedures may influence the ability of aged animals to acquire and to utilize spatial information in the swim task. Investigations of the neurobiological bases for agerelated deficits in spatial tasks have focused on the hippocampus due to the susceptibility of hippocampal afferents to aging (Hyman, Van Hoesen, Damasio, & Barnes, 1984; Geinisman & Bondareff, 1976) as well as the findings that performance of spatial discrimination in the swim task depends on the functional integrity of the hippocampus (Morris, Garrud, Rawling, & O’Keefe, 1982; Morris, Shenk, Tweedie, & Jarrard, 1990). Age-related deficits in the acquisition of the swim task or spatial memory have been associated with changes in the septohippocampal system (Fischer, Gage, & Bjorklund, 1989; Gallagher & Nicolle, 1993; Luine & Hearns, 1990) and loss of perforant path input (Geinisman & Bondareff, 1976; Geinisman, deToledo-Morrell, & Morrell, 1986; Foster et al., 1991). There is also additional evidence that long-term potentiation in the hippocampal formation is impaired in aged rats in a
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manner related to deficits in maintenance of learned responses (cf. Barnes, 1994). In addition, there is growing evidence that stress and stress-related hormones can impair synaptic plasticity and maze learning (Foy, Stanton, Levine, & Thompson, 1987; Shors, Foy, Levine, & Thompson, 1990; Diamond, Bennett, Stevens, Wilson, & Rose, 1990; Shors & Dryver, 1992; Pavlides, Watanabe, & McEwen, 1993; Kerr, Huggett, & Abraham, 1994; Bodnoff, Humphreys, Lehman, Diamond, Rose, & Meaney, 1995). To the extent that long-term potentiation reflects processes important to performance in the swim task, the present findings suggest that the intense stress of immersion in water (Mabry et al., 1995a) in aged rats, compared to young adult rats, may impair synaptic plasticity necessary for acquisition of learned responses in the swim task. The present findings suggest further that habituation procedures might partially ameliorate such stress-induced impairments of synaptic plasticity in aged rats. These procedures may be useful, then, in separating those age-related cognitive deficits based on changes in memory mechanisms in the aging brain from those deficits based on stress-related neuroendocrine regulation of neural plasticity and memory. REFERENCES Barnes, C. A. (1994). Normal aging: Regionally specific changes in hippocampal synaptic transmission. Trends in Neuroscience, 17, 13–18. Barnes, C. A., Forster, M. J., Fleshner, M., Ahanotu, E. N., Laudenslager, M. L., Masseo, R. S., Maier, S. F., & Lal, H. (1991). Exercise does not modify spatial memory, brain autoimmunity, or antibody response in aged F-344 rats. Neurobiology of Aging, 12, 47–53. Barnes, C. A., & McNaughton, B. L. (1985). An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses. Behavioral Neuroscience, 99, 1040–1048. Bodnoff, R. R., Humphreys, A. G., Lehman, J. C., Diamond, D. M., Rose, G. M., & Meaney, M. J. (1995). Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. Journal of Neuroscience, 15, 61–69. Bohus, B., Grubits, J., Kovacs, G., & Lissak, K. (1970). Effects of corticosteroids on passive avoidance behavior of rats. Acta Physiologica Academiae Scientiarum Hungaricae, 38, 381– 391. Brandeis, R., Brandys, Y., & Yehuda, S. (1989). The use of the Morris water maze in the study of memory and learning. International Journal of Neuroscience, 48, 29–69. Clark, A. S., Magnusson, K. R., & Cotman, C. W. (1992). In vitro autoradiography of hippocampal excitatory amino acid binding in aged Fischer 344 rats: Relationship to performance on the Morris Water Maze. Behavioral Neuroscience, 106, 324– 335.
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AGE AND STRESS EFFECTS ON SPATIAL PERFORMANCE De Wied, D., & Croiset, G. (1991). Stress modulation of learning and memory processes. Methods and Achievements in Experimental Pathology, 15, 167–199. Diamond, D. M., Bennett, M. C., Stevens, K. E., Wilson, R. L., & Rose, G. M. (1990). Exposure to a novel environment interferes with the induction of hippocampal prime burst potentiation in the behaving rat. Psychobiology, 18, 273–281. Fischer, W., Gage, F. H., & Bjorklund, A. (1989). Degenerative changes in forebrain cholinergic nuclei correlate with cognitive impairments in aged rats. European Journal of Neuroscience, 1, 34–45. Fleg, J. L., Tzankoff, S. P., & Lakatta, E. G. (1985). Age-related augmentation of plasma catecholamines during dynamic exercise in healthy males. Journal of Applied Physiology, 59, 1033–1039. Foster, T. C., Barnes, C. A., Rao, G., & McNaughton, B. L. (1991). Increase in perforant path quantal size in aged F-344 rats. Neurobiology of Aging, 12, 441–448. Foy, M. R., Stanton, M. E., Levine, S., & Thompson, R. F. (1987). Behavioral stress impairs long-term potentiation in rodent hippocampus. Behavioral and Neural Biology, 48, 138–149. Gage, F. H., Dunnett, S. B., & Bjorklund, A. (1984). Spatial learning and motor deficits in aged rats. Neurobiology of Aging, 5, 43–48. Gallagher, M., Burwell, R., & Burchinal, M. (1993). Severity of spatial learning impairment in aging: Development of a learning index for performance in the Morris water maze. Behavioral Neuroscience, 107, 618–626. Gallagher, M., & Nicolle, M. M. (1993). Animals models of normal aging: Relationship between cognitive decline and markers in hippocampal circuitry. Behavioural Brain Research, 57, 155–162. Gallagher, M., & Pelleymounter, M. A. (1988). Spatial learning deficits in old rats: A model for memory decline in the aged. Neurobiology of Aging, 9, 549–556. Geinisman, Y., deToledo-Morrell, L., & Morrell, F. (1986). Agedrats need a preserved complement of perforated axospinous synapses per hippocampal neuron to maintain good spatial memory. Brain Research, 398, 266–275. Geinisman, Y., & Bondareff, W. (1976). Decrease in the number of synapses in the senescent brain: A quantitative electron microscopic analysis of the dentate gyrus molecular layer in the rat. Mechanisms of Ageing and Development, 5, 11–23. Gold, P. E. (1992). Modulation of memory processing: Enhancement of memory in rodents and humans. In L. R. Squire and N. Butters (Eds.), Neuropsychology of memory, 2nd ed., (pp. 402–414). New York: Guilford.
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Kerr, D. S., Huggett, A. M., and Abraham, W. C. (1994). Modulation of hippocampal long-term potentiation and depression by corticosteroid receptor activation. Psychobiology, 22, 123– 133. Konarska, M., Stewart, R. E., & McCarty, R. (1989). Habituation of sympathetic-adrenal medullary responses following exposure to chronic intermittent stress. Physiology and Behavior, 45, 255–261. Konarska, M., Stewart, R. E., & McCarty, R. (1990a). Habituation and sensitization of plasma catecholamine responses to chronic intermittent stress: Effects of stressor intensity. Physiology and Behavior, 47, 647–652. Konarska, M., Stewart, R. E., & McCarty, R. (1990b). Habituation of plasma catecholamine responses to chronic intermittent restraint stress. Psychobiology, 18, 30–34. Lindner, M. D., Balch, A. H., & VanderMaelen, C. P. (1992). Short forms of the ‘‘reference-’’ and ‘‘working-memory’’ Morris water maze for assessing age-related deficits. Behavioral and Neural Biology, 58, 94–102. Lindner, M. D., & Gribkoff, V. K. (1991). Relationship between performance in the Morris water task, visual acuity, and thermoregulatory function in aged F-344 rats. Behavioural Brain Research, 45, 45–55. Lorens, S. A., Hata, N., Van De Kar, L. D., Guschwan, M., Goral, J., Lee, J. M., Hamilton, M. E., Bethea, C., and Clancy, J., Jr. (1990). Neurochemical, endocrine and immunological responses to stress in young and old Fisher 344 male rats. Neurobiology of Aging, 11, 139–150. Luine, V., & Hearns, M. (1990). Spatial memory deficits in aged rats: contribution of cholinergic system assessed by ChAT. Brain Research, 523, 321–324. Mabry, T. R., Gold, P. E., & McCarty, R. (1995a). Age-related changes in plasma catecholamine responses to acute swim stress. Neurobiology of Learning and Memory, 63, 260–268. Mabry, T. R., Gold, P. E., & McCarty, R. (1995b). Age-related changes in plasma catecholamine responses to chronic intermittent stress. Physiology and Behavior, 58, 49–56. Mabry, T. R., Gold, P. E., & McCarty, R. (1995c). Age-related changes in plasma catecholamine and glucose responses of F-344 rats to a single footshock as used in inhibitory avoidance training. Neurobiology of Learning and Memory, 64, 146–155. McCarty, R. (1985). Sympathetic-adrenal medullary and cardiovascular responses to acute cold stress in adult and aged rats. Journal of the Autonomic Nervous System, 12, 15–22. McCarty, R. (1986). Age-related alterations in sympathetic-adrenal medullary responses to stress. Gerontology, 32, 172–183.
Gold, P. E., McGaugh, J. L., Hankins, L. L., Rose, R. P., & Vasquez, B. J. (1981). Age dependent changes in retention in rats. Experimental Aging Research, 8, 53–58.
McGaugh, J. L. (1989). Involvement of hormonal and neuromodulatory systems in the regulation of memory storage. Annual Review of Neuroscience, 12, 255–287.
Gold, P. E., & Stone, W. S. (1988). Neuroendocrine factors in agerelated memory dysfunctions: Studies in animals and humans. Neurobiology of Aging, 9, 709–717.
McNamara, R. K., & Skelton, R. W. (1993). The neuropharmacological and neurochemical basis of place learning in the Morris water maze. Brain Research Reviews, 18, 33–49.
Hyman, B. T., Van Hoesen, G. W., Damasio, A. R., & Barnes, C. L. (1984). Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science, 225, 1168–1170.
Morris, R. G. M., Garrud, P., Rawlins, J. N. P., & O’Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681–683.
Issa, A. M., Rowe, W., Gauthier, S., & Meaney, M. J. (1990). Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. Journal of Neuroscience, 10, 3247–3254.
Morris, R. G. M., Shenk, F., Tweedie, F., & Jarrard, L. E. (1990). Ibotenate lesions of hippocampus and/or subiculum: dissociating components of allocentric spatial learning. European Journal of Neuroscience, 2, 1016–1028.
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Palmer, G. J., Ziegler, M. G., & Lake, C. R. (1978). Response of norepinephrine and blood pressure to stress increases with age. Journal of Gerontology, 33, 482–487. Panakhova, E., Buresova, O., & Bures, J. (1984). Persistence of spatial memory in the Morris water tank task. International Journal of Psychopharmacology, 2, 5–10. Pavlides, C., Watanabe, Y., & McEwen, B. S. (1993). Effects of glucocorticoids on hippocampal long-term potentiation. Hippocampus, 3, 183–192. Rapp, P. R., Rosenberg, R. A., & Gallagher, M. (1987). An evaluation of spatial information processing in aged rats. Behavioral Neuroscience, 101, 3–12. Riegle, G. D. (1973). Chronic stress effects on adrenocortical responsiveness in young and aged rats. Neuroendrocrinology, 11, 1–10. Riegle, G., and Hess, G. (1972). Chronic and acute dexamethasone suppression of stress activation of the adrenal cortex in young and aged rats. Neuroendrocrinology, 9, 175–187. Sapolsky, R. M., Krey, L. C., and McEwen, B. S. (1984). Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. Proceedings of the National Academy of Sciences USA 81, 6174–6177.
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Shors, T. J., & Dryver, E. (1992). Stress impedes exploration and acquisition of spatial information in the eight-arm radial maze. Psychobiology, 20, 247–253. Shors, T. J., Foy, M. R., Levine, S., & Thompson, R. F. (1990). Unpredictable and uncontrollable stress impairs neuronal plasticity in the rat hippocampus. Brain Research Bulletin, 24, 663–667. Tandon, P., Mundy, W. R., Ali, S. F., Nanry, K., Rogers, B. C., & Tilson, H. A. (1991). Age-dependent changes in receptor-stimulated phosphoinositide turnover in the rat hippocampus. Pharmacology, Biochemistry and Behavior, 38, 861–867. Winocur, G. (1988). A neuropsychological analysis of memory loss with age. Neurobiology of Aging, 9, 487–494. Young, J. B., Rowe, J. W., Pallotta, J. A., Sparrow, D., & Landsberg, L. (1980). Enhanced plasma norepinephrine response to upright posture and oral glucose administration in elderly human subjects. Metabolism, 29, 532–539. Ziegler, M. G., Lake, C. R., & Kopin, I. J. (1976). Plasma noradrenaline increases with age. Nature, 261, 333–335. Zornetzer, S. F., Thompson, R., & Rogers, J. (1982). Rapid forgetting in aged rats. Behavioral and Neural Biology, 36, 49–60.
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Age and Stress History Effects on Spatial Performance in a Swim Task in Fischer-344 Rats T. R. MABRY,1 R. MCCARTY, P. E. GOLD,
AND
T. C. FOSTER2
Department of Psychology, Gilmer Hall, University of Virginia, Charlottesville, Virginia 22903
Palmer, Ziegler, & Lake, 1978; Young, Rowe, Pallotta, Sparrow, & Landsberg, 1980; Sapolsky, Krey, & McEwen, 1984; Fleg, Tzankoff, Lakatta, & Lakatta, 1985; McCarty, 1985; Lorens, Hata, Van De Kar, Guschwan, Goral, Lee, Hamilton, Bethea, & Clancy, 1990; Mabry, Gold, & McCarty, 1995a,b,c). For example, compared to young adult rats, aged rats exhibit potentiated plasma catecholamine responses, especially increases in plasma epinephrine levels, after placement in water at temperatures routinely employed for swim task training (McCarty 1985, 1986; Mabry et al., 1995a). With the considerable evidence that the plasma level of stress-related hormones near the time of training can regulate learning and memory (Bohus, Grubits, Kovacs, & Lissak, 1970; McGaugh, 1989; De Wied & Croiset, 1991; Gold, 1992), the possibility arises that agerelated changes in learning and memory may reflect alterations not only in memory storage mechanisms per se, but also in neuroendocrine responses known to modulate memory storage processes (Gold & Stone, 1988; Issa, Rowe, Gauthier, & Meaney, 1990; Gold, 1992). An important feature of the stress response is that habituation of the response is seen with repeated exposure to a stressful experience. For example, when compared to rats experiencing water immersion for the first time, plasma catecholamine levels show diminished responses to water immersion in rats that had received daily exposure to the same stressor over several weeks (Konarska, Stewart, & McCarty, 1989, 1990a,b). Swim tasks are widely used to examine age-related deficits in spatial memory (e.g., Gallagher & Pelleymounter, 1988; Brandeis, Brandys, & Yehuda, 1989; Foster, Barnes, Rao, & McNaughton, 1991; Lindner, Balch, & VanderMaelen, 1992; McNamara & Skelton, 1993). In some cases (e.g., Rapp,
This study determined whether prior habituation to water immersion would ameliorate age-related deficits in learning and memory in a swim task. Aged (22 months) and young adult (3 months) rats were immersed in water (307C) for 15 min on each of 28 consecutive days before training in the swim task. Additional groups of agematched animals served as handled controls. Training on a spatial discrimination version of the water task was conducted over 5 days with two trials per day (1-h intertrial interval). A probe trial was substituted for the last trial on the fifth day to assess the rats’ use of spatial information. Three days later, rats received cue discrimination training to find a visible platform. In the spatial task, prior habituation to water immersion ameliorated deficits in acquisition within each day (i.e., at a 1-h intertrial interval) but not across days (at 24 h). The results obtained with the 24-h interval confirm the rapid forgetting characteristic of aged rats in many tasks. The stress-habituation procedures reduced age-related deficits seen on the probe trial and on cue discrimination training. These findings indicate that several aspects of age-related impairments in the swim task, often attributed to primary age-related deficits in learning and memory processes per se, may instead be secondary to age-related differences in stress responses to water immersion. q 1996 Academic Press, Inc.
Aged animals exhibit enhanced plasma catecholamine and corticosterone responses to acute stress (Riegle & Hess, 1972; Ziegler, Lake, & Kopin, 1976; 1 Present address: Department of Behavior Science and Leadership, U.S. Air Force Academy, CO 80840. 2 This research was supported in part by U.S. Public Health Service Grants AG07648, NS32914, and NS31830 and by a grant from the American Federation for Aging Research. Address correspondence and reprint requests to Dr. Thomas Foster, Department of Psychology, 102 Gilmer Hall, University of Virginia, Charlottesville, Virginia 22903-2477. Fax: (804) 982-4785. Email: [email protected].
1 1074-7427/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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Rosenberg, & Gallagher, 1987; Clark, Magnusson, & Cotman, 1992; Gage, Dunnett, & Bjorklund, 1984; Tandon, Mundy, Ali, Nanry, Rogers, & Tilson, 1991; Lindner et al., 1992), acquisition trials presented across many days reveal age-related deficits early in training but aged rats eventually approach the performance of young rats. Moreover, aged rats exhibit no deficits on later training on the cue version of the task, with the findings generally interpreted to reveal age-related impairments in spatial learning coupled with relative preservation of cued learning (e.g., Rapp et al., 1987). However, the extensive training (up to 30 days), together with available information about stress responses and adaptation of those responses, suggests a quite different view. This alternative view is that the absence of deficits late in training, i.e., after many days of immersion in water, may reflect habituation of stress responses, thereby attenuating an impairing impact of stress hormone responses on learning. According to this view, performance of aged rats would eventually approach that of young rats and later tests on cued learning would reveal no deficits; these are findings reported previously (Rapp et al., 1987). Assuming that repeated exposure to water immersion results in a diminished stress response in both young adult and aged rats, repeated exposure to immersion in water provides a possible manipulation with which to decrease the otherwise exaggerated stress responses in aged rats and, thereby, to examine the contribution of these responses to age-related memory deficits. The present experiment tested the hypothesis that prior exposure to water immersion would improve the acquisition and retention of spatial information in the swim task. The performance of both young adult and aged rats that had been exposed to water immersion on each of 28 consecutive days prior to training was compared to that of age-matched rats with no prior water exposure. METHOD Animals Young adult (3 months, N Å 32) and aged (22 months, N Å 32) male Fischer-344 rats were obtained from the National Institute on Aging colonies maintained by Harlan Sprague–Dawley, Inc. (Indianapolis, IN). Upon arrival in our vivarium, rats were housed individually in suspended metal cages with ad libitum access to food and water. The vivarium rooms were maintained on a 12-h light–dark cycle (lights on 0700–1900 h) at an ambient temperature of 22 { 17C.
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Stress Habituation Procedures Animals were randomly assigned to one of two conditions within each age group. Chronically stressed animals (CS) were weighed and then immersed in 307C water for 15 min each day for 28 consecutive days. The apparatus was a standard 20gallon aquarium that was subdivided into four compartments (15 1 36 1 30 cm) and fitted with a plexiglass top. A small hole was cut in the plexiglass top above each compartment. The diameter of the hole did not allow escape from the water, but did provide a place for each rat to grasp with its mouth and/ or paws. Within 3-4 sessions, rats learned to swim directly to the hole and remain there for the entire session and therefore expended minimal effort to stay afloat. Of relevance to the outcomes of this manipulation, exercise per se apparently does not modify spatial memory in aged Fischer-344 rats (Barnes, Forster, Fleshner, Ahanacu, Laudenslager, Mazzeo, Maier, & Lal, 1991). Age-matched handled controls (HC) were weighed and returned to their home cages each day. All manipulations occurred between 0830 and 1130 h each day. Swim Task Protocol All rats were tested on both spatial and nonspatial versions of the swim task starting the day after the 28th water immersion session. The apparatus was an all-black circular pool (164 cm diameter and 45 cm depth). The pool was filled with water maintained at 30 { 17C and was located in a room that had colored paper and cardboard of various shapes on the walls. Several pieces of laboratory equipment, a wall clock, and a stepladder were also located near the pool as additional spatial cues. The escape platform for the spatial version of the task was circular (12 cm in diameter) and black in color. The top of the platform was positioned approximately 1 cm below the surface of the water. The platform used in the cue discrimination version of the task had similar dimensions, but a white band was painted on its sides to increase contrast between it and the black areas of the pool. The visible platform was positioned approximately 2 cm above the water level and was topped by wire mesh to facilitate climbing onto the platform surface. Spatial discrimination procedures. Prior to spatial discrimination training, each rat was given an adaptation session in the pool. Each rat was (1) placed on the platform for 30 s; (2) allowed to swim without the platform present for 30 s; (3) placed onto
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the platform for an additional 10 s; and (4) allowed to practice climbing onto the platform from three different directions after its forepaws were placed on the platform. Each rat was then placed under a heat lamp for several minutes. One hour after the adaptation session, training began on the spatial task. The platform was placed in one of the four quadrants. This location was fixed for each rat throughout the training period, but the goal location was equally distributed across all quadrants for the experiment. Each rat was placed into the water, facing the wall, at one of eight starting locations. The starting location was randomly selected for each trial. All starting locations were equally used across the experiment. Path length and latency to find the platform were recorded by a computer-based video camera tracking system (Videomex - V, Columbus Instruments, Columbus, OH). Maximum trial length was 60 s. If a rat found the platform, it was allowed to remain there for 30 s prior to being returned to its home cage. If a rat did not locate the platform within the 60-s time limit, it was placed onto the platform for 30 s by the experimenter. After removal from the pool, each rat was warmed under a heat lamp for a short period between trials. The intertrial interval was 1 h. Two trials per day were conducted over 4 consecutive days. On the fifth day, an additional spatial training trial was conducted during the first trial of the day. The second trial consisted of a probe trial during which the platform was removed and each rat was allowed to swim freely for 60 s. Total time spent in each quadrant was recorded to assess retention of the platform location. All trials took place between 1030 and 1345 h. Cue discrimination procedures. Three days after completion of the spatial task, all rats were tested on a cue discrimination task to assess visual acuity and motor ability. Generally, cued training is conducted first to eliminate impaired animals prior to spatial task testing (Foster et al., 1991). However, we conducted the cue discrimination task last in order to avoid the possibility of masking the effect of differential stress history on spatial performance by subjecting all animals to water immersion. In this task, rats had to find the location of the visible platform when both the starting location and the platform location were varied from trial to trial. If the rat did not find the platform within 60 s, it was placed onto the platform by the experimenter and was allowed to remain there for 30 s. The in-
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TABLE 1 Changes in Body Weight (g, Day 28–Day 1) after 28 Days of Chronic Intermittent Swim Stress at 307C for 15 min per Day for Young Adult and Aged F-344 Male Rats Stress History
Age
Handled controls
Chronic stress
Young Aged
36 { 5 (16) 05 { 4 (11)
5 { 5 (16) 032 { 4 (13)
Note. Values are means { SEM. Numbers in parentheses indicate number of animals in each group. The effects of both stress history and age were statistically significant (see text).
tertrial interval was approximately 30 s. Rats received five blocks of 3 trials over 1 day. The interblock interval was approximately 15 min. Path length and latency were recorded using the same video tracking system. All testing was conducted between 1000 and 1645 h. Statistical Analysis Behavioral data were analyzed using a repeatedmeasures analysis of variance (ANOVA). The repeated measures were the different days, blocks of training, and pool quadrants for each rat on the spatial and cue discrimination tasks and probe trial, respectively. Repeated-measures ANOVA post hoc comparisons within age or stress history factors were performed to examine the specificity of main effects interactions. Post hoc comparisons of age effects on individual trial blocks were analyzed using factorial ANOVAs. RESULTS Five aged rats (three HC and two CS) were unable to complete the swim trials in either the spatial or cue discrimination tasks and were not included in the analyses. A two-way ANOVA revealed significant effects of age and stress history on changes in body weight (g, Day 28–Day 1) over the water immersion preexposure period (Table 1). In general, aged rats lost body weight, while young adult rats gained body weight during the preexposure period, F(1, 55) Å 75.57, p £ .0001. In addition, the habituation procedure had a significant effect on body weight such that aged CS rats lost more body weight and young adult CS rats gained less body weight
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training was confirmed by post hoc analyses for simple effects which indicated a significant decrease in escape latency across days only for young adult animals [F(3, 90) Å 11.54, p £ .0001]. A stress history influence on escape latency was detected as an age X stress history interaction [F(1, 159) Å 4.88, p £ .05]. Post hoc comparisons of the age and stress interaction indicated no age difference for the CS animals; however, aged HC rats had significantly higher escape latencies than did young HC rats [F(1, 78) Å 22.48, p £ .0001].
FIG. 1. Effects of age on acquisition of spatial discrimination in the Morris swim task. Mean latency (A) and mean path length (B) to locate the escape platform are shown as a function of training over 4 days for chronic stress (circles) and handled control animals (squares) for both young adult (filled symbols) and aged rats (open symbols). Error bars equal SEM.
than did age-matched HC rats, F(1, 55) Å 41.56, p £ .0001. Spatial Discrimination Latency. Figure 1 illustrates the change in performance parameters for the four groups across the first 4 days of training on the spatial discrimination task. Only young rats exhibited an obvious reduction in latency over the 4 days of training. Overall, latency measures were highest in aged HC animals, followed by the age-matched CS group (Fig. 1A). A repeated-measures ANOVA indicated significant interaction of day 1 age [F(3, 159) Å 5.50, p £ .005]. The age-related difference in latency over days of
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Path length. The pattern of results obtained for mean path length was somewhat different than that for mean latency. While the general shape of the line graph for each group was maintained, the relationship between groups was altered (Fig. 1B). For the last 2 days of training, discernibly higher values were observed in the aged HC group than in the other three groups. Repeated-measures analysis of escape path length did not indicate significant main effects for age, stress history, or training across days. However, there were significant interactions for age X stress history [F(1, 159) Å 4.12, p £ .05] and age X day [F(1, 159) Å 7.87, p £ .0001]. Simple effects post hoc comparisons indicated that the path length decreased over the days of training for the young rats [F(3, 90) Å 5.18, p £ .005] and increased for aged rats [F(3, 69) Å 4.96, p £ .005] (Fig. 1B). A significant effect of stress history on path length was observed for aged animals [F(1, 69) Å 5.39, p £ .05]. The greater path length for the aged animals during the last 2 training days and the influence of stress on this group was largely due to poor performance by aged HC rats on trial 2 of each day of training. Figure 2 illustrates the escape path lengths on trials 1 and 2 for the four groups of rats on the last 2 full days of training. Aged HC rats exhibited equally poor performance across trials within a day, while aged CS rats, like younger animals, exhibited a tendency for reduced path length on the second trial of each day. A comparison of the average difference in path length (trial 2–trial 1) across the 4 days of training indicated no effect of stress history and a significant effect of age [F(1, 53) Å 4.64, p £ .05]. Post hoc comparisons indicated a significant age effect for the HC animals [F(1, 26) Å 4.69, p £ .05], while no difference was observed between young adult and aged animals in the CS condition. Thus, prior exposure to water immersion attenuated the age-related deficit in acquisition within a day (i.e., with a 1-h intertrial interval) but not across days (24-h interval).
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trial indicated a significant stress history effect only for aged animals [F(1, 23) Å 8.66, p £ .001] and a significant age difference only for the HC animals [F(1, 26) Å 11.15, p £ .005]. Thus, the age-related difference was not evident in those rats with prior water immersion histories. Individual ANOVAs examining differential quadrant search for each group revealed that for chronically stressed animals, both young [F(3, 63) Å 4.54, p £ .0073] and old [F(3, 51) Å 6.75, p £ .001] rats spent significantly more time searching the goal quadrant. For handled controls, only the young group spent significantly more time in the goal quadrant [F(3, 63) Å 9.52, p £ .0001]. Cue Discrimination Mean escape latencies on the cued discrimination task were higher for aged compared to young adult animals from the first to the last block of training and initial latencies were notably higher for aged HC rats (Fig. 4A). Unlike the results obtained in the spatial discrimination task, all groups exhibited learning over the course of training. A repeated-measures ANOVA indicated a significant age X trial block interaction [F(4, 212) Å 3.62, p £ .01). Post hoc comparisons revealed a significant difference between the two age groups on each trial block. While the influence of stress history approached signifi-
FIG. 2. Stress history of aged animals influenced the improvement in performance of spatial discrimination normally observed across training trials. Mean path length (cm) to escape is illustrated for trials one (filled) and two (open) on the last 2 days of training [Days 3(A) and 4(B)]. In contrast to young adult rats and aged CS rats, aged HC rats failed to exhibit reduced escape path length over the 1-h intertrial interval. Error bars equal SEM.
Probe trial. To determine whether animals had learned the spatial location of the platform and to test for retention across the 1-h intertrial interval, a 60-s probe trial was presented as the second trial on Day 5. Animals that learn and retain the spatial location of the escape platform spend more time in the goal quadrant. As illustrated in Fig. 3, aged handled control animals did not exhibit a differential search pattern, spending approximately an equal portion of their time in each quadrant. An ANOVA on the percentage of time animals spent searching the goal quadrant indicated a significant age X stress history interaction [F(1, 53) Å 5.16, p £ .05]. Post hoc analyses of performance on the probe
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FIG. 3. Percentage of time spent searching each quadrant during the spatial task probe trial on Day 5. Significantly more time was spent searching the goal (Goal) rather than the opposite quadrant (Opp) by young adult rats in the chronic stress (filled) and handled control groups (diagonal lines), as well as aged chronic stress animals (open). The differential search pattern indicates use of a spatial search strategy. Only the aged handled control animals (vertical lines) did not exhibit a differential search pattern. Values are means and SEMs are indicated.
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a large age effect for the HC group [F(1, 100) Å 35.75, p £ .0001) as well as an age X block interaction for HC animals [F(4, 100) Å 5.36, p £ .001]. Thus, prior water immersion history diminished the age-related differences on acquisition of the cue task as that history had done on the spatial task. Examination of the escape path length revealed a stress history influence on the initial performance of aged rats; however, with continued training all animals acquired the task to about the same extent. A repeated-measures ANOVA of escape path length indicated significant interactions of age X stress history [F(1, 212) Å 15.37, p £ .0005], block X age [F(4, 212) Å 4.28, p £ .005), and block X age X stress history [F(4, 212) Å 3.59, p £ .01). Similar to latency measures, both age groups exhibited a decreased path length across trial blocks [young: F(4, 120) Å 7.90, p £ .0001; aged: F(4, 92) Å 4.91, p £ .005] and aged rats exhibited a significant stress history effect [F(1, 92) Å 15.23, p £ .001]. However, while young adult rats exhibited overall shorter path lengths compared to aged rats, post hoc comparisons for each stress history group indicated an age effect only for the HC animals [F(1, 100) Å 34.82, p £ .0001] and an age X block interaction [F(4, 100) Å 6.32, p £ .0001]. Post hoc analysis for each trial block indicated that significant differences between age groups were observed only on trial blocks 1 through 3, and by the end of training, older animals traversed the same distance as young animals to reach the escape platform (Fig. 4B). FIG. 4. Effects of age on acquisition of cue discrimination in the Morris swim task. Mean latency (A) and mean path length (B) to locate the escape platform are shown as a function of training over blocks of trials (three trials per block) for chronic stress (circles) and handled control animals (squares) for both young adult (filled symbols) and aged rats (open symbols). Error bars equal SEM.
cance [F(1, 212) Å 3.27, p Å .07], a significant age X stress history X block interaction was observed [F(4, 212) Å 3.52, p £ .01]. The interactions were due, in large part, to longer escape latencies for the aged HC animals early in training. Simple effects analyses indicated that both age groups exhibited decreased latencies across blocks of training [young: F(4, 120) Å 10.13, p £ .0001; old: F(4, 92) Å 3.43, p £ .05], and a significant stress history effect was observed for the aged animals [F(1, 92) Å 7.29, p £ .05]. In addition, simple effects analyses for each stress history group indicated a small but significant age effect for CS animals [F(1, 112) Å 5.67, p £ .05] and
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DISCUSSION By using procedures shown in other studies to result in habituation of stress responses to water immersion in laboratory rats, the present study was designed to determine whether the performance of aged animals in a swim task would be improved. The results indicate that age-related learning deficits are reduced by stress habituation procedures. Furthermore, under the conditions employed, the habituation procedure appears to benefit only aged animals; stress history influences on the performance of young adult animals were not observed. Because of the stressful nature of the swim task, as defined by very large increases in circulating catecholamine levels after immersion in water, and the age-related differences in the catecholamine response (Mabry et al., 1995a), interpretation of age-related deficits in learning and memory in this task are likely to be complicated by age-related differences in stress responses. Stress effects were evidenced by the ability of aged
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CS but not HC rats to exhibit savings across the 1h retention period (Fig. 2). In addition, the results obtained with probe trials provide a clear indication that stress habituation procedures can augment the use of spatial information in aged rats; aged CS but not HC animals exhibited spatial search bias during the probe trial. The ability of aged CS rats to retain information within a day of training is remarkable considering the difficulty of the task employed here, i.e., only two trials each day with a 1-h intertrial interval. The ability of aged animals to learn and to retain information over short intertrial intervals, and yet forget this same information when tested over longer time periods, is consistent with findings of many previous studies using a wide range of tasks (e.g., Gage et al., 1984; Rapp et al., 1987; Foster et al., 1991; Gold, McGaugh, Hankins, Rose, & Vasquez, 1981; Lindner et al., 1992; Winocur, 1988). In the case of the spatial version of the swim tasks employing short (60–90 s) intertrial intervals, aged rats exhibit improvement in performance across trials within a day and age-related differences emerge as poor performance on the first trial examined across days of training (Foster et al., 1991; Gage et al., 1984; Rapp et al., 1987). This pattern of performance results in a ‘‘saw toothed’’ appearance of behavioral measures which is conspicuously absent for aged HC rats exposed to a 1-h intertrial interval, due mainly to a failure of aged HC animals to improve within a day. Panakhova, Buresova, and Bures (1984) have shown that the 1-h intertrial interval is taxing for memory processes of young adult rats and Lindner et al. (1992), using a similar testing procedure, have demonstrated large and reliable age-related deficits. Taken together, the results suggest that memory deficits observed at a 1-h intertrial interval may be augmented in aged animals due to the stress of the testing procedure. Importantly, stress habituation did not alleviate all age-related deficits in the swim task. Compared to young adult rats, impairments in 24-h retention (spatial task) were evident in aged rats with and without prior water immersion histories. Thus, the habituation procedures did not ameliorate age-related memory deficits on the spatial task over a 24h retention interval. A more rapid rate of forgetting of newly acquired spatial information has been noted by several researchers (Barnes & McNaughton 1985; Foster et al., 1991; Tandon et al., 1991; Zornetzer, Thompson, & Rogers, 1982). Thus, while improved utilization or acquisition of information can be fostered in aged animals by the water immersion procedure, serious memory deficits remain.
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The influence of stress history on learning was not limited to the spatial task. On the cued discrimination task, aged HC animals initially exhibited an acquisition deficit but their performance improved with training. As a result, the escape path length was comparable between all groups by trial blocks 4 and 5 of cue discrimination training. It is important to note that training on the cue task was conducted following spatial training, and all trials were massed into a single day with relatively short intertrial intervals. Our previous work using a similar training procedure indicates that, when animals are trained using massed trials and short intertrial intervals, age-related differences in performance are evident during the initial training trials on both cue and spatial tasks, but these differences rapidly disappear (Foster et al., 1991). Consistent with the idea that differences are due to the initial response to the swim procedure, the results of the current study indicate that age-differences observed early in training are absent in animals previously exposed to water immersion. Using a two trial per day training procedure, Rapp et al. (1987) examined age-related acquisition deficits of spatial and cue discrimination. When naive rats were initially trained on the spatial or cued version, an age-related acquisition deficit was observed. Interestingly, no acquisition deficits were observed for transfer training on the spatial task after 20 days of swim experience or when animals were switched to cue training after 29 days of spatial training in the pool. Taken together, the results suggest that rather than an aging effect specific to spatial learning, the ability of aged animals to perform in the swim task may involve an interaction of age and stress level. While improvement was observed for escape latency during cue discrimination, aged rats did not reach final latencies as low as those of young adult rats. Results from both the cue and spatial discrimination tasks confirm previous findings that aged male Fischer-344 rats exhibit slower swim speeds and longer escape latencies. Therefore, as noted in several past experiments (Foster et al., 1991; Lindner & Gribkoff 1991; Lindner et al., 1992), latency itself is not a good measure with which to differentiate cognitive function between ages. In addition, measures of path length alone can be misleading (Gallagher, Burwell, & Burchinal, 1993). For example, path length measures suggest that the performance of aged animals deteriorated across days on the spatial task (Fig. 1). However, the shorter mean path length on the first day of training is due to a tendency of animals to paw the walls of the pool,
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resulting in vigorous activity in the absence of translation through space. As such, escape path length appears to increase in the absence of a change in latency as animals change their strategy from searching the pool wall to searching the pool. Regardless, the probe trial measures indicate that when the experimental situation is arranged to minimize stress responses, aged animals can exploit information required for performance of swim tasks and could learn the tasks to approximately the same extent as do young adult animals. While plasma catecholamine and corticosterone levels were not specifically measured during training in the present experiment, a reduction in responsiveness to chronic intermittent stress has been observed for young adult and aged rats (Riegle, 1973; Konarska et al., 1989, 1990a,b). The significant changes in body weight between the aged-matched CS and HC groups over the preexposure phase of this experiment are consistent with findings reported by Konarska et al. (1990a) for young adult Sprague–Dawley rats. In their study, young adult CS rats had significantly smaller gains in body weights compared to HC rats over 26 days of chronic intermittent exposure to water immersion. The CS rats in that study also exhibited attenuated plasma norepinephrine and epinephrine responses compared to the responses of young adult rats exposed to water immersion for the first time. Taken together, the results indicate that stress responses are modified by stress history procedures as employed in the present experiment and that such procedures may influence the ability of aged animals to acquire and to utilize spatial information in the swim task. Investigations of the neurobiological bases for agerelated deficits in spatial tasks have focused on the hippocampus due to the susceptibility of hippocampal afferents to aging (Hyman, Van Hoesen, Damasio, & Barnes, 1984; Geinisman & Bondareff, 1976) as well as the findings that performance of spatial discrimination in the swim task depends on the functional integrity of the hippocampus (Morris, Garrud, Rawling, & O’Keefe, 1982; Morris, Shenk, Tweedie, & Jarrard, 1990). Age-related deficits in the acquisition of the swim task or spatial memory have been associated with changes in the septohippocampal system (Fischer, Gage, & Bjorklund, 1989; Gallagher & Nicolle, 1993; Luine & Hearns, 1990) and loss of perforant path input (Geinisman & Bondareff, 1976; Geinisman, deToledo-Morrell, & Morrell, 1986; Foster et al., 1991). There is also additional evidence that long-term potentiation in the hippocampal formation is impaired in aged rats in a
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manner related to deficits in maintenance of learned responses (cf. Barnes, 1994). In addition, there is growing evidence that stress and stress-related hormones can impair synaptic plasticity and maze learning (Foy, Stanton, Levine, & Thompson, 1987; Shors, Foy, Levine, & Thompson, 1990; Diamond, Bennett, Stevens, Wilson, & Rose, 1990; Shors & Dryver, 1992; Pavlides, Watanabe, & McEwen, 1993; Kerr, Huggett, & Abraham, 1994; Bodnoff, Humphreys, Lehman, Diamond, Rose, & Meaney, 1995). To the extent that long-term potentiation reflects processes important to performance in the swim task, the present findings suggest that the intense stress of immersion in water (Mabry et al., 1995a) in aged rats, compared to young adult rats, may impair synaptic plasticity necessary for acquisition of learned responses in the swim task. The present findings suggest further that habituation procedures might partially ameliorate such stress-induced impairments of synaptic plasticity in aged rats. These procedures may be useful, then, in separating those age-related cognitive deficits based on changes in memory mechanisms in the aging brain from those deficits based on stress-related neuroendocrine regulation of neural plasticity and memory. REFERENCES Barnes, C. A. (1994). Normal aging: Regionally specific changes in hippocampal synaptic transmission. Trends in Neuroscience, 17, 13–18. Barnes, C. A., Forster, M. J., Fleshner, M., Ahanotu, E. N., Laudenslager, M. L., Masseo, R. S., Maier, S. F., & Lal, H. (1991). Exercise does not modify spatial memory, brain autoimmunity, or antibody response in aged F-344 rats. Neurobiology of Aging, 12, 47–53. Barnes, C. A., & McNaughton, B. L. (1985). An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses. Behavioral Neuroscience, 99, 1040–1048. Bodnoff, R. R., Humphreys, A. G., Lehman, J. C., Diamond, D. M., Rose, G. M., & Meaney, M. J. (1995). Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. Journal of Neuroscience, 15, 61–69. Bohus, B., Grubits, J., Kovacs, G., & Lissak, K. (1970). Effects of corticosteroids on passive avoidance behavior of rats. Acta Physiologica Academiae Scientiarum Hungaricae, 38, 381– 391. Brandeis, R., Brandys, Y., & Yehuda, S. (1989). The use of the Morris water maze in the study of memory and learning. International Journal of Neuroscience, 48, 29–69. Clark, A. S., Magnusson, K. R., & Cotman, C. W. (1992). In vitro autoradiography of hippocampal excitatory amino acid binding in aged Fischer 344 rats: Relationship to performance on the Morris Water Maze. Behavioral Neuroscience, 106, 324– 335.
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Kerr, D. S., Huggett, A. M., and Abraham, W. C. (1994). Modulation of hippocampal long-term potentiation and depression by corticosteroid receptor activation. Psychobiology, 22, 123– 133. Konarska, M., Stewart, R. E., & McCarty, R. (1989). Habituation of sympathetic-adrenal medullary responses following exposure to chronic intermittent stress. Physiology and Behavior, 45, 255–261. Konarska, M., Stewart, R. E., & McCarty, R. (1990a). Habituation and sensitization of plasma catecholamine responses to chronic intermittent stress: Effects of stressor intensity. Physiology and Behavior, 47, 647–652. Konarska, M., Stewart, R. E., & McCarty, R. (1990b). Habituation of plasma catecholamine responses to chronic intermittent restraint stress. Psychobiology, 18, 30–34. Lindner, M. D., Balch, A. H., & VanderMaelen, C. P. (1992). Short forms of the ‘‘reference-’’ and ‘‘working-memory’’ Morris water maze for assessing age-related deficits. Behavioral and Neural Biology, 58, 94–102. Lindner, M. D., & Gribkoff, V. K. (1991). Relationship between performance in the Morris water task, visual acuity, and thermoregulatory function in aged F-344 rats. Behavioural Brain Research, 45, 45–55. Lorens, S. A., Hata, N., Van De Kar, L. D., Guschwan, M., Goral, J., Lee, J. M., Hamilton, M. E., Bethea, C., and Clancy, J., Jr. (1990). Neurochemical, endocrine and immunological responses to stress in young and old Fisher 344 male rats. Neurobiology of Aging, 11, 139–150. Luine, V., & Hearns, M. (1990). Spatial memory deficits in aged rats: contribution of cholinergic system assessed by ChAT. Brain Research, 523, 321–324. Mabry, T. R., Gold, P. E., & McCarty, R. (1995a). Age-related changes in plasma catecholamine responses to acute swim stress. Neurobiology of Learning and Memory, 63, 260–268. Mabry, T. R., Gold, P. E., & McCarty, R. (1995b). Age-related changes in plasma catecholamine responses to chronic intermittent stress. Physiology and Behavior, 58, 49–56. Mabry, T. R., Gold, P. E., & McCarty, R. (1995c). Age-related changes in plasma catecholamine and glucose responses of F-344 rats to a single footshock as used in inhibitory avoidance training. Neurobiology of Learning and Memory, 64, 146–155. McCarty, R. (1985). Sympathetic-adrenal medullary and cardiovascular responses to acute cold stress in adult and aged rats. Journal of the Autonomic Nervous System, 12, 15–22. McCarty, R. (1986). Age-related alterations in sympathetic-adrenal medullary responses to stress. Gerontology, 32, 172–183.
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