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Passive Avoidance and Complex Maze Learning in the Senescence Accelerated Mouse (SAM)

Age and Strain Comparisons of SAM P8 and R1

^a Behavior Neuroscience Section, Laboratory of Neurosciences
^b Gerontology Research Center, National Institute on Aging, Baltimore, Maryland
^c Department of Psychology, Johns Hopkins University, Baltimore, Maryland

Donald K. Ingram, Molecular Physiology and Genetics Section, Nathan W. Shock Laboratories, GRC, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224 E-mail: ingramd{at}grc.nia.nih.gov.

Decision Editor: John A. Faulkner, PhD

	Abstract

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Two strains of the senescence accelerated mouse, P8 and R1,were tested in footshock-motivated passive avoidance (PA; P8, 3–21 months; R1, 3–24 months) and 14-unit T-maze (P8 and R1, 9, and 15 months) tasks. For PA, entry to a dark chamber from a lighted chamber was followed by a brief shock. Latency to enter the dark chamber 24 hours later served as a measure of retention. Two days of active avoidance training in a straight runway preceded 2 days (8 trials/day) of testing in the 14-unit T-maze. For PA retention, older P8 mice entered the dark chamber more quickly than older R1 mice, whereas no differences were observed between young P8 or R1 mice. In the 14-unit T-maze, age-related learning performance deficits were reflected in higher error scores for older mice. P8 mice were actually superior learners; that is, they had lower error scores compared with those of age-matched R1 counterparts. Although PA learning results were in agreement with other reports, results obtained in the 14-unit T-maze were not consistent with previous reports of learning impairments in the P8 senescence accelerated mouse.

IT has been over two decades since Takeda and colleagues ⁽¹⁾ reported their observations on senescence accelerated mice (SAM) derived from the AKR/J strain with characteristics of accelerated aging including a shortened median life span in a prone strain (P1, 11.9 months) compared with a longer median life span in a resistant strain (R1, 17.5 months). Since these reports, other strains of mice prone to senescence acceleration have been bred and derived over numerous generations ⁽²⁾, including a P8 strain that reportedly exhibits age-related deficits in learning and memory that are manifested early in its life span ⁽³⁾.

In behavioral studies, P8 SAM have most often been compared with the R1 strain ⁽⁴⁾. The P8 mouse has been reported to be deficient to the R1 as early as 2 months of age. With increasing age these deficiencies become more obvious in a variety of simple shock-motivated avoidance paradigms ⁽⁵⁾. In passive avoidance (PA) paradigms, deficits have been observed in acquisition ⁽⁶⁾ and retention tests ⁽⁷⁾⁽⁸⁾. However, the type of PA apparatus and the procedures used have been reported to have effects on both acquisition and retention in P8 mice ⁽³⁾. For instance, 6-month-old and 11-month-old P8 mice have been observed to be deficient compared with R1 counterparts in multiple-trial acquisition training to a criterion in a step-down PA task, but these same mice were not deficient in retention ⁽⁸⁾. Flood and colleagues ⁽⁹⁾ failed to observe age-related impairment of acquisition in 4- to 12-month-old P8 mice in step-through PA.

Compared with R1 mice, deficits have also been observed in P8 mice in acquisition of one-way ⁽⁷⁾⁽⁸⁾ and two-way active avoidance ⁽⁸⁾, and in a T-maze avoidance paradigm ⁽¹⁰⁾. Flood and Morley ⁽¹⁰⁾ utilized a footshock-motivated T-maze avoidance paradigm to test SAM and observed that P8 mice 9 months or older were impaired in the number of trials to the first avoidance in acquisition compared with R1 counterparts. In a 1-week retention test, P8 mice 8 months old and older took significantly more trials to make an initial avoidance response and required more trials to reach a criterion of 5 out of 6 correct avoidance responses than did younger P8 or 4- and 12-month-old R1 mice.

Flood and colleagues ⁽⁹⁾ demonstrated that these deficits in retention in 8- and 12-month-old P8 mice could be attenuated with posttraining administration of cholinergic agonists (arecoline or tacrine) or a serotonergic agonist (mianserin), but that increasingly higher doses of the cholinergic agonists at 8 and 12 months were required to improve performance, whereas the opposite was true for serotonergic agonists; that is, lower doses were required to improve performance at 12 months of age than at 4 or 8 months of age in P8 mice. In another study, Flood and colleagues ⁽¹¹⁾ demonstrated that posttraining intrahippocampal injection of a glutamatergic agonist (L-glutamate) acting on the N-methyl-D-aspartate receptor or a cholinergic agonist (arecholine) could also attenuate deficits in retention in P8 mice, but again higher doses of the drugs were required at 8 and 12 months of age to demonstrate comparable levels of performance in R1 mice. Farr and colleagues ⁽¹²⁾ further implicated hippocampal involvment in learning the T-maze in studies with CD-1 mice in which the hippocampus was permanently (bilateral electrolytic lesions) or temporarily (lidocaine administration) disabled. Thus, learning performance disruption in this task in the P8 mouse has implicated the cholinergic and glutamatergic hippocampal systems.

Testing in complex spatial learning tasks that require involvement of hippocampal circuitry has produced more ambiguous results. Miyamoto ⁽⁶⁾ reported a slight impairment in reference and working memory in a food-motivated radial arm maze. Nishiyama and colleagues ⁽⁷⁾ reported impairments in amount of time required to find a submerged platform in a Morris water maze in 11-month-old P8 compared with 11-month-old R1 mice, whereas 6-month-old P8 and R1 mice did not differ. Contrary to these findings, Ingram and colleagues ⁽¹³⁾ compared the performance of three age groups (3, 7, and 13 months) of C57BL/6J, SAM P8, and SAM R1 mice in distance traveled to locate a submerged platform in a water maze and observed that C57BL/6J were the worst performers. P8 and R1 were similar in performance, with no age differences observed. Using a similar protocol to compare 4- and 15-month-old P8 and R1 mice, but applying more sensitive performance parameters, Markowska and colleagues ⁽¹⁴⁾ reported that 15-month-old P8 mice took longer to find the submerged platform and did worse in probe trials in a water maze test. However, these investigators have also noted that motivational, emotional, or sensorimotor factors may have contributed to the strain differences in water maze performance.

In the present study we evaluated the performance of different ages of P8 and R1 mice in acquisition and retention in a step through, shock-motivated PA test to confirm previous findings. We also evaluated the acquisition performance of P8 and R1 mice of different ages in a shock-motivated 14-unit T-maze. This complex maze task appears to differ from other maze tests, such as the radial arm maze and the Morris water maze, in that the use or need for spatial or sensory cues is minimized ⁽¹⁵⁾. Rather, the animal must learn a series of position discriminations, ostensibly relying on an internal, response-driven algorithm to learn the series of 14 sequential position discriminations. Age-related differences in acquisition of this task have been observed in a number of strains of rats and mice ^(15)(16). This task is sensitive to damage of the septohippocampal systems ⁽¹⁷⁾ and to manipulation of the cholinergic ^(18)(19)(20) and glutamatergic systems ^(16)(21).

	Methods

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Subjects
SAM that were derived from breeding pairs of senescence-prone (SAMP8/Ta/NIA) and senescence-resistant (SAMR1/Ta/NIA) mice donated by Takeda Chemical Industries (Osaka, Japan) were maintained in a breeding colony at the Gerontology Research Center (GRC). The mice were housed in plastic cages with wood chips for bedding located in a metal rack. Food (NIH-07) and water from an automated watering system were provided ad libitum. The room was maintained at 21°C and on a 12 hour light/12 hour dark photocycle (lights on 6 AM EST). All testing was conducted during the light phase of the photocycle.

Sentinel mice were housed in the colony room and were tested monthly for the following specific pathogens: murine encephalomyelitis virus, mycoplasma, mouse hepatitus virus, and Sendai virus. Tests of the sentinel animals revealed no significant or elevated levels of any of these specific pathogens during the course of this study.

A total of 53 virgin, naive male SAM of different ages were tested in PA, with 23 being P8 mice (age range 3–21 months) and 30 being R1 mice (age range 3–24 months). For 14-unit T-maze testing, 9-month-old (n = 8 for P8 and R1) and 15-month-old (n = 7 for P8 and R1) virgin, male mice were used.

Passive Avoidance Conditioning
A step-through PA box was constructed of plastic and had a solid, stainless-steel floor with a 1-cm gap in the middle wired to receive scrambled shock from a Coulbourn Instruments (E13-08; Lehigh Valley, PA) grid floor shocker. A switch box was used to initiate and terminate the shock. A table lamp with a flexible neck was used to illuminate the start chamber with a 60 W light bulb. The entire apparatus was housed on a small table top.

For the experiment, all mice were brought to the testing room at least 30 minutes prior to testing, and the lights in the room were turned off to allow the animals to acclimate to the darkened room. A table lamp over the start chamber was illuminated and remained on throughout testing. For the experiment each mouse was picked up gently by its tail and removed from the home cage and placed onto the grid floor in the illuminated area of the PA box, facing away from the guillotine door. The timer was initiated as soon as the mouse was placed into the chamber. After 5 seconds the door to the darkened area of the chamber was opened. Once the mouse entered the darkened area of the chamber, the door was closed, and scrambled footshock (0.3 mA) was delivered for 5 seconds. Approximately 15 seconds after shock termination, the mouse was removed from the dark chamber and then returned to its home cage. On the following day, approximately 24 hours later, each mouse was given a retention test that was identical to the first day except that shock was not initiated once the mouse walked into the darkened chamber from the lighted one. If a mouse failed to walk into the dark chamber within 600 seconds, then the timer was stopped, a maximum 600-second latency was recorded, and the mouse was returned to its home cage. The latency (seconds) to enter the darkened chamber was measured for both acquisition (time from first exposure to the lighted PA chamber until the mouse entered the darkened chamber) and retention (time from entry to lighted chamber until the mouse entered the darkened chamber 24 hours later).

Straight Runway Training and 14-Unit T-Maze Testing
The straight runway apparatus has been described in detail previously ⁽¹⁸⁾. This one-way active avoidance chamber (2 m long) basically consisted of clear plastic sides with a diagonally oriented stainless-steel grid floor wired to receive scrambled shock from a grid floor shocker (Coulbourn Instruments E13-08). Eight aluminum legs attached to the bottom of the runway served to elevate it above a moveable wooden table. The entire apparatus was surrounded by wood walls painted gray.

An automated 14-unit T-maze (2 m square), described in detail previously ⁽¹⁸⁾, was constructed of clear plastic. The maze had a diagonally oriented stainless-steel grid floor that was wired in series to a grid floor shocker (Coulbourn Instruments E13-08) to deliver scrambled shock through the grid floor. A handheld switch was used to initiate a clock that, when timed out, turned on the grid floor shocker. This switch was also used to terminate the grid floor shock. The plastic portion of the maze was attached to a steel cable and could be hoisted by means of a pulley system to clean the grid floor of the maze between each trial.

The mice were placed into the maze room and allowed to acclimate for at least 30 minutes prior to the start of pretraining in active avoidance in the straight runway (days 1 and 2) and prior to 14-unit T-maze testing (days 3 and 4). For straight runway pretraining, each mouse was removed gently by the tail from its home cage and placed into a black box with a moveable rear wall and guillotine door. Identical black boxes served as start and goal boxes. The black box was placed into a start area over the grid floor in the straight runway. The guillotine door on the box was raised, and the mouse was pushed gently from the black box by advancing the moveable back wall forward to expel the animal into the runway. To successfully avoid footshock (0.3 mA), the mouse had to move down the runway and enter an identical black box with a guillotine door within 10 seconds; otherwise, footshock was initiated until the mouse escaped to the black goal box. Once the mouse entered the goal box, a guillotine door was closed, and the mouse was removed to a holding area until the next trial 2 minutes later. If a mouse failed to escape shock within 60 seconds, it was removed from the runway to the goal box. Three failures to escape within 60 seconds resulted in the mouse being removed from the experiment. On day 1 each mouse received 20 massed practice trials (2-minute intertrial interval [ITI]). On day 2 each mouse was trained to a criterion of 13 out of 15 correct avoidances of footshock (maximum = 20 trials). Mice that successfully met the criteria began training in the 14-unit T-maze on the following day.

As in straight runway pretraining, each mouse was removed gently from its home cage and placed into a black box that had a moveable rear wall and served interchangeably as a start and goal box. The box was placed into the start area of the 14-unit T-maze (Fig. 1) over the grid floor; the mouse was pushed out into the initial segment of the maze; a guillotine door from the start area was closed; and the shock avoidance contingency (10 seconds; 0.3 mA) was initiated by means of the handheld switch. The mouse had 10 seconds to move through the first gate in the maze to avoid footshock, or footshock was initiated and remained on until the mouse passed through the gate to the second section of the maze. Once the mouse passed the gate and the guillotine door was closed, the shock avoidance contingency was reset, and the mouse again had 10 seconds to move past a second gate to a third section to avoid footshock. This contingency was reset a total of four times as the mouse traversed the five sections of the maze to arrive at the goal box in the final section. On days 3 and 4 each mouse received four massed practice trials (2-minute ITI) in the morning and afternoon for a total of 16 trials. Failure to move through the maze within 600 seconds resulted in the mouse being removed and placed into the goal box. If the mouse failed to meet this criterion on any of three trials, it was removed from the experiment.

View larger version (36K): [in this window] [in a new window]   Figure 1. Configuration of 14-unit T-maze. Arrows denote the correct pathway. Errors are scored as any deviation from this pathway.

The number of correct avoidances of footshock during straight runway training for each mouse was determined and converted to the percentage of correct avoidances of shock. A one-way analysis of variance (ANOVA) was then calculated to determine if differences existed in avoidance performance among the groups.

Data for each of the four dependent variables (errors, runtime, shock frequency, and duration) of 14-unit T-maze performance were submitted to 2 (strain) by 2 (age) by 4 (4 blocks of 4 trials) repeated measures ANOVA. Newman–Keuls post hoc tests were conducted to determine the locus of differences among groups for main effects. Interactions were evaluated by performing an ANOVA at each block of trials and then performing a Newman–Keuls post hoc test of the means.

	Results

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Survival Data
Fig. 2 displays the survival curves for male P8 (n = 22) and R1 (n = 28) SAM within a selected cohort maintained for a longevity study in the GRC colony. The median life span was observed to be 504 (± 40.35) versus 693 (± 39.87) days for P8 and R1 mice, respectively. A Mantel–Cox analysis of the survival data revealed that the R1 mice survived significantly longer than did the P8 group; C = 36.62, p < .00001.

View larger version (16K): [in this window] [in a new window]   Figure 2. Survival curves (days) for senescence accelerated mice (SAM) R1 and P8 strains in the Gerontology Research Center colony.

For PA retention, age again determined a large proportion of the variance for P8 (23%; p < .01), but not for R1 (5%; p > .05). As shown in Fig. 3a, P8 mice younger than 15 months of age entered the darkened chamber during the acquisition trial more quickly than did R1 mice of the same age. For the retention test (Fig. 3b), aged P8 mice were less likely to inhibit the tendency to enter a darkened chamber (i.e., had shorter latencies) 24 hours following a brief aversive event in the same chamber.

Straight Runway and 14-Unit T-Maze
The percentage of correct shock avoidances during 2 days of straight runway pretraining are presented in Table 1 . A one-way ANOVA revealed no significant differences in avoidance performance between any of the groups; F(3,31) = 0.47, p > .05.

As shown in Fig. 4 (line graph), the learning curves for young P8 mice (mean errors for each block of four trials) were superior to all other groups, and the curve for the aged P8 mice was nearly identical to that of the young R1 mice. This observation became more evident when the mean for all 16 learning trials for each group was graphed (bar graph, Fig. 4). Overall, it was clear that P8 mice were better performers than R1 mice in the maze task.

View larger version (33K): [in this window] [in a new window]   Figure 4. A, Mean errors (deviations from correct pathway) across blocks of four trials in the 14-unit T-maze for 9- and 15-month-old R1 and P8 mice. B, Mean errors per trial for 9- and 15-month-old R1 and P8 mice in the 14-unit T-maze.

View larger version (21K): [in this window] [in a new window]   Figure 5. Mean scores across blocks of four trials for each of the performance measures: A, runtime; B, shock duration; and C, shock frequency.

	Discussion

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In the present study of SAM strains, differences emerged in acquisition during a PA test with young P8 mice (<15 months) requiring less time to enter a darkened chamber in a shock-motivated, step-through PA task than R1 mice. Compared with their R1 counterparts in a 24-hour retention test, aged P8 SAM exhibited worse performance in that they entered the darkened chamber more quickly where they had been shocked 24 hours previously compared with young P8 SAM. Our observation of deficient retention performance for P8 mice agrees with several previous reports ^(3)(22)(23). As Flood and Morley ⁽³⁾ noted in their recent review, the results obtained in PA acquisition and retention tests may be greatly affected by the conditions established or controlled for by the experimenter and the type of apparatus used by the experimenter in PA testing.

In a 14-unit T-maze, which required the mice to learn a series of position discriminations while moving through a maze to avoid footshock, older mice were poorer performers (i.e., made more errors and had longer runtimes). This finding agrees with a number of other studies using this task in rats and mice ⁽¹⁵⁾. However, P8 SAM were observed to be superior performers in this task compared with R1 mice.

Thus, the current study is in agreement with other studies that have reported age-related deficits in simple avoidance tasks in P8 SAM that are not observed in the R1 strain. The results obtained in the 14-unit T-maze, however, present problems for the SAM model of accelerated senescence in learning and memory in the P8 strain, particularly when the results of a number of other studies using this task are considered. Robust age-related deficits in acquisition of this task have been observed in a variety of strains of rats and mice ^(15)(16). Moreover, in another study, using a Morris-type water maze, no age or strain differences were observed between P8 and R1 mice ⁽¹³⁾. However, Markowska and colleagues ⁽¹⁴⁾ observed a slight but significant impairment in probe trial performance of aged P8 SAM compared with R1 mice, a measure that is arguably more sensitive for memory of the location of a submerged platform in the water maze test.

Numerous reports have documented deficiencies in simple avoidance tasks in the SAM P8 strain of mouse, particulary in various types of PA tasks ⁽⁸⁾. Strain differences between P8 and R1 mice have been documented as early as 2 months of age ⁽⁵⁾. We observed strain differences at early ages, but only in the acquisition trials for the young P8 mice (3–9 months of age). Differences emerged in retention performance with age between R1 and P8, as noted in the divergence of the slopes of the regression lines (Fig. 3), with older P8 mice having shorter latencies. The findings for the retention measure may be interpreted as a deficiency in memory (i.e., remembering the mild shock received in the darkened chamber on the acquisition trial 24 hours previously).

View larger version (21K): [in this window] [in a new window]   Figure 3. Performance in a 24-hour step-through passive avoidance test. A, Regression of age on initial latency to enter avoidance chamber. B, Regression of age on latency to enter avoidance chamber 24 hours following exposure to (0.3 mA) footshock.

An age-related change in footshock sensitivity, while unlikely, might also explain the present results for retention. Miyamoto and colleagues ⁽⁶⁾ reported no age differences in footshock sensitivity of P8 and R1 mice up to 12 months of age but did note strain differences at 2 months of age as measured by a jump response to the footshock stimulus. Flinch responses were slightly but not significantly higher in P8 compared with R1 mice at 8 and 12 months of age. However, in the present study the P8 mice, regardless of age, had faster runtimes and received less shock and fewer shocks than did their R1 counterparts in the 14-unit T-maze, suggesting that the results in PA were not due to a decreased sensitivity to shock. In addition, no significant difference between groups was observed for active avoidance training in a straight runway.

Still another explanation for the results obtained in the PA task would be that the age-related deficits resulted from an emotional deficit in the P8 mouse. Specifically, the ability to inhibit the tendency to enter the darkened chamber results not from a deficiency to remember the aversive event but a blunted emotional response to the event. Markowska and colleagues ⁽¹⁴⁾ had observed that P8 mice, independent of age, were less anxious in both a plus maze and in an open field, as measured by number of defecations. Miyamoto and colleagues ⁽⁵⁾ also have reported reduced anxiety in the P8 compared with the R1 mouse, as measured by a reduced latency to ingest a novel food (i.e., gustatory neophobia). Ohta and colleagues ⁽²⁴⁾ observed that P8 mice 2 and 8 months of age were able to learn a delayed discrimination of a food reward in an operant task (bar press to a light or tone stimulus) as quickly as age-matched R1 mice. In retention tests at 2.5-, 5-, and 10-second delay intervals, P8 mice of both ages again performed as well as R1 mice to the positive discrimination stimuli. However, during negative discrimination trials in which the mouse had to inhibit a response to a stimulus, the 8-month-old P8 mice made more errors (i.e., were poorer at inhibiting the response to bar press) than were 8-month-old R1 mice. Thus, simple tests of avoidance performance may provide an inadequate assessment of memory processes in P8 mice because of these emotional factors.

More perplexing for the P8 mouse as a model for age-related learning impairment are the results obtained in the 14-unit T-maze. Confirming results obtained by using numerous other strains of rats and mice, an age-related impairment in learning this complex maze was observed. However, P8 mice, regardless of age, were observed to be better performers than R1 mice (i.e, made fewer errors). An age-related deficit in runtime indicated that older mice were slower. However, P8 mice again moved through the maze faster than R1 mice with decreasing runtimes across blocks of trials as another index of learning.

The results obtained in the present study, and those of others, confirm that age-related deficits in simple avoidance are evident in the SAM P8 strain of mouse. The validity of the P8 strain as a model of accelerated senescence in learning ability is challenged, however, by the results obtained in the 14-unit T-maze task. The present findings conflict with those of others ⁽⁸⁾ that have reported that the SAM P8 strain suffers from age-related impairment in simple and complex learning, perhaps caused by decreased cholinergic activity or cell loss. Further, our results appear to conflict with studies implicating the accumulation of amyloid-beta in hippocampus of the P8 mouse with deficient performance in shock-motivated T-maze ^(25)(26) performance.

Another possibility would be that the SAM P8 strain does not experience deficits in complex tasks requiring the learning of a series of position discriminations (i.e., 14-unit T-maze) but does experience learning deficits in tasks that require spatial learning (i.e., radial arm maze or Morris water maze). The conflicting findings suggest that further experiments in complex tasks that can be devised to test spatial or nonspatial learning are merited to test this hypothesis. Tasks that would appear likely candidates for testing this hypothesis include the Morris water maze, radial arm maze, and the holeboard apparatus.

As Jucker and Ingram ⁽²⁷⁾ stated in their review of mouse models for aging research, the SAM P8 strain may be valuable for studying aspects related to human aging and disease, such as brain weight loss, and atrophy in the brain including atrophy of large neurons. However, the relationship of these age-related structural changes in the brain to behavior (i.e., learning and memory) requires further study and clarification. There appears to be no generalized cognitive deficit in the P8 strain compared with the R1 strain.

Received December 14, 2000

Accepted September 28, 2001

	References

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