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Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2009.
14.1. INTRODUCTION
Water maze tasks have been used for over a quarter century in testing rodent spatial navigation memory [1]. Although initially developed for rats, they have also been useful in evaluating memory in mice, often using scaled down pool sizes. The major advantage of the water maze tasks over dry mazes is increased motivation to escape, and hence more rapid performance within the maze. Typical trials in water mazes are limited to 60 sec, while dry maze trials often last much longer. This permits higher throughput and increased efficiency when large numbers of animals require evaluation.
The original Morris maze used an open pool with a hidden platform just below the water level midway between the pool wall and the center of the pool. The rodent is placed in the pool, typically facing the wall, in one of four arbitrarily defined quadrants, and permitted to explore the pool. Extramaze cues surround the pool to orient the rodent as it navigates within the pool. Initially animals stumble upon the platform, climb onto it and are forced to remain for a short period before being removed to consolidate the experience. They are then removed from the platform and placed into a different quadrant from the first trial and again given the opportunity to explore the pool. Once again the platform is encountered and the animal escapes the pool by climbing onto the platform. Often a third and in some versions up to six trials are performed. The time spent prior to finding the platform is recorded as “latency to escape” and is averaged for each day’s performance. The procedure is repeated over 2–14 days with the platform remaining in the same location each day, making this a reference memory task.
After 3–10 days of training, the rodents are administered a “probe” trial (actually an extinction trial) in which the platform is removed and memory for platform location assessed. A number of measurements have been proposed to infer the strength of the “memory” of the mouse for the platform location. The simplest is time spent in the “target” quadrant (i.e., the one that previously contained the platform). More elaborate measurements include the average swim distance from the previous platform location or the number of crossings over the exact location of the platform. Many of these measurements involve videotaping of the rodent’s performance and application of computerized software to analyze the performance. However, given that the mice must still be shuttled manually into the pool and off the platform (and rescued if drowning), there is no meaningful personnel efficiency achieved by the use of computerized analysis (the behaviorist must remain at the pool for each rodent).
There are many variations on these procedures. Some have used intermediate probe trials after days 3, 6, and 9, for example, and used comparisons of these performances as an index of rate of learning [2]. Others have converted the normal reference memory version of the water maze to a working memory model by measuring the number of trials to reach a latency criterion at one location and then measuring trials to criterion at a new platform location [3]. In general, this open pool Morris water maze approach is useful in discriminating memory dysfunction in amyloid precursor protein (APP) transgenic mice [4–8]. In our own work with the water maze task, we found in some cases that mice were impaired when measuring latency, but not on the probe trial [9]. In the Barnes maze, these mice showed no significant deficits. However, when the same mice were tested on the radial arm water maze, the APP transgenic mice were significantly impaired. Although we originally included both the open pool Morris water maze and the radial arm water maze (and Barnes maze) as components of a 6-wk behavioral test battery [10], we have now abbreviated this to a 2-wk battery in which a shortened version of the radial arm water maze is the primary cognitive task [11].
The radial arm water maze involves the imposition of a radial arm maze onto a pool. This approach was first developed for rats [12,13]. This is implemented by insertion of triangular wedges into the pool that reach above the surface of the water, forming swim alleys surrounding a central open region (Figure 14.1). The platform is placed within one of the alleys (goal arm) and the mouse is started in one of the other swim arms. Although our initial work focused on a working memory version of this task [14,15], we have found a reference memory variant of the radial arm water maze that can consistently reveal deficits in transgenic mouse memory performance with as few as 2 days of training, increasing the flexibility of scheduling behavioral testing. This latter adaptation, developed in consultation with David Diamond, takes advantage of optimal spacing of trials to minimize the time needed for acquisition of the task. Moreover, the measurement of errors does not require use of video cameras or computers to obtain reliable data regarding performance. Depending on the pool size, up to 16 arms can been used and the contingencies organized to separately detect reference versus working memory errors [16]. The design flexibility of the dry radial arm maze can be combined with the motivational advantages of the water maze format.
FIGURE 14.1
The radial arm water maze. Shown are the pool used for behavioral testing with metal inserts/dividers in place forming swim alleys and a central swim area. The platform shown is the visible platform that protrudes just slightly above the water and is (more...)
14.2. METHODS
14.2.1. Animal Subjects
Our work has focused exclusively on transgenic mouse models of amyloid deposition or tau pathology. Our APP mice have been derived from the Tg2576 line [4] bred with a mutant PS1 line 5.1 [17] as described by Holcomb et al. [18]. As a result these mice are of a mixed genetic background. It should be noted that many inbred mouse lines carry a retinal degeneration gene mutation [19,20] that does not impair performance on many murine behavioral tests (including the visual cliff [21]), but does cause severe deficits in spatial navigation tasks [22]. The JAX laboratories Web site indicates whether a given strain is known to possess one of these rd mutations and provides primer pairs to detect the most prevalent rd1 mutation in individual mice when genotyping. It is essential that mouse lines either be investigated for presence of a background strain carrying an rd mutation, or that individual mice be tested for this mutation. Our Tg2576 line carried the rd mutation via inclusion of the SJL strain. However, genotyping and selective breeding have eliminated this mutation from the background of our APP animals.
Mice should be generally healthy and free of open wounds that might become infected by exposure to water. Thus, we do not test mice within 7 days of a surgical procedure. For the APP-only mice, we can detect behavioral deficits in modest-sized cohorts (6–8) around 12–15 mo of age. For many studies we prefer older mice (20–24 mo) as this more closely resembles conditions of aged Alzheimer’s disease (AD) patients. We always include a cohort of untreated nontransgenic littermate mice in any drug/therapy trials to act as a positive control (if the nontransgenic mice fail to learn, there is a problem with the behavioral testing procedure).
14.2.2. Equipment
Pool size is not an essential variable, but should be constrained for practical reasons (e.g., ability of the experimenter to reach all parts of the pool). For mice we have used a 1 m pool that is 30 cm deep. We constructed pie-shaped wedges out of a sheet of stainless steel (plastic or sheet aluminum may also be suitable) that was 24 cm wide and 60 cm long. These were then bent at the center of the long axis to form a 60° angle. They were placed into the pool to form a “V” 24 cm high with a vertex 30 cm from the edge of the pool. By equally spacing six of these inserts into the pool, we form six swim alleys of 30 cm in length with a 40-cm wide central region (Figure 14.1). The pool is then filled with water to a depth of 14 cm (10 cm from the top of the inserts) at a temperature of 20.5°C. A platform should be placed in one swim alley just below the water line. We use inverted terra cotta pots (10 cm diameter) that are painted the same color as the inside of the pool and positioned 1 cm beneath the surface of the water. A pool liner may be used instead of paint to achieve a uniform color that can be replaced instead of cleaned and repainted (black works very nicely). We do not find it necessary to add paint or milk to the water to increase opacity.
14.2.3. Working Memory Procedure
Prior to cognitive testing mice are administered a small neurological test battery consisting of wire hang and balance beam (day 1), Y-maze testing (day 2), and 3 days of accelerating rotorod testing. Mice failing to perform adequately in these tasks are removed from the cognitive testing group. All of these tasks are administered by the same individual who will perform the cognitive testing. Mice appear somewhat more sensitive to changes in experimenter than rats are, suggesting this induces a stress response that interferes with normal cognitive abilities. We have found that simply transporting mice up and down an elevator impairs performance on these cognitive function tasks.
The general radial arm water maze procedure involves placing the mouse into one arm of the maze other than the goal arm, and releasing the mouse to begin swimming. Most mice swim readily and explore the maze. When a mouse enters a swim arm other than the goal arm, the mouse is charged with one error (a mouse is considered to enter the arm when all four limbs move into the swim alley). Occasionally, mice stop swimming and float, or they swim in the central regions without making an arm entry. For each 15-sec period a mouse fails to enter an arm for whatever reason it is charged one error. In this manner, a mouse failing to swim accumulates four errors, which is a score typical of mice that have not learned the platform location. Mice that consistently fail to swim are removed from the study. The trial continues for 60 sec or until the mouse ascends the platform. If a mouse does not locate the platform within 60 sec, it is guided to the platform. The mouse is removed after 15 sec on the platform and either started in another trial, or dried with a towel and placed in its home cage (with a heat lamp available in one corner). Both error number and latency to find the platform are recorded.
In order to test working memory, the goal arm location within the maze was changed each day. Within each day, a mouse was given four consecutive 60-sec acquisition trials, followed 30 min later by a fifth (retention) trial. The next day, the platform was moved to a new location, and the mouse had to learn the new platform location. The rationale for the 30-min delay on the retention trial was that short-term forgetting is common in AD patients. It was hoped that the mice would learn the new platform location during the first four trials when the inter-trial interval was 15 sec (registration of the material to be learned), and then demonstrate poor performance at the 30 min time point (the recall point in testing for memory deficits clinically). Thus far we have not found mice that learned location by trial 4 but failed to remember on trial 5, as we had hoped might occur. Instead we find that APP transgenic mice fail to improve over the acquisition trials, and, as expected, perform poorly on the retention trial as well.
One of the limitations to this procedure was that mice were slow to acquire the procedural aspects of the testing (understanding there was a platform and that the platform moved each day). This may be a result of the ethologically unlikely possibility that escape location in a natural environment would change daily. As a general criterion, we felt that when the mice as a group reached a criterion of one or fewer errors on trials 4 and 5, they had learned the task. On some occasions, non-transgenic cohorts would reach this criterion within 10 days of continuous testing. Other cohorts could require 15 days to reach this learning criterion. Thus, in order to maintain consistent performance, the same investigator must be available for a period of up to 2 wk for 3–4 hr at the same time of day. Although it is conceivable that training could be suspended for the weekend, we never fully investigated this variable. Instead, to simplify the testing procedure we opted to examine the reference memory version of the maze described below.
14.2.4. Reference Memory Procedure
For reference memory testing we began by running mice for 15 trials on each of 2 days. The goal arm was constant for these 2 days, and the mouse waas placed pseudorandomly (no repeats) in a different start arm for each trial. Moreover, the trials on day 1 alternated between using a visible platform above the water and a hidden platform in the same arm. On day 2, all trials used the hidden platform. Moreover, the goal arm for each mouse was different (to minimize possible effects of odor trails). This was predetermined on a score sheet that the experimenter used to determine the start arm and goal arm for each trial for each mouse (examples of these score sheets are available from the author).
One problem with 15 trials per day is that older mice can get fatigued from swimming for this long a period without rest. Thus we designed a testing schedule whereby the mice had a rest period after each trial. Mice were assigned to groups of four (treatment conditions should be equally distributed in these testing groups). Typically two groups of four mice were tested in parallel. First, mouse 1 of group 1 was administered trial 1, then mouse 2 of group 1, mouse 3, and mouse 4. After mouse 4 of group 1 was tested on trial 1, mouse 1 of group 1 was administered trial 2. Mice 2–4 of that group then followed. After each trial, mice were returned to their home cages with a heat lamp available in the corner (one lamp served all four cages).
After all mice in group 1 received six trials, a second group of four mice were administered their first six trials in the same fashion as group 1. First, mouse 1, trial 1, then mouse 2, trial 1, etc. After all four mice were administered six trials, the first group of four mice was administered trials 7–12. Then group 2 was administered trials 7–12. Finally, group 1 was administered trials 13–15, and then group 2 was administered trials 13–15. The entire process can be accomplished in 3–4 hr. This permits a second series of eight mice to be tested on the same day.
On day 2 the entire process was repeated, except the platform was hidden for all trials. We have never fully investigated whether the alternation of visible and hidden platforms on day 1 is essential for good learning to occur, thus this may be considered optional.
For most cohorts of mice, this resulted in average scores of one error or less for the “positive” control groups (usually nontransgenic mice). On some occasions the control mice may not have reached this criterion (for example old mice or occasionally some inbred lines). In these circumstances we ran a reversal trial on day 3 (a new goal arm location for each mouse not adjacent to the initial goal arm; all trials used the hidden platform). This also sometimes revealed deficits in performing the reversal task in treatment groups that were not easily distinguished in the first 2 days of testing. If performance is still poor after the first day of reversal testing, a second day of reversal testing can be performed.
The 2-day reference memory version of the radial arm water maze is the most efficient method we have found for testing in this procedure. Most cohorts of control mice learn the task within 30 trials. For the working memory version, 50–75 trials are necessary for the mice to demonstrate solid learning of platform location. Similar numbers apply to the Morris open pool version of the water maze. We feel that this procedure optimally spaces trials so that mice have some immediate recollection of the events and a rest period so that fatigue is not a factor, and that longer rest periods during testing permit some consolidation to occur within the day, rather than between days.
14.2.5. Visible Platform in an Open Pool
Irrespective of whether reversal training is performed, the last day of testing used a visible platform in an open pool (inserts removed). The visible platform has ensigns located above the water while the platform remains slightly below the water. The mouse was started in the same location for each trial, and the location of the visible platform was moved for each mouse. Latency to reach the platform was recorded. Mice were shuttled just as on day 1 of radial arm maze testing (mouse 1, trial 1; mouse 2, trial 1; etc.). Fifteen trials were performed. The purpose of the visible platform task is to assess if mice have the performance skills necessary for the water maze tasks. Mice failing to reach a criterion of 20 sec latency for the last three trials of the visible platform task were considered to be impaired. These mice may have been blind or impaired motorically and thus not capable of being evaluated for cognitive function. Very few mice completing the testing protocol fail to meet this criterion.
14.3. REPRESENTATIVE DATA
Figure 14.2 shows results from the working memory version of the radial arm water maze. Shown are three blocks of results summed over 3 days each. The first block represents data from days 1–3, the second block from days 4–6, and the third block from days 7–9. On the first trial of each block, mice are performing at chance levels as the platform is in a new location. In all cases, the transgenic mice show only modest (and not significant) improvement in their performance over the five trials (the last trial being a retention trial). However, by the last block of trials (days 7–9) we found that the nontransgenic mice reached the criterion of less than one error (on the retention trial 5). At this point there was also a significant difference between the transgenic and nontransgenic mice.
FIGURE 14.2
Typical data for the working memory version of the radial arm water maze. Fifteen-mo-old nontransgenic or APP+PS1 transgenic mice were given five trials daily as described in the text. Four trials were continuous (solid line) and the fifth trial was administered (more...)
Figure 14.3 shows the results from the 2-day reference memory version of the water maze. Note that on day 1 both groups improve slightly in their performance. However, by day 2 the nontransgenic mice are able to find the platform with few errors. The performance of the nontransgenic mice is significantly better than the transgenic mice on blocks 6–10 of the radial arm water maze task.
FIGURE 14.3
Typical data for the 2-day reference version of the radial arm water maze. Data shown are for 25-mo-old nontransgenic (NonTg) and untreated APP Tg 2576 derived mice (APP). Data presented are averages of three trial blocks. The horizontal dashed line represents (more...)
14.4. ANALYSIS AND INTERPRETATION
One of the issues regarding the radial arm maze results is that individual mouse data is noisy. Some mice simply by fortune find the platform on their first arm entry of the first day. As a result, the data are portrayed most favorably with some degree of summation over trials and/or days. If large sample sizes are used (> 25 mice), it would seem plausible to include data for every trial when presenting the data. However, in most studies using transgenic or aged mice, numbers are a limiting resource. While we aim for a sample size of 10 in most experimental designs, we sometimes are limited to final sample sizes as low as five after attrition because of death, or culling because of motoric deficiencies (rare) or skin lesions (more common in older mice). There are many ways of accomplishing this averaging for presentation purposes. In Figure 14.2, we collapse over 3-day blocks in the working memory version of the maze, as each trial reflects a different stage of learning. In most of our published studies with this method [9,10,14,15,21,23,24], we averaged the final 2–3 days of testing after the nontransgenic mice had reached the learning criterion. We typically discarded the first 5–10 days of training from data analysis as this was the time when the mice were still acquiring procedural aspects of the task. However, this is not the only method to demonstrate clear differences in transgenic mice. The group led by Ottavio Arancio averages all days for each of the five trials, and still observes clear differences caused by the presence of amyloid [25,26]. Thus, there can be several alternative means of presenting these results. Although we collect the latency data, we feel latencies are affected by variables other than mnemonic functions (swim speed) and reporting significant effects in latency when there were no differences in errors seems deceptive to us.
For the 2-day water maze, we average over blocks of three trials for each mouse. These three trial blocks become 10 data points used for statistical analysis. For all studies (working and reference), we first perform a repeated measures analysis of variance (ANOVA) to seek a main effect of genotype and trials. We then perform post-hoc means comparisons using Fischer’s LSD test with the statistical program Statview (SAS) to identify group differences on specific trials or blocks.
A final comment on statistical analysis regards experiments testing for drug or other therapeutic effects in mouse models of neurodegeneration. We emphasize in these studies that the inclusion of the positive control group (in our case, nontransgenic mice) is simply to validate the success of the behavioral testing process. However, we do not include these mice in the statistical analysis to determine the effect of the therapeutic modality. These analyses should directly compare the treated and untreated disease model mice, without reference to the nontransgenic data. Only if the treated and untreated transgenic groups differ is there truly an effect of the treatment. We have witnessed and reviewed manuscripts that show a significant difference between untreated disease model mice (transgenic) and positive control (nontransgenic) mice, but fail to reach significance in comparing treated transgenic mice and nontransgenic mice. The authors sometimes attempt to conclude (erroneously) that there was then an effect of their treatment. This violates a cardinal rule of statistics that failure to detect a difference does not mean there is no difference, only that the study was unable to detect it. Statistically significant differences in performance between treated and untreated disease model groups are essential to argue for benefits of the therapy.
ACKNOWLEDGMENTS
We thank David Diamond and Gary Arendash for years of assistance in developing these methods and collecting data relevant to this technique. We thank Jennifer Alamed, our laboratory behaviorist, for collecting data and aiding in the figures for the manuscript. DGM is supported by the following awards from the National Institutes of Health: AG04418, AG15490, AG18478, AG 25509, AG25711, and NS48355, and is a supervisor for AG031291.
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