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Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press; 2009.

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Methods of Behavior Analysis in Neuroscience. 2nd edition.

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Chapter 13Spatial Navigation (Water Maze) Tasks

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13.1. INTRODUCTION

Since the early part of the 20th century, a variety of experimental procedures have been developed for animals that employ the escape from water as a means to motivate learning and memory processes [1–4]. Water maze tasks primarily designed to measure spatial learning and recall have become quite useful for evaluating the effects of aging, experimental lesions, and drug effects, especially in rodents. For more than 25 years the Morris water maze (MWM) [5] has been the task most extensively used and accepted by behavioral physiologists and pharmacologists. A cursory literature search revealed that well over 2500 journal articles have been published since 1982 in which this model (or variations of the model) was used to assess and compare spatial learning and memory in rodents.

The MWM, while simple at first glance, is a challenging task for rodents that employs a variety of sophisticated mnemonic processes. These processes encompass the acquisition and spatial localization of relevant visual cues that are subsequently processed, consolidated, retained, and then retrieved in order to successfully navigate and thereby locate a hidden platform to escape the water [5] (see also review [6]). The general processes used for “visuospatial navigation” in rats also contribute considerably to human day-to-day cognitive processes. Importantly, several lines of evidence confirm the utility of the model for investigations relevant to the study of neurodegenerative and neuropsychiatric illnesses where cognition is impaired (e.g., Alzheimer’s disease, Parkinson’s disease, schizophrenia). While one would readily acknowledge the differences in complexity between human and rodent behaviors, several salient observations regarding the utility of the MWM are notable: (1) The functional integrity of forebrain cholinergic systems, which are essential for efficient performance of the MWM, appears to be consistently disrupted in patients who suffer from AD. This disruption correlates well with the degree of dementia (see reviews [7,8]) and is also present in many PD patients who suffer cognitive decline [9,10]. (2) Cortical and hippocampal projections from the nucleus basalis magnocellularis (NBM) and medial septum (MS), respectively, are reproducibly devastated in AD (reviewed [7]) and accordingly, reductions in central cholinergic activity in rodents resulting from brain lesions (e.g., NBM, MS, etc.) and age reproducibly impair spatial learning in the MWM (reviewed [6]). (3) Other data implicate the hippocampus as an essential structure for place learning [11], which, incidentally, is commonly atrophic in patients with AD [12,13]. It is interesting to note that the hippocampal formation (in particular the hippocampal-dentate complex and the adjacent entorhinal cortex), which undergoes significant degeneration with age (and particularly so in the setting of dementia), is believed to be intimately involved in cognitive mapping and the facilitation of context-dependent behavior in a changing spatio-temporal setting (reviewed [14]). Evidence to support this premise is now available from living humans where computerized “virtual water maze tasks” have been shown to be highly sensitive to hippocampal dysfunction. For example, in a virtual analogue of the classic MWM hidden platform task (with a three-dimensional pool), patients with unilateral hippocampal resections were severely impaired in their performance relative to age-matched controls and age-matched patients who had extra-hippocampal resections [15]. (4) Anticholinergic agents (e.g., scopolamine), which are routinely used to impair performance in the MWM, also impair memory in humans and worsen the dementia in those with AD [16] (see also review [17]). (5) Finally, it is also important to note that spatial orientation, navigation, learning, and recall (which are used extensively in the MWM) are quite commonly disrupted in patients with dementia. Visuospatial and visuoperceptual deficits and topographic disorientation are detectable very early in the course of AD and become more pronounced as the disease progresses [18–20]. The common observations of spatial and visual agnosia in AD patients also indicate the disruption of complex processes that involve both visual pathways and mnemonic processing [21,22].

The MWM procedure offers a number of advantages as a means of assessing cognitive function in rodents when compared to others methods: (1) It requires no pretraining period and can be accomplished in a short period of time with a relatively modest number of animals. For example, young adult, unimpaired (control) rats can accomplish the most commonly employed versions of the task with asymptotic levels of performance achieved in 10–20 trials, generally requiring no more than a few days of testing. (2) Through the use of “training” as well as “probe” or “transfer” trials, learning as well as retrieval processes (spatial bias) [5] can be analyzed and compared between groups. (3) The confounding nature of olfactory trails or cues is eliminated. (4) Through the use of video tracking devices and the measure of swim speeds, non-mnemonic behaviors or strategies (i.e., taxon, praxis, thygmotaxis, etc.) can be delineated and motoric or motivational deficits can be identified. (5) Visible platform tests can identify gross visual deficits that might confound interpretation of results obtained from standard MWM testing. (6) By changing the platform location, both learning and relearning experiments can be accomplished. Accordingly, several doses of experimental drugs can be tested in the same group of animals. (7) While immersion into water may be somewhat unpleasant, more aversive procedures such as food deprivation or exposure to electric shock are circumvented. (8) Through the use of curtains, partitions, etc., operation of the video tracking system by the experimenter out of site of the test subjects also reduces distraction. (9) Finally, the MWM is quite easy to set up in a relatively small laboratory, is comparatively less expensive to operate than many types of behavioral tasks, and is easy to master by research and technical personnel. We have found the method quite useful in drug discovery and development studies for screening compounds for potential cognitive enhancing effects [23], as well as delineating deleterious effects of neurotoxicants on cognition [24]. For a more extensive discussion of the various MWM procedures and their advantages, see Morris [5] and reviews [6,25,26].

13.2. STANDARD PROCEDURES

The MWM generally consists of a large circular pool of water maintained at room temperature (or slightly above) with a fixed platform hidden just below (i.e., ~ 1.0 cm) the surface of the water. The platform is rendered invisible by one of several means: (1) adding an agent (i.e., powdered milk or a nontoxic dye or food coloring agent) to render the water opaque; (2) having a clear Plexiglas platform in clear water; (3) or having the platform painted the same color as the pool wall and floor (e.g., black on black). Rats are tested individually and placed into various quadrants of the pool and the time elapsed and/or the distance traversed to reach the hidden platform is recorded. Various objects or geometric images (e.g., circles, squares, triangles) are often placed in the testing room or hung on the wall so that the rats can use these visual cues as a means of navigating in the maze. With each subsequent entry into the maze the rats progressively become more efficient at locating the platform, thus escaping the water by learning the location of the platform relative to the distal visual cues. The learning curves are thus compared between groups. An illustration of a typical MWM setup (as used in our laboratory) appears in Figure 13.1. The inset at the top right illustrates typical learning behavior (under vehicle control conditions) on day 1 of a two trial per day × 6 day hidden platform task when test subjects search throughout the pool before locating the escape platform. The inset at the middle right illustrates the search behavior on day 6 when the subject has learned the task and can easily locate the platform in a matter of seconds. Finally, the inset on the bottom right illustrates the clear bias for the previous platform location during the probe trial on day 7 of testing after the escape platform has been removed.

FIGURE 13.1. Diagrammatic illustration of the Morris water maze testing room and apparatus.

FIGURE 13.1

Diagrammatic illustration of the Morris water maze testing room and apparatus.

13.2.1. Methodology

13.2.1.1. Testing Apparatus

  1. Maze testing should be conducted in a large circular pool (e.g., rats, diameter: 180 cm, height: 76 cm; mice, diameter: 100–120 cm, height: 76 cm) made of plastic (e.g., Bonar Plastics, Noonan, Georgia, USA) and painted black.
  2. Fill the pool to a depth of 35 cm of water (maintained at 25°C + 1.0°C) to cover an invisible (black) 10-cm square platform. The platform should be submerged approximately 1.0 cm below the surface of the water and placed in the center of the northeast quadrant.
    Note: We have found that using a black platform in a pool with the sides and floor painted black obviates the need for addition of agents to render the water opaque. If the experimenter is unsure whether or not the platform is still visible, closing the curtains to eliminate spatial cues and subsequently testing a few rats will resolve this question. While rats can use egocentric cues to eventually acquire the location of the platform, they will not rapidly (or efficiently) become more successful with each entry into the pool if the platform is invisible and room lighting is diffuse (i.e., when most of the allocentric cues are eliminated).
  3. The pool should be located in a large room with a number of extramaze visual cues, including highly visible (reflective) geometric images (squares, triangles, circles, etc.) hung on the wall, diffuse lighting, and black curtains to hide the experimenter and the awaiting rats. Swimming activity of each rat may be monitored via a television camera mounted overhead, which relays information including latency to and the platform, total distance traveled, time and distance spent in each quadrant, etc., to a video tracking system. Tracking may be accomplished via a white rat on a black background.
    Note: We have found the Noldus EthoVision® system (Leesburg, Virginia, USA) to be a very reliable system that is also easy to set up. Several other vendors market similar systems (e.g., San Diego Instruments, Columbus Instruments).

13.2.1.2. Hidden Platform Test

We commonly employ a method in which each rat is given two trials per day for six consecutive days.

  1. Each day, a trial is initiated by placing each rat in the water facing the pool wall in one of the four quadrants (designated NE, NW, SE, SW), which are set up on the computer software so that each quadrant is equal in area. The daily order of entry into individual quadrants is randomized so that all four quadrants are used once every two days.
    Note: Do not place the rat in adjacent quadrants sequentially since the rat may adopt a positional or other non-mnemonic strategy (e.g., all right turns) to locate the platform. Further, the order should be changed on each subsequent day of testing.
  2. For each trial, the rat is allowed to swim a maximum of 90 sec to and the hidden platform. When successful, the rat is allowed a 30-sec rest period on the platform (timed manually with a stopwatch). If unsuccessful within the allotted time period, the rat is given a score of 90 sec and is then physically placed on the platform and allowed the 30-sec rest period. In either case the rat is immediately given the next trial (inter-trial interval = 30 sec) after the rest period.
    Note: In some cases the rat may fall or jump off of the platform and resume swimming before the elapsed 30-sec interval. When this occurs, the stopwatch should be immediately stopped and the rat retrieved and placed on the platform again. The stopwatch should be reactivated so that the remainder of the time interval (30 sec) is enforced. This assures that each rat has equal time to observe spatial cues after each trial.

13.2.1.3. Transfer Test (Probe Trials)

On day 7 (i.e., 24 hr following the last hidden platform trial) a probe trial is conducted in which the platform is removed from the pool to measure spatial bias for the previous platform location [5]. This is accomplished by measuring the percentage of time spent (and distance swam) in the previous target quadrant as well as the number of crossings over the previous platform location. These assessments provide a second estimate of the strength and accuracy of the memory of the previous platform location.

  1. Place each rat in the pool and track the animal for 90 sec. This may be repeated one time (if necessary), since in some cases an unusual level of variance in performance will be observed in this first trial. It is assumed that some of the rats are in some way disoriented after the change in testing conditions.
    Note : More than two trials may result in “extinction” effects (see section “Alternative Procedures” below) with less time spent in the target quadrant, and is thus undesirable for a measure of spatial bias.
  2. The time elapsed and distance swam in the previous target quadrant is recorded. An annulus ring can be circumscribed around the previous target location (on the computer screen) to localize it more closely. The number of crossings through this region may be recorded. Alternatively, crossings of the actual 10-cm square platform target outlined in the previous trials can be recorded and compared between groups.

13.2.1.4. Visible Platform Tests

A visible platform test may be performed to determine if a drug or other experimental manipulation results in crude alterations in visual acuity that might confound the analyses of data that depend on the use of distal visual cues for task performance. One must be aware, however, of certain behaviors that might be interpreted as impaired visual acuity. For example, the absence of search behaviors or thymgotaxis (swimming constantly along the perimeter of the pool) might be misinterpreted as visual deficits since the animal does not locate the platform in a reasonable period of time. Thus, animals must make attempts to cross the pool and then be impaired at locating the platform in order for an interpretation of visual deficits to be made.

  1. Immediately following the probe trial on day 7, place the platform into the pool in the quadrant located diametrically opposite the original position (SW quadrant).
  2. A cover (available from San Diego Instruments, Inc. and other vendors), which is rendered highly visible (i.e., with light-reflective glossy or neon paint), is attached to the platform to raise the surface above the water level (approximately 1.5 cm).
  3. Room lighting may be changed so that the extramaze cues are no longer available and the visible platform is more highly illuminated.
    Note: The video tracker is not necessary for this procedure and only a stopwatch is needed.
  4. Allow each rat one trial in order to acclimate to the new set of conditions and locate the platform visually. This is accomplished by lowering the rat into the water in the NE quadrant and allowing the rat to locate the platform. No time limit is placed on this first trial. Once the platform is located, allow the rat 30 sec on the platform. The rat should then immediately be given a second trial in the same manner and the latency to and the platform measured as a comparison of visual acuity.
    Note: This procedure may be repeated additional times; however, the platform location should be changed on each subsequent trial to ensure that visual location of the platform is actually made from a distance and the rat is not first using nearby stationary visual cues.

13.2.1.5. Relearning Phases

After completion of the first seven days of water maze testing and a rest period (generally at least 1 wk and often longer), a second series of trials (phase 2) may be conducted as described above (hidden platform test section), except that the location of the platform is changed to a different quadrant. Daily performances (average of two trials/day/rat) are then compared as described above. This method may be used in order to compare different drug doses or other additional manipulations with the same groups of animals.

Note: It must be realized that learning curves will generally be steeper than in the first phase of testing since a number of factors not associated with the actual platform location will have been previously learned (e.g., use of visual cues to navigate, the fact that escape is not associated with the pool wall, etc.).

13.2.2. Statistical Analyses

13.2.2.1. Hidden Platform Test

For the hidden platform test, we generally average the latencies and the distances swam across the two trials for each rat each day. These means are then analyzed across the six days of testing. A two-way repeated measures analysis of variance (ANOVA) is used for main effects (i.e., group or treatment comparisons) with day as the repeated measure and latency or distance swam as the dependent variable. The Student Newman-Keuls test is used for post-hoc analyses.

13.2.2.2. Transfer Test (Probe Trials)

For probe trials the means are compared between groups via a one-way ANOVA and again, the Student Newman-Keuls test is used for post-hoc analyses.

13.2.2.3. Visible Platform Test

For the visible platform test, the means are also compared between groups via a one-way ANOVA and the Student Newman-Keuls test is used for post-hoc analyses.

13.2.2.4. Relearning Phases

The relearning phase is analyzed identically to the hidden platform test described above.

13.2.3. Representative Data

Several representative MWM hidden platform studies under vehicle control conditions from our laboratory appear in Figure 13.2. The acquisition curves for rats given one trial per day for 14 consecutive days, two trials per day for six consecutive days, or four trials per day for four consecutive days are illustrated. We have used each of these methods in our laboratory in previous studies. Using each of these approaches, the rats learned to locate the hidden platform with progressively shorter latencies over the course of the study. We have found that young vehicle-treated test subjects (i.e., not age impaired or impaired by an amnestic drugs) given only one trial per day are somewhat less efficient at learning the task, but more sensitive to pro-cognitive agents (e.g., nicotine, see reference [27]) than subjects given multiple trials per day. Further, we have found the two- and four-trial-per-day methods to be useful for amnestic-reversal studies (see references [28,29]).

FIGURE 13.2. Illustration of acquisition curves for several versions of the Morris water maze hidden platform test in young adult Wistar rats.

FIGURE 13.2

Illustration of acquisition curves for several versions of the Morris water maze hidden platform test in young adult Wistar rats. The latency in seconds (left) and the distance swam in centimeters (right) to and the hidden platform are presented for each (more...)

An MWM study conduced in our laboratory in young (3–4 mo) and aged (22–24 mo) male Fisher 344 rats is presented in Figure 13.3. Figure 13.3A illustrates the efficiency of each experimental group to locate a hidden platform in a water maze task on 10 consecutive days of testing (two trials per day). As expected, under saline conditions the young rats learned to locate the hidden platform with progressively shorter latencies until the end of the study, while the aged rats administered saline were less efficient. For the latency comparisons, there was a highly significant main effect (p < 0.001), a significant trial effect (p < 0.001), and a significant group × trial interaction (p < 0.01). Post-hoc analyses indicated that performance by the young animals was superior to that of the aged animals across a number of days of testing. Further, the acetylcholinersterase inhibitor (and commonly prescribed AD therapeutic agent) donepezil (0.75 mg/kg) (in aged rats) was associated with superior performance over aged saline controls across several days of testing. In addition, all rats treated with donepezil reached a near-asymptotic level of performance (i.e., latencies less that 20 sec) by day 10 of testing, whereas this was not the case for aged rats administered saline.

FIGURE 13.3. Effects of age and the Alzheimer’s disease therapeutic agent, donepezil, on performance of the MWM.

FIGURE 13.3

Effects of age and the Alzheimer’s disease therapeutic agent, donepezil, on performance of the MWM. (a) Hidden platform test. Each point represents the mean latency in sec ± SEM of two trials per day for 10 consecutive days of testing. (more...)

Figures 13.3B and 13.3C illustrate the performance of probe trials by the various test groups. As noted above, these experiments are performed after hidden platform tests (in this case 48 hr later) and reflect a “spatial bias” of animals toward the previous location of the hidden platform. The results are analyzed separately from the hidden platform tests and offer a second, easily performed method of estimating the strength and accuracy of the original learning process [6]. It is important to note that since the pool is divided into four quadrants of equal area, a chance level of performance would mean that the percent of time or distance swam (of the total) in the previous target quadrant would generally approximate 25%. As indicated in both Figures 13.3B and 13.3C, there were statistically significant (group-related) effects on performance (i.e., percent of time spent in the previous target quadrant and crossings over the previous platform area, respectively). Namely, aged vehicle-treated rats demonstrated less spatial bias than young vehicle-treated subjects, and donepezil partially reversed this impairment in aged subjects.

In summary, these data support the argument that the MWM (as conducted in our laboratory) is sensitive to the impairing effects of aging on spatial navigation, learning, and recall, and further, that the procedure is sensitive to the positive effects of a well-known pro-cognitive agent (i.e., a positive control).

13.3. ALTERNATIVE PROCEDURES

A number of variations of the water maze tasks described above have been employed for the study of memory processes in rats and a full review of these procedures in beyond the scope of this chapter. A short summary of a few of these procedures is outlined below, however. For a more detailed overview of these and additional water maze procedures see Morris [5] and reviews [6,25].

13.3.1. Place Recall Test

In this procedure, hidden platform tests are first performed as described above in intact animals so that the location of the platform is well learned. Subsequently, the rats are experimentally manipulated (i.e., given brain lesions, drugs, or other physiological manipulations, etc.) and then retested with either additional hidden platform tests or probe trials. Thus, the effects of the experimental manipulations on all processes used to solve the task, with the exception of learning and memory formation, may be studied. Namely, processes such as memory retrieval and spatial bias, as well as motoric, sensory, and motivational effects of the manipulations may be delineated.

13.3.2. Platform Discrimination Procedures

These methods require rats to discriminate between two visible platforms in order to successfully escape the water (Figure 13.4, left). One of the platforms is rigid and able to sustain the weight of the rat, while the other platform is floating (often made of styrofoam) and not able to sustain the rat’s weight. Both spatial and nonspatial versions of this task have been used. In the spatial version of the task, the platforms appear identical (visually) and rats are required to discern the viable platform by learning its location relative to distal visual cues in the room. In the nonspatial version of the task, the rats learn to visually discriminate between two platforms of different appearance. For example, discrimination between platforms may be engendered via a difference in shape, brightness, or painted pattern. Curtains are drawn to exclude the influence of extramaze cues.

FIGURE 13.4. Illustration of platform discrimination and working memory procedures in the Morris water maze.

FIGURE 13.4

Illustration of platform discrimination and working memory procedures in the Morris water maze.

13.3.3. Working Memory Procedures

Working memory procedures in the MWM (sometimes referred to as spatial “matching to sample” procedures) generally involve a two-trials-per-day paradigm in which a hidden platform is located in one of four quadrants and randomly relocated on each of several subsequent days of testing (Figure 13.4, right). The assumption drawn is that each rat will obtain information regarding the location of the platform on the first trial, which will be of benefit for discerning its position on trial two. The ITI can be manipulated in order to alter the difficulty of the task.

13.3.4. Extinction

While not commonly used for this purpose, the behavioral process known as extinction can also be assessed in the MWM. Extinction occurs when the relations among stimuli recognized during acquisition are no longer valid and the previously established responses are suppressed. Accordingly, preferences for a spatial location decrease in the water maze as the animal learns that the cues no longer predict the location of the hidden platform [30]. Extinction in this context is considered a type of cognitive flexibility, a form of fluid intelligence that encompasses the ability to inhibit strong response preferences in order to explore alternative solution paths [31]. In contrast to the more common MWM studies where acquisition (hidden platform testing) and retention (probe trials) are the focus, in extinction experiments subjects are first trained in the hidden platform test to an asymptotic level of performance (defined as a latency to find the hidden platform of less than 10–15 sec for four consecutive trials). We have found in unpublished studies that 10–12 days (two trials per day) is more than sufficient to reach this asymptotic level in young vehicle-control subjects. Subsequently (i.e., on the following day after the last hidden platform test), four or more consecutive probe trials are conducted to assess the subject’s ability to decrease (i.e., extinguish) its spatial bias for the previous platform location.

13.4. SUMMARY AND CONCLUSIONS

The MWM equipped with a video tracking system has become a commonly used and well-accepted behavioral task for rodents. It is quite easy to set up in a relatively small laboratory, is comparatively less expensive to operate than many types of behavioral tasks, and is easy to master by research and technical personnel. It uses a number of mnemonic processes in rats that are relevant to the study of human learning and memory and disorders thereof. In addition, it is a very versatile paradigm, which can be used to study both spatial and nonspatial (discriminative) learning, as well as working memory processes and extinction, and offers several means of delineating and dissociating confounding non-mnemonic processes.

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