B

Subject #57

Path Length = 1278.2 cm

Subject #57

Path Length = 1278.2 cm

30 mg/kg SL327

FIGURE 9 Path tracking in the probe test. Representative probe trial of a mouse in the Morris water maze task. (A) The swim path trace shown here provides an excellent example of a selective search. This particular subject was trained with the platform located in the northeast quadrant. During the probe trial, this mouse spent 56% of the time in the correct quadrant and crossed the exact area where the platform had been nine times. Adult male 129S3/SvImJ mice (formerly 129/Sv-+p+Tyr-c+Mgf-slJ/J; Jackson Laboratory, Bar Harbor, ME) were used in these experiments and those in Figure 8. (B) The path of an animal whose learning during training was blocked with an inhibitor of Mitogen Activated Protein Kinase (MAP Kinase) activation. The animal swims randomly throughout the tank. Data and figure courtesy of Joel Selcher (16).

colored marker directly above the escape platform, and the location of the platform remains constant throughout training. Training typically consists of two blocks of four trials a day for 3 consecutive days. Escape latencies are determined for each trial, and animals quickly learn to swim to the marked platform in order to escape the water. These visible platform data serve as a useful control for any impairments seen in the hidden platform version. If differences in controls versus experimentals are seen in the hidden platform version but not the visible platform version, one can conclude that the difference is likely not due to changes in motivation to escape the pool or to changes in the motor abilities necessary to execute the task.

The Morris water maze task has been used extensively since its introduction, and in many ways it has been the "gold standard" of spatial learning tasks for the last two decades. It has been used many times in order to probe the involvement of specific anatomical structures and specific molecules in hippocampus-dependent spatial learning. It is important to keep in mind that Richard Morris himself has demonstrated that the task overall is cognitively quite complex and can be experimentally dissociated into at least two components. One component is learning the task (i.e., that there is a platform, that spatial cues are relevant). A second component is learning the specific location of the escape platform. Some types of lesions can lead to a loss in an animal's ability to learn the task, while not affecting the ability of the animal to learn a specific platform location, for example. These considerations do not limit the utility of the task but rather point out the importance of considering the complexity of the task when interpreting the resulting data. For example, a deficit may not be the result of a deficit in spatial learning per se but rather in learning the parameters of the task. Of course, this caveat applies to learning tasks in general; it's just that this aspect has been best explored with the Morris water maze.

The principal practical limitations of the water maze are that it requires a fairly large dedicated room, it is messy (in the housekeeping sense), and the training and testing periods are fairly long. Thus, in contrast to a single-training-trial task such as fear conditioning, there is no temporally well-defined period of learning. This can present some practical difficulties when trying to design experiments using drug administration, or where one is trying to measure learning-associated biochemical or physiological changes.

Another practical limitation to the water maze is that it is a fairly rigorous and demanding task physically for the animals under study. This consideration is most pronounced when undertaking experiments on old or otherwise infirm animals. However, in these circumstances, an alternative is available, commonly referred to as the Barnes maze.

The Barnes Maze

Carol Barnes has had a long-standing interest in aging-related memory decline and developed a circular hole-board maze task to use as an assessment of spatial learning (8). This task is applicable in circumstances where the strength and stamina of the animals under study may be limiting because it involves only mild locomotor activity. In addition, the measured parameter is errors, not time to complete the task, so the speed at which the animal completes the task is not a factor.

The Barnes maze is essentially a well-lit round table with many holes around the periphery (see Figure 10). Rodents find open, well-lit spaces aversive and they will search around the platform trying to find a safe, dark haven. All the holes around the periphery but one lead simply to a drop-off to the floor. However, one hole leads to an escape chamber, that is a darkened box secured under the hole. Upon locating this hole animals will enter the chamber to escape the lit surface.

The spatial learning in the task involves visual cues placed on the four walls around the table top. The escape hole is always located in a constant place relative to these spatial cues, and much like the water maze the animal must use these cues to learn the location of the escape hole. Performance can be quantitated in its simplest form by

FIGURE 10 Diagram of the basic components of the Barnes maze. Animals learn to locate an escape chamber using visual cues placed on the walls of the room. Learning is assessed as a decrease in the number of errors an animal makes in locating the escape chamber.

simply counting the number of errors an animal makes before it finally finds the escape hole. An error is of course defined as an attempt to enter a nonescape hole. In one of the first examples of the use of this task, aged rats displayed impairment in the rate of acquisition of spatial memory involving navigation around the circular platform (8).

E. Taste Learning

Taste learning and conditioned taste aversion are fascinating behavioral phenomena that have only relatively recently begun to be studied mechanistically in rodents. One reason for being interested in these forms of learning is that they are clearly cortex-dependent and may represent the closest rodent homologue to high-order human learning of factual information. Regardless of whether this last speculation is correct, taste learning is without a doubt one of the most robust and ethologically relevant forms of rodent learning currently under study.

Conditioned Taste Aversion

Conditioned taste aversion is a form of associative learning; in this case, an animal learns to associate the novel taste of a new foodstuff (CS) with subsequent illness (US) resulting from ingestion of some nausea-inducing agent. As we discussed in the last chapter, the adaptiveness of this form of learning is clear; by preventing subsequent ingestion of sickening foods, survival is enhanced. For this reason, evolution has selected for robust learning under these conditions, and animals learn after a single pairing of a novel taste with a nausea-inducing agent to avoid that taste in the future. This single-trial learning is also quite robust in that there can be a rather long delay—often measured in hours— between the novel taste and toxin.

A typical conditioned taste aversion paradigm is to pair a novel taste with intraperitoneal injection of a malaise-inducing agent such as LiCl (see Figure 11). Pairing intake of a novel taste with LiCl significantly suppresses subsequent intake of that taste either as a solid food or in drinking water. In these experiments, the effect of LiCl is typically compared to NaCl injected controls.

Conditioned taste aversion is selective for novel tastes. If an animal has experienced a taste previously, it is no longer successful in serving as a CS in conditioned taste aversion. Behavioralists term this phenomenon latent inhibition. A "latent" memory for the taste is formed, inhibiting subsequent formation of an association with the toxic agent. Again, ethologically, this makes sense—if a foodstuff has been previously tried and found nonaversive, it should thereafter be taken out of consideration as a toxic agent. This aspect of taste learning is particularly fascinating and still mysterious.

The implications of latent inhibition of taste aversion are twofold. First, somewhere in the taste processing centers of the CNS is a novelty detector, a system that is

FIGURE 11 Conditioned taste aversion. Mice all received 10-minute access to blueberry bar, a novel taste stimulus, followed by injection of LiCl or NaCl. Pairing of solid novel food with LiCl, which produces nausea, produces a conditioned taste aversion (CTA). CTA is indicated by the observation that mice injected with LiCl following access to the blueberry bar consume significantly less than Nad-injected controls when tested for food consumption 24 hours later (***p < .001 by one-way ANOVA). Data and figure courtesy of Mike Swank (9).

FIGURE 11 Conditioned taste aversion. Mice all received 10-minute access to blueberry bar, a novel taste stimulus, followed by injection of LiCl or NaCl. Pairing of solid novel food with LiCl, which produces nausea, produces a conditioned taste aversion (CTA). CTA is indicated by the observation that mice injected with LiCl following access to the blueberry bar consume significantly less than Nad-injected controls when tested for food consumption 24 hours later (***p < .001 by one-way ANOVA). Data and figure courtesy of Mike Swank (9).

able to tag a taste as something that the animal has never before experienced. If you take a few minutes to consider this, it will become apparent what a conundrum this is. How can you know that something is an unknown? Is there a recorded list somewhere in the brain that contains every taste ever experienced by the animal, against which every subsequent taste is compared throughout the animal's lifetime? Or is there a system present that has a prearranged matrix of every conceivable potential taste combination that an animal will ever experience, from which tastes are scratched off after they are first experienced? It is food for thought, so to speak. The second implication is that every novel taste experience is a learning experience. Automatically when a taste is first experienced if forms a memory trace that is perpetuated for the lifetime of the animal. This second consideration brings us to our next form of taste learning—novel taste learning and neophobia.

Novel Taste Learning and Neophobia

Neophobia is the characteristic fear of novel foods and ensures that animals ingest only small quantities of new foodstuffs. If no illness results upon consumption of the new food, and assuming the food is reasonably palatable, animals will increase their intakes on subsequent exposures. This is readily demonstrated in the laboratory. When rats or mice are presented with highly palatable solutions of saccharin or sucrose, they will consume small amounts on the first exposure; on subsequent exposures, the animals drink more. In these types of experiments, animals are usually maintained on water deprivation so that they are motivated to drink.

Michael Swank recently developed a variation of this procedure that uses solid food in nondeprived mice (see reference 9 and Figure 12). In developing a novel taste learning paradigm Michael found that Kellogg's Nutri-Grain blueberry breakfast bars are readily consumed by rodents and that consumption of this food is easy to measure. During a single 10-minute exposure to the novel blueberry bar, mice will consume around 200-300 mgs (see Figure 12). On subsequent exposures, the mice will double their intakes, thus demonstrating an attenuation of the initial neophobia. This attenuation of neophobia is a behavioral measure of memory for the novel taste.

One very appealing aspect of these simple taste learning paradigms is that the learning is robust and automatic. The learning is a simple single-trial experience (simply exposure to a novel taste) that results in lifelong memory. Also, there is a fairly clear consensus that the insular cortex is the primary site of learning and memory for novel tastes, so the relevant brain region

FIGURE 12 Neophobia. Neophobia during first access to a novel solid food is attenuated on second exposure. Mice were given ten-minute access to a novel taste, Nutri-Grain blueberry bar, and intakes were recorded. Ten-minute intakes on the second day are significantly higher, demonstrating attenuation of neophobia through familiarization. (*p < .05 by one-way ANOVA). Data and figure courtesy of Mike Swank (9).

FIGURE 12 Neophobia. Neophobia during first access to a novel solid food is attenuated on second exposure. Mice were given ten-minute access to a novel taste, Nutri-Grain blueberry bar, and intakes were recorded. Ten-minute intakes on the second day are significantly higher, demonstrating attenuation of neophobia through familiarization. (*p < .05 by one-way ANOVA). Data and figure courtesy of Mike Swank (9).

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