Trends in Neurosciences
In search of a better mouse test
Section snippets
Diversity, the raw material for test evolution
The search for better tests is made a little easier because there is no standard implementation of any single test that is deeply entrenched. Instead, most tests are done in a manner that is unique to each laboratory [3]. For example, on the submerged-platform water-escape task, details of the apparatus and procedures vary widely (Fig. 1). There is considerable evidence that parametric differences in the details of many tasks are important for the outcome of genetic experiments 4, 5, 6. Minor
Inbred strains and mutants: one world
The need to gather behavioral data on a wide range of inbred strains brings into focus the shortcomings of some tests. To have maximal utility, a good behavioral test should yield valid data for most of the commonly used inbred strains. Of course, much contemporary research in neuroscience involves single-gene mutations rather than inbred strains, but the conclusion applies equally to mutants. It is widely appreciated that some strains do not perform well on certain tests 19, 20, and the wisdom
The simplest case: exploratory activity
Because deficits are often expected in a study of mutations, a crucial consideration for any test is the meaning of low or zero test scores. It is important that mice do not fail for a reason that is unrelated to what the test purports to measure. We assert that tests of simple, ubiquitously performed behaviors usually yield meaningful data for most mice. For example, the 129S1/SvImJ strain exhibits surprisingly low exploration on the second test trial in an open field or Y-maze (Fig. 3), often
Human versus machine: which to trust?
Another meaningful zero score occurs in a test of hunger, in which mice are observed for a short time in the home cage eating their usual laboratory chow that is presented in a familiar glass dish. The amount of food eaten increases steadily with the duration of deprivation. But there are two ways in which to measure eating: the actual mass of food consumed and the time spent eating, as judged by a trained observer. Within a single laboratory these two measures correlate strongly, but when we
The dilemma of uncooperative mice
Some tests are effectively undermined by non-performance. For 129S1/ SvImJ mice (Fig. 3), the index of alternation between arms of a Y-maze on the second day often cannot be computed owing to a lack of exploration. A similar problem is encountered with the Barnes maze, a test of spatial memory in which mice must locate an open hole among 12 or more holes along the periphery of a large disk to escape from bright light. Many mice ‘freeze’ in the center of the disk and never escape at all. For
The challenge of devious adaptations
Equally vexing are devious adaptations to complex tasks. Mice trained to avoid electric shock in a two-way shuttle box often resort to clever ruses to avoid shock without running, including widely splayed legs to bridge grid bars of the same voltage safely, standing on one bar and leaning nonchalantly against a plastic wall, and finding a safe zone between photocell beams. Even the simple rotarod test of motor coordination can be circumvented by our furry subjects. Many mice flatten themselves
Sink, swim or float: those are the options
The advantages and disadvantages of using escape from water to motivate learning in mice are well known 25, 26. Neuroscientists have been warned that many strains perform poorly on the submerged-platform water-escape test task [19], which is better suited to rats than to mice [27], yet it is used widely for the study of memory in mice. The A/J strain is an implacable wall-hugger in the circular water tank [21]. Most of the variance among different mouse strains and mutants is attributable to
An obvious problem with no easy solution
Further work needs to be done on several behavioral tests to ensure that valid data can be obtained for most of the commonly used inbred mouse strains. If low scores are not interpretable for some inbred strains because of non-performance or devious adaptations, then it is possible that a knockout strain might perform poorly for the same reasons. If one wishes to explore the genetics of memory, for example, it is essential that low scores on a task be valid indicators of poor memory. This point
Acknowledgments
Our work is supported by grants from the National Science and Engineering Research Council, the Department of Veterans Affairs, and USPHS Grants AA12714, AA10276, AA13464, AA06243 and DA 05828. We thank Molly Bogue of the Mouse Phenome Project for information used to generate Fig. 2, and Deborah Finn and René Hen for help with the investigation shown in Fig. 3.
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