The availability of “inducible” or “conditional” knockouts, in which a specific gene can be inactivated at any point during development or inactivated only in tissue-specific cells, should provide an important tool to bypass the problem of developmental interactions (Holmes, 2001; Nelson, 1997).
Some knockout mice have sensory or perceptual deficiencies that can confound interpretations of altered complex behaviors, such as learning, parenting, mating, or aggression (e.g., (Cases et al., 1995; Young et al., 2002). For example, genetically altered mice may suffer from retinal degeneration and fail to perform adequately in tasks such as use of a Morris water maze, which often requires that animals use extramaze visual cues (Hengemihle et al., 1999).
Vision is assessed with a variety of tests, including the visual-placement test and the visual cliff (Zhong et al., 1996). Auditory abilities are assessed with either a clicker-orientation test or an acoustic-startle test (Crawley et al., 2000; Jero et al., 2001; Weisenburger, 2001). Olfactory ability is determined by how long it takes an animal to discover highly odoriferous food (such as cookies, peanut butter, bacon, or cheese) hidden beneath the cage bedding (Nelson et al., 1995) or by odor-discrimination tests (Sundberg et al., 1982). Pain sensitivity can be tested with paw removal from a hot plate or a tail-flick test (Rubinstein et al., 1996); the motor skills of transgenic mice should be assessed before this test to avoid tissue damage caused by slow reaction, rather than high pain thresholds, but in any case, the stimulus should always be terminated after a predetermined time interval selected to avoid tissue damage. The proposed procedures for assessing general motor skills in transgenic mice before behavioral testing and the criteria for early removal of an animal from a potentially painful or distressful stimulus should be described in detail in the animal-use protocol.
After assessment of sensory abilities, motor abilities and coordination should be assessed. Many strains of mice (such as waltzers, weavers, and staggerers) suffer from movement difficulties that could affect locomotion, coordination, or grooming (Brown et al., 2000). Such motor deficiencies could also affect performance in any behavioral assessment that requires movement (such as depressing a lever or running a maze) or performance of specific behaviors (such as aggression, mating, or parenting). Many transgenic mice display movement or gait disorders (for example, dopamine 1A receptor–/– and GM2/GD2 synthase–/– mice). For instance, mice that are engineered to lack a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase) and that express only the simple ganglioside molecular species GM3 and GD3 develop substantial and progressive behavioral neuropathies, including deficits in reflexes, strength, coordina-