Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.
Do structures exist within the embryonic central nervous system that guide axons across the midline during development of the great cerebral commissures (corpus callosum, anterior commissure)? With the use of serial section and reconstructive computer graphic techniques we have found that during normal ontogeny of the mouse forebrain and before the arrival of the pioneer fibers of the corpus callosum at the midline, a population of primitive glial cells migrates medially (through the fused walls of the dorsal septum) from the ependymal zones of each hemisphere. At the midline, and well rostral to the lamina terminalis, these cells unite to form a bridgelike structure or "sling" suspended below the longitudinal cerebral fissure. The first callosal axons grow along the surface of this cellular bridge as they travel toward the contralateral side of the brain. The "sling" disappears neonatally. The fibers of the anterior commissure grow within the lamina terminalis along a different type of preformed glial structure. Movement of these axons occurs through an aligned system of glial processes separated by wide extracellular spaces. Do these transient glial tissues actually provide guidance cues to the commissural axons? Analyses of three situations in which the glial "sling" is genetically or surgically impaired or nonexistent indicate that this structure does, indeed, play an essential role in the development of the corpus callosum. We have analyzed (1) the embryonic stages of a congenitally acallosal mouse mutant (strain BALB/cCF), (2) several pouch stages of a primitive acallosal marsupial, Didelphys virginiana (opossum), and (3) animals in which the "sling" had been lesioned surgically through the uterine wall in the normal embryo (strain C57BL/6J). In the acallosal mouse mutant fusion of the septal midline is delayed by about 72 hours and the "sling" does not form. Although the would-be callosal axons approach the midline on schedule, they do not cross. Instead, the callosal fibers whirl into a pair of large neuromas adjacent to the longitudinal fissure. Similarly, in the opossum, fusion of the medial septal walls and formation of the glial "sling" are also lacking. However, in this species, instead of traveling dorsally, the "callosal" axons turn ventrally and pass contralaterally by way of the anterior commissure pathway. Surgical disunion of the glial "sling" also resulted in acallosal individuals. The callosal pathology in these affected animals mimicked exactly that of the genetically lesioned mutant. Our observations suggest that many different types of oriented glial tissues exist within the embryonic neural anlage. We propose that such tissues have the ability to influence the directionality of axonal movements and, thereby, play a crucial role in establishing orderly fiber projections within the developing central nervous system.
ABSTRACT:It is sometimes supposed that standardizing tests of mouse behavior will ensure similar results in different laboratories. We evaluated this supposition by conducting behavioral tests with identical apparatus and test protocols in independent laboratories. Eight genetic groups of mice, including equal numbers of males and females, were either bred locally or shipped from the supplier and then tested on six behaviors simultaneously in three laboratories (Albany, NY; Edmonton, AB; Portland, OR). The behaviors included locomotor activity in a small box, the elevated plus maze, accelerating rotarod, visible platform water escape, cocaine activation of locomotor activity, and ethanol preference in a twobottle test. A preliminary report of this study presented a conventional analysis of conventional measures that revealed strong effects of both genotype and laboratory as well as noteworthy interactions between genotype and laboratory. We now report a more detailed analysis of additional measures and view the data for each test in different ways. Whether mice were shipped from a supplier or bred locally had negligible effects for almost every measure in the six tests, and sex differences were also absent or very small for most behaviors, whereas genetic effects were almost always large. For locomotor activity, cocaine activation, and elevated plus maze, the analysis demonstrated the strong dependence of genetic differences in behavior on the laboratory giving the tests. For ethanol preference and water escape learning, on the other hand, the three labs obtained essentially the same results for key indicators of behavior. Thus, it is clear that the strong dependence of results on the specific laboratory is itself dependent on the task in question. Our results suggest that there may be advantages of test standardization, but laboratory environments probably can never be made sufficiently similar to guarantee identical results on a wide range of tests in a wide range of labs. Interpretations of our results by colleagues in neuroscience as well as the mass media are reviewed. Pessimistic views, prevalent in the media but relatively uncommon among neuroscientists, of mouse behavioral tests as being highly unreliable are contradicted by our data. Despite the presence of noteworthy interactions between genotype and lab environment, most of the larger differences between inbred strains were replicated across the three labs. Strain differences of moderate effects size, on the other hand, often differed markedly among labs, especially those involving three 129-derived strains. Implications for behavioral screening of targeted and induced mutations in mice are discussed.
If we conduct the same experiment in two laboratories or repeat a classical study many years later, will we obtain the same results? Recent research with mice in neural and behavioral genetics yielded different results in different laboratories for certain phenotypes, and these findings suggested to some researchers that behavior may be too unstable for fine-scale genetic analysis. Here we expand the range of data on this question to additional laboratories and phenotypes, and, for the first time in this field, we formally compare recent data with experiments conducted 30 -50 years ago. For ethanol preference and locomotor activity, strain differences have been highly stable over a period of 40 -50 years, and most strain correlations are in the range of r ؍ 0.85-0.98, as high as or higher than for brain weight. For anxiety-related behavior on the elevated plus maze, on the other hand, strain means often differ dramatically across laboratories or even when the same laboratory is moved to another site within a university. When a wide range of phenotypes is considered, no inbred strain appears to be exceptionally stable or labile across laboratories in any general sense, and there is no tendency to observe higher correlations among studies done more recently. Phenotypic drift over decades for most of the behaviors examined appears to be minimal.agonistic behavior ͉ anxiety ͉ ethanol preference ͉ gene-environment interaction ͉ locomotor activity
It makes sense to attribute a definite percentage ofvariation in some measure of behavior to variation in heredity only if of heredity and environment are truly additive. Additivity is often tested by examining the interaction effect in a two-way of variance (ANOV A) or its equivalent multiple regression model. If this effect is not statistically significant at the a = 0.05 is common practice in certain fields (e.g., human behavior genetics) to conclude that the two factors really are additive and linear models, which assume additivity. Comparing several simple models of nonadditive, interactive relationships heredity and environment, however, reveals thatANOV A often fails to detect nonadditivity because it has mueh less power of interaction than in tests of main effects. Likewise, the sample sizes needed to detect real interactions are substantially than those needed to detect main effects. Data transformations that reduce interaction effects also change drastically the ofthe causal model and may conceal theoretically interesting and practically useful relationships. Ifthe goal ofpartitioning mutually exclusive causes and calculating "heritability" coefficients is abandoned, interactive relationships can be more seriously and can enhance our understanding of the ways living things develop.
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