It is now recognized that many common behaviors of great importance to society and public health are influenced substantially by genes, and, furthermore, are genetically complex. These behaviors include abusive patterns of self-administration of alcohol and other drugs as well as other psychiatric disorders such as depression, impulsivity, and schizophrenia. The rapid growth of mammalian genetics has focused on the mouse as a model organism having well-documented genetic homologies with humans. Numerous targeted mutations in mice have been created to serve as models for hereditary human diseases, but behavioral effects of these knockout and transgenic manipulations are often assessed by scientists with little experience in evaluation of mouse behavior. Techniques have been devised to map genes with relatively modest effects on complex behaviors (quantitative trait loci or QTLs), offering the promise that the specific genes underlying complex traits can be identified and serve as targets for innovative therapies. The replicability of these mapping findings, as well as the analysis of the more subtle effects of gene knockouts, requires the use of closely comparable behavioral tests in different laboratories. However, when this project was visualized, standard procedures for testing mouse behaviors were not currently available. Instead, many behavioral assessment protocols tend to be unique to each laboratory testing mice.

"Animal models of psychiatric diseases: To man from mouse", June 19-20, 1995

An initial meeting was convened by the MacArthur Foundation. Participants recognized that a rich diversity of behaviors is expressed by mice and that the capabilities of this species do indeed make it an ideal model mammal for genetic and pharmacological research on behavior. It was also agreed that there was an important need for standard testing protocols in many domains of behavior, and that genetic norms were needed for comparison with genetically and pharmacologically altered animals. The rapid proliferation of targeted mutant mice has revealed many interesting constellations of behavioral response differences, each created by the elimination of function of a single, candidate gene. As studies in this area have progressed, it has also become clear that the behavioral "footprint" of the knockout often differed dramatically depending upon which genetic background (strain) the mutant was placed. In the extreme case, a behaviourally viable knockout with subtle behavioral differences from its wild-type background strain of residence has proven to be non-viable when placed upon another common inbred strain of mice. Thus, the group furthermore concluded that such genetic norms, characterizing the behavioral baselines of a number of standard mouse strains, would be useful for considering appropriate genetic background strains on which to place the next generation of targeted mutants (e.g., tissue-specific and conditional knockouts).

Several scientific meetings in 1996 (e.g., NIH Workshop on Behavioral Phenotypes of Inbred Strains, Society for Neuroscience short course "What's Wrong with My Mouse?") subsequently highlighted the growing interest in testing mouse behavior as well as the lack of a common and convenient methodology. A review of some available tests (J.N. Crawley et al., Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132:107-124, 1997) documented the need for careful standardization, and the paucity of systematic information available for more than one or two standard inbred mouse strains.

Two subsequent meetings of a somewhat differently-configured working group were convened by the Office of Behavioral and Social Sciences Research of the NIH. The first of these resulted in funding the experiment reported on this website, i.e., a small, multi-site study to evaluate some standard behavioral tests. Participants subsequently drafted a specific proposal for the pilot study. A second meeting was convened of a much larger group on July 13-14, 1997, to discuss tasks in the general behavioural domains surrounding activity and anxiety. The larger group has subsequently remained in email contact, and is working toward the goal of establishing a website which will serve as a repository for phenotypic data.

Finally, on May 9-11, 1999, The Jackson Laboratory convened a "Strain Characteristics Database Summit" to discuss mouse phenotyping. This group determined that a large-scale multi-year effort to collect and systematically database phenotypic information about certain selected inbred mouse strains would be an area that should be pursued.

Rationale for the Study Described Here: General Principles of Genetics and Behavior.

Behavior is a property of a whole organism and functions at the level of the individual. Genes code for proteins and function at the molecular level. A gene does not code for a single behavioral phenotype in the whole organism, or even for a component of a behavioral phenotype or specific psychological process. Rather, most genes have multiple phenotypic effects (pleiotropy) and influence behavior via diverse physiological and developmental pathways. An additional complexity is introduced because the molecular activities of many genes are regulated by features of the external environment or by behavior itself.

Consequently, it is expected that behavioral effects of a mutation will depend to some extent on the animal's environment (gene x environment interaction). The specific features of the environment that are most effective in modulating gene activity will, of course, depend on the specific gene and in most cases are presently unknown. Gene products are part of an integrated metabolic system. Therefore, the effects of a mutation are also expected to depend on genotype at other loci (epistasis) and on the genetic background of the host strain.

There may be need for a battery of behavioral tests. In order to claim that a mutation alters a gene that is important for a specific psychological process (e.g., memory), its specificity must be evaluated by measuring a wide array of other processes. A neurological/psychological syndrome of effects should be documented, and it should be established that the mutation does not affect some functions, if this is indeed true. Many tests assumed to be indices of a specific psychological process can be interpreted unambiguously only when the animal possesses a normal level of other functions (e.g., sensory acuity, motor coordination).

Although several good proposals have been made, there is currently no widely accepted battery of behavioral tests covering the range of behavioral endpoints important for the understanding of human disease. Individual tests exist for certain functions, but these differ in many details among laboratories. It is important that a comprehensive battery be constructed with the aid of well established methods of psychological testing. On the other hand, standardization would presume that tests of psychological constructs are well-developed. It may actually be the case that no single test, in any behavioral domain, holds enough construct validity to be nominated as a standard.

This study provides an initial attempt to address the question of cross-laboratory stability of mouse strain differences in behavior. The test battery employed was constructed such that the protocols could be easily and completely standardized across the three sites, without overriding concern for whether those procedures might actually be the "best" for that task. For example, should mice be phenotyped in the light or dark portion of their light cycle? We standardized on the light portion of the cycle so as to not disrupt other ongoing research in the collaborators' laboratories. In addition, the study provides the first examination of whether the breeding mice "in-house" or shipping them in from vendors provides a critical variable for behavioral tests in laboratory mice.

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