ILAR Journal Online, Volume 41(3) 2000: Mouse Behavioral Models in Biomedical Research

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ILAR Journal V41(3) 2000
Mouse Behavioral Models in Biomedical Research

Introduction

Use of House Mice in Biomedical Research
John G. Vandenbergh

"Mice are the most widely used experimental mammals, having made important contributions in most areas of biomedical research" (Festing and Lovell 1981, p. 42).

What was true in 1981 is even more true today. The number of laboratory mice used as a model for human and animal biomedical research continues to grow at a rapid rate. The mouse's usefulness as a biomedical model has been sharply enhanced by recent advances in the ability to experimentally modify its genome. In this issue of ILAR Journal, a group of experts focus on the role of the mouse in biobehavioral research. Our goal is to review selected parts of the literature on lboratory mouse behavior and to assess behvioral measurement procedures that may be useful to invetigators utilizing this common biomedical model.

The word mouse in the English language can be traced back to the Latin mus, then to the Greek mys, and finally to the ancient Sanskrit mush (Silver 1995). Mush in ancient Sanskrit means "to steal." Well named, the house mouse, mus sp., has been an effective thief of human food supplies since the beginning of agriculture. The earliest association between the house mouse and human habitation is in a neolithic community in Turkey c. 6500-5650 BC (Brothwell 1981). The house mouse proved it is a highly adaptable mammal by dispersing widely along with its human hosts. Mice are found s commensals in diverse human structured habitats throughout the world and as feral mice in a wide variety of natural habitats (Bronson 1984). Although the wild house mouse remains a serious pest to humans, over the past century humans have begun to "steal" back from the mouse.

How and what did we steal from the lowly mouse? Beginning about the turn of the century, mouse fanciers in England and the United States were breeding mice for unusual coat color as well as other characteristics. They were long preceded by Chinese mouse fanciers as early as 307 AD, but there is no evidence that mice from China contributed to the gene pool of the modern laboratory mouse (Fsting and Lovell 1981). In Europe, the mouse was used as early as 1614 by Robert Hooke in his studies of oxygen in living systems (Masson JH 1940 as quoted in Festing and Lovell 1981). The use of the mouse became more common as specific strains were eveloped. Particularly notable in the United States was Miss Abbie Lathrop (Figure 1), a retired school teacher who bred "fancy" mice on her farm in Massachusetts around the turn of the 20th Century (Morse 1978). The mice from her colony soon became part of biologic research programs at Harvard University and the University of Pennsylvania, when it was noted that the strains developed tumors.

Miss Lathrop's "Fancy" mice were initially brought into the laboratory in 1902 by Prof. Ernest Castle of Harvard. Soon thereafter, his student, Clarence Little, and other associates developed strains from Miss Lathrop's original colony such as the now commonly used CBA, C3H, C57BL/6, and BALB/c strains. Work on thse mice was focused on clarifying the genetic basis of cancer. Additional research on the mouse soon branched into many areas of biology; however, behvior was not one of them until much later. Clarence Little went on to participate in the founding of The Jackson Laboratory in Bar Harbor, Maine, in 1929 and served as its first director (Russell 1978; Snell and Reed 1993). The Jackson Laboratory has grown into the primary repository of mouse strains and a major biomedical research center.

The house mouse, Mus musculus domesticus, became the mammalian model of choice in basic and applied biomedical research because of its high degree of adaptability and because highly inbred strains became available with traits relevant to many important human diseases. One specific mouse strain, termed the 129 strain, and its substrains became valuable when it was found to be particularly suitable for the derivatio of embryonic stem cells that can be genetically manipulated in culture and then returned to a host mouse uterus (Simpson et al. 1997). Studies utilizing direct genomic manipulation of the substrains of the 129 mouse have allowed for "targeted mutation" technology to produce mice with specific phenotypic characteristics as well as mice in which human disease genes were expressed. It is now the most commonly used strain for genetic manipulation. The significant increase in the number of publications based on research utilizing targeted mutant mice uring the 1990s is likely to continue (Figure 2).

Other rodents, especially the Norway rat, also became common laboratory experimental models. "The rat" rapidly became the most frequently used species in behavioral studies, especially those involving learning (Beach 1950). It continues to be heavily used in biomedical research because of its fertility, size, and tractability. Once a rich background of data was built up there was even greater reason to select the rat for behavioral and other biomedical studies. Geneticists, however, remained focused on the house mouse largely due to the availability of inbred strains. Inbred strains of the laboratory mouse have been used more extensively than any other laboratory mammal to uncover mammalian genes related to specific phenotypes (Festing 1996).

With the rat as the model of choie for many years in behavioral research and the mouse as a growing model of choice in genetic research, a disconnect has become evident. The opportunities presented by the new tools of ouse genetics have enormous potential for advancing behavioral neuroscience through understanding how neural systems work and how behavior develops and is expressed in the indiviual. More information must be gathered on the behavior of the mouse so that behavioral phenotypes altered by genetic manipulation can be detected and measured. The behavioral phenotypes examined in this issue will include learning and memory as well as behaviors that relate to such adaptive functions in the mouse as motor behavior, aggression, and reproduction.

Often, complex phenotypes are altered in unexpected ways by a targeted gene alteration. To increase the probability of detecting important targeted as well as serendipitous effects from such manipulations, information on mouse behavior must be reviewed and gaps in our information base must be filled. The purpose of this issue is to review the current state of our knowledge on the behavior of the house mouse and to point out areas in which we may still be able to "steal" information from this adaptable creature just as it has stolen our food for centuries.

The articles in this issue provide an analysis of the procedures available for assessing the behavioral phenotype of wild-type and genetically altered mice. Behavior is such a broad topic that not all areas could be covered. The articles by Crawley (2000) and by McClearn and Vandenbergh (2000) focus on some of the procedures and limitations on behavioral tests used in pharmacologic studies. Next are a set of papers describing specific adaptive behaviors such as aggression by Nelson and Chiavegatto (2000) and learning and other species-typical behaviors by Brown, Stanford, and Schellinck (2000). A thread running through the papers is the concern with potential confounding variables. Because behavior is at the apex of underlying genetic, developmental, and experiential factors, reduction of varibility of these factors will enhance the sensitivity of behavioral tests and the confidence that can be placed in them.

References

Beach FA. 1950. The snark wasa bojum. Am Psychol 5:115-124.

Bronson FH. 1984. The adaptability of the house mouse. Sci Am 250:116-125.

Brothwell D. 1981. The Pleistocene and Holocene archeology of the house mouse and related species. In: Berry RJ, editor. Symposium of the Zoological Society of London. Vol. 47: The Biology of the House Mouse. London: Academic Press. p 1-13.

Brown E, Stanford L, Schellinck HM. 2000. Developing standardized behvioral tests for knockout and mutant mice. ILAR J 41:163-174.

Crawley JN. 2000. Behavioral phenotyping of transgenic and knockout mice: Experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. ILAR J 41:136-143.

Festing MFW. 1996. Origins and characteristics of inbred strains of mice. In: Lyon MF, Rastan S, Brown SDM, editors. Genetic Variants and Strains of the Laboratory Mouse. 3rd ed. Oxford: Oxford University Press.

Festing MFW, Lovell DP. 1981. Domestication and development of the mouse as a laboratory animal. In: Berry RJ, editor. Symposium of the Zoological Society of London. Vol. 47: The Biology of the House Mouse. London: Academic Press. p 43-62.

McClearn GE, Vandenbergh DJ. 2000. Structure and limits of animal models: Examples from alcohol research. ILAR J 41:144-152.

Morse HC III. 1978. Origins of Inbred Mice. New York: Academic Press.

Nelson RJ, Chiavegatto S. 2000. Aggression in knockout mice. ILAR J 41:153-162.

Russell ES. 1978. Origins and history of mouse inbred strains: Contributions of Clarence Cook Little. In: Morce HC, editor. Origins of Inbred Mice. New York: Academic Press. p 33-43.

Silver LM. 1995. Mouse Genetics. New York: Oxford University Press.

Simpson EM, Linder CC, Sargent EE, Davisson MT, Mobraaten LE, Sharp JJ. 1997. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat Genet 16:19-27.

Snell GD, Reed S. 1993. William Ernest Castle, pioneer mammalian geneticst. Genetics 133:751-753.

FIGURE 1 Miss Abbie Lathrop at Cranby. Redrawn from the Springfield Sunday Republican, October 5, 1913. With permission from Morse HC III. 1978. Origins of Inbred Mice. New York:Academic Press.

FIGURE 2 The production and utilization of targeted mutant mice are growing rapidly. Presented are the actual and projected number of publications that cite targeted mice. The values for 1985-1995 were obtained using SilverPlatter^TM to search MEDLINE EXPRESS. Values for 1996-2001 were projected utilizing the historical rate of increase of publications citing transgenic mice, derived by pro-nuclear injection, during the period 1990-1995. These projections may be an underrepresentation of future publications because of the wide utility of these mice in all areas of human health and the concomitant success of the human genome project. With permission from Simpson EM, Linder CC, Sargent EE, Davisson MT, Mobraaten LE, Sharp JJ. 1997. Genetic variations among 129 substrains and its importance for targeted mutatenesis in mice. Nat Genet 16:19-27.