Exp. Anim. 60(4), 347–354, 2011

—Review— Review Series: Wild Mice in Laboratory Science A New Twist on Behavioral Genetics by Incorporating Wild-Derived Strains

Tsuyoshi KOIDE1, 6), Kazutaka IKEDA2), Michihiro OGASAWARA3), Toshihiko SHIROISHI4, 6), Kazuo MORIWAKI5), and Aki TAKAHASHI1, 6)

1)Mouse Genomics Resource Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, 2)Division of Psychobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585, 3)Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo 113-8421, 4)Mammalian Genetics Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, 5)RIKEN BioResource Center, Tsukuba 305-0074, and 6)Department of Genetics, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Kanagawa 240-0193, Japan

Abstract: Behavior has been proven to be extremely variable among human individuals. One of the most important factors for such variations of behavior is genetic diversity. A variety of mouse strains are reportedly suitable animal models for investigating the genetic basis of large individual differences in behavior. Laboratory strains have been shown to exhibit different behavioral traits due to variations in their genetic background. However, they show low-level genetic polymorphism because the original colony used for establishing the strains comprises a relatively small number of mice. Furthermore, because the laboratory strains were derived from fancy mice, they have lost the original behavioral phenotype of wild mice. Therefore, incorporation of inbred strains derived from wild mice of different mouse subspecies for behavioral studies is a marked advantage. In the long-term process of establishing a variety of wild-derived inbred strains from wild mice captured all over the world, a number of strains have been established. We previously identified a marked variety in behavioral traits using a Mishima battery. This review reports on the usefulness of wild-derived strains for genetic analyses of behavioral phenotypes in mice. Key words: anxiety, behavior, genetic diversity, strain difference, wild mouse

Introduction the course of animal . Therefore, charac- terizing the mechanisms of behavioral variation is di- Behavioral differences among affect survival rectly related to understanding the mechanisms of evolu- in a wild environment; thus, behavior is one of the major tion and domestication, products of natural and artificial targets of natural selection. Also, behavioral phenotypes selection, respectively. A number of reports have shown that are useful for human life are often selected during that individual variation in behavior is greatly influenced

(Received 18 January 2011 / Accepted 28 February 2011) Address corresponding: T. Koide, Mouse Genomics Resource Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan 348 H. Koide, ET AL. by genetic factors in many animal species. In mice, genetic admixtures between these major subspecies experiments have shown efficient groups have been observed. In Europe, a hybrid zone selection of targeted behavior traits such as anxiety-re- from Denmark to Bulgaria separates two subspecies lated traits in several generations, suggesting the exis- groups, Domesticus and Musculus, but nonrandom tence of genetic factors related to these behavioral phe- mtDNA flow from Domesticus to Musculus was found notypes [7]. in Sweden [2, 8]. In Japanese mice, M. m. molossinus, Laboratory strains have been used as models of indi- it was shown that genetic mixing has occurred between vidual diversity as comparison of different inbred strains the Musculus and Castaneus subspecies groups [33]. reveals clear phenotypic differences in a variety of traits. Several research groups have been involved in establish- However, there is a limitation in using laboratory strains ing a variety of inbred strains from wild mice captured for studying individual variation. Most laboratory strains in different areas of the world [2, 13, 18]. The descen- originated from a relatively small group of fancy mouse dants of these wild mice were established as wild-derived colonies mostly belonging to M. m. domesticus subspe- inbred strains (wild strains) after at least 20 generations cies [2, 9, 28, 32]. Although mice in these colonies show of brother-sister mating (Table 1) [10, 14, 15, 18]. Nine some heterogeneity, genetic variation is relatively lim- strains, PGN2, BFM/2, HMI, NJL, BLG2, CHD, SWN, ited among them. In other words, many laboratory KJR, and MSM, have been established in the National strains established from these fancy mice share common Institute of Genetics, Japan. Because these wild-derived genetic polymorphisms. It is expected that the lack of strains have not been subjected to deliberate attempts at heterogeneity causes relatively limited variation in be- domestication during inbreeding, they still show the havioral phenotypes among strains. Furthermore, as characteristic behavior of wildness, such as quick move- these laboratory strains originated in breeding colonies ments, aggression, and higher responsiveness to handling of fancy mice, the behavioral phenotype is normally by humans. In addition to a series of wild-derived obedient and clearly different from that observed in wild strains, a fancy mouse-derived strain, JF1, was also es- mice. In this regard, using wild-derived mouse strains tablished. JF1 has a characteristic coat color with white may be very advantageous for studying novel behav- spotting on a black coat due to piebald mutation and is ioral phenotypes and more diverse behavior. highly obedient and easy to handle [15]. These geneti- cally defined wild- and fancy-derived strains have Wild Mice and Wild Strains proven to be useful for a variety of genetic and behav- ioral studies [14]. A panel of these wild- and fancy- Wild house mice, Mus musculus species, are distrib- derived strains including a reference laboratory strain, uted widely throughout the world where people produce C57BL/6, is now known as the Mishima battery (Table and store agricultural crops. These mice are believed to 1) [10]. The wild- and fancy-derived strains of the have originated in a region around the Indian subconti- Mishima battery except for C57BL/6 and CAST/Ei are nent and to have migrated over many generations [2]. available upon request from the National Institute of The Mus musculus species is divided into at least three Genetics (http://www.shigen.nig.ac.jp/mouse/nig/) and major subspecies groups, Domesticus, Musculus, and RIKEN BioResource Center (http://www.brc.riken.go. Castaneus, based on the genetic profiles, such as poly- jp/lab/animal/en/). These wild derived strains are dif- morphisms of biochemical markers, mtDNA, and nucle- ferent in their external characters. The body weights ar genes (Fig. 1) [2, 17, 21, 23]. Although, further markedly differ among the strains (Fig. 2). Although taxonomic subdivisions have been applied based on their males are generally heavier than females, the MSM geographical distribution and morphological character- strain, which was originally captured in Mishima City, istics, these local subspecies have been classed as het- Japan, and classified as M. m. molossinus [17], did not erogeneous with the major subspecies groups because show such a clear difference in body weight between clear genetic differences have not been identified among males and females. Laboratory strains are generally these subdivided taxonomic subspecies. Furthermore, heavier than wild-derived strains, and MSM is the small- BEHAVIOR GENETICS IN WILD MOUSE STRAINS 349

Fig. 1. Geographical distribution of subspecies groups for wild mice and the origins of wild-derived strains. Each subspecies group is categorized based on the genetic profi le of wild mice that were systemized further taxonomically. Wild-derived strains and their original capture sites are indicated.

Table 1. Mouse strains in the Mishima battery Type Strain name Subspecies group Subspecifi c name Place of collection Introduction year Fancy mice C57BL/6J Domesticus Wild mice PGN2/Ms Domesticus M.m. domesticus Pigeon, Ontario, Canada 1979 Wild mice BFM/2Ms Domesticus M.m. brevirostris Montpellier, France 1980 Wild mice HMI/Ms Castaneus M.m. castaneus Heimei, Taiwan 1986 Wild mice CAST/Ei Castaneus M.m. castaneus Thailand 1989 Wild mice NJL/Ms Musculus M.m. musculus Northern Jutland, Denmark 1980 Wild mice BLG2/Ms Musculus M.m. musculus General Toshevo, Bulgaria 1981 Wild mice CHD/Ms Musculus M.m. gansuensis Chengdu, China 1981 Wild mice SWN/Ms Musculus M.m. musculus Suwon, Korea 1984 Wild mice KJR/Ms Musculus M.m. musculus Kojuri, Korea 1984 Wild mice MSM/Ms Musculus M.m. molossinus Mishima, Japan 1978 Fancy mice JF1/Ms Musculus M.m. molossinus Japan * 1987 *JF1 was found in Denmark, but characterized as a Japanese fancy mouse by a genetic study [14]. Introduction year: Year founder mice were introduced into an animal facility in the National Institute of Genetics. 350 H. KOIDE, ET AL.

Fig. 2. Strain differences in body weights in the Mishima battery. Body weights were measured at 8–12 weeks of age. In each strain, 10 mice each for Fig. 3. A matrix diagram showing degrees of polymorphism based males and females were used for measurement. on SSLP typing for 104 different microsatellite markers Error bars indicate SEM. Data were taken from distributed throughout the entire genome. The values in- a previous report [10]. dicate the frequency of polymorphism between two strains. This fi gure is based on that of Koide et al. [14]. est in the Mishima battery, less than half of the body Triplet-repeat sequences, such as repeats of CAG and weight of laboratory strains of both sexes. Because three CAA, which encode polyglutamines, are frequently ob- other strains, CHD, SWN, and KJR, which originated in served in the coding regions of genes. A systematic the Far East, also showed small body weights, it is search for genes carrying CAG repeats in public data- speculated that the phenotype of a smaller body size was bases identifi ed 62 loci carrying CAG/CAA trinucleotide fi xed in the wild population during migration of the an- repeats [21]. Polymorphisms of these repeat sequences cestral mouse population towards the East. were studied in 62 loci among 16 inbred mouse strains by PCR amplifi cation following sequence analysis. Fur- Genetic Profi les of Wild and ther phylogenetic analysis using data on variations in the Laboratory Strains repeat length revealed that the branching patterns from a reconstructed neighbor-joining (NJ) tree showed that In addition to variation in their external phenotypes, 14 inbred strains, excluding ZBN, a different species genetic differences were observed among these wild- (Mus spicilegus), were clustered into 3 groups: Domes- derived strains. Several studies characterizing polymor- ticus, Castaneus, and Musculus (Fig. 4). Laboratory phisms in genomic sequences have been carried out to strains B6, C3H/HeJ, and DBA/2 were also shown to clarify the genetic profi les of these wild-derived strains cocluster into the Domesticus subspecies group, as pre- [14, 16, 21]. Polymorphisms in repeat numbers of CA viously mentioned. dinucleotides in microsatellite marker polymorphisms In addition to these repetitive sequences, 21 nuclear were studied by simple-sequence length polymorphism genes were characterized in the sequence polymorphism (SSLP) analysis using the agarose-gel electrophoresis of these wild-derived strains [16]. An NJ tree construct- method employing genomic DNA of these wild-derived ed from the sequence polymorphism data showed the strains [14]. The results showed that the frequency of clustering of wild-derived strains into subspecies groups. microsatellite polymorphisms among wild-derived Although two strains of the Castaneus subspecies group strains is higher than 80%, and more polymorphic than did not cocluster in the same group, their sequences were between common laboratory strains, C57BL/6 (B6) and identical to each other in six gene loci out of 21 genes. DBA/2, which showed a frequency of 49% (Fig. 3). These results strongly suggest that the wild-derived These results indicate that higher diversity can be ex- strains used in these studies can be classifi ed into three pected by adding these wild-derived strains to the mouse subspecies groups, Domesticus, Musculus, and Casta- resource pool of laboratory strains. neus. BEHAVIOR GENETICS IN WILD MOUSE STRAINS 351

Home-cage activities Activities in the dark phase were signifi cantly different among strains. Two strains, NJL and KJR, were highly active, while four strains, BFM/2, HMI, BLG2, and JF1, exhibited lower activities. Most of the strains are inac- tive during the light phase, but CAST/Ei showed an exceptionally high level of activity [14]. The increased light-phase activity of CAST/Ei is due to the earlier on- set of the active phase in advance of the dark phase.

Open-fi eld test In the open-fi eld test, where each mouse is placed in a large, bright arena that provokes the animal’s innate anxiety, the animal’s behavioral character is observed in detail. For example, the KJR strain, which shows high- level activity in the open-fi eld and home-cage tests, showed strong avoidance of the center area of the open- Fig. 4. Phylogenetic tree of wild-derived strains. A fi eld, and marked emotion-related defecation and jump- neighbor-joining tree was constructed based on ing. This behavior of the KJR strain may be interpreted CAG/CAA repeat polymorphism for 31 repeat loci of 16 inbred mouse strains. Three subspecies as a high-anxiety response induced by the novel, open, groups, Domesticus, Castaneus, and Musculus, and bright environment. On the other hand, fancy-de- were clearly different in terms of their genetic profi les. The AVZ strain became extinct during rived JF1 showed pronounced immobility in the arena, the course of establishing inbred strains. This which is also another expression of a high level of anx- fi gure is based on that of Ogasawara et al. [21]. iety. CHD, NJL, and especially MSM exhibited pro- longed grooming behavior in the arena, and these strains took a long time to habituate to this novel situation. Behavioral Traits in Wild Strains Grooming is often interpreted as displacement behavior, by which animals try to balance themselves in the pres- As a high level of interstrain genetic polymorphisms ence of extreme fear or anxiety [1, 6]. Since these strains was observed, marked phenotypic variation is also ex- showed high anxiety-like behaviors in other tests of pected among these wild-derived strains. In order to anxiety, it is likely that the prolonged grooming behav- study behavioral differences, a variety of behavioral ior in MSM is associated with the displacement. There- analyses have been applied to the Mishima battery [10, fore, the behavioral expression of anxiety is different 14, 22, 25]. The results obtained in these studies are among wild-derived strains and, thus, these detailed good examples of the usefulness of the Mishima battery. characterizations are useful to precisely illustrate an To date, the following behavioral tests have been con- animal’s character. Finally, PGN2 showed pronounced ducted: home-cage activity, open-fi eld, light-dark box, jumping behavior. This strain also exhibited a high fre- passive avoidance, active avoidance, tail-fl ick sensitiv- quency of rearing but not locomotion. Thus, PGN2 mice ity, hot-plate sensitivity, capsaicin sensitivity, and mor- are preferentially highly active in a vertical direction. phine sensitivity tests. All the phenotypes studied in these tests showed signifi cant strain-related differences. Light-dark box test Most of the data from these tests have already been de- Innate avoidance of a bright environment was mea- posited in the Mouse Phenome Database (http://phenome. sured by employing the light-dark box test. KJR and jax.org/). Here, we briefl y summarize most of the results MSM stayed in the dark box for the longest time, and of these tests (Fig. 5). CAST/Ei, NJL, BFM/2, and HMI stayed for the shortest 352 H. KOIDE, ET AL.

Fig. 5. Heat map plot of strain differences in behavioral traits. Strain differences in spontaneous activity (home-cage activity), anxiety- like behaviors (open-fi eld test, light-dark box test), avoidance learning (passive avoidance test), pain sensitivity (hot-plate test, tail-fl ick test), capsaicin sensitivity, and morphine sensitivity (open-fi eld, hot-plate, tail-fl ick) are summarized as a heat map. Z scores were calculated using the average value in each strain. Note that in the pain sensitivity test, a higher Z value means a longer latency to react to the heat stimuli. Therefore, strains with lower Z values have higher pain sensitivities. Cells with no data are colored grey. times. Again, the results showed higher levels of anxiety Pain sensitivity tests in KJR and MSM. When the total number of transitions It is thought that the hot-plate response at 52°C medi- between the two boxes, light and dark chambers, was ates the central response to moderate heat stimuli but measured, two strains, B6 and CAST/Ei, showed higher that the tail-fl ick response mediates the spinal refl ex to numbers of transitions, and all other strains showed high temperatures. As a result of hot-plate and tail-fl ick relatively lower-level transition. Thus, together with the tests, signifi cant strain effects were observed in both the above behavioral results, B6 and CAST/Ei were charac- hot-plate and tail-fl ick tests. The results clearly showed terized as strains less prone to anxiety. that diverse pain sensitivity exists among strains. In the hot-plate test, three strains, JF1, KJR, and SWN, proved Passive avoidance test to be insensitive to heat, and MSM was moderately in- In the passive avoidance test, B6, BFM/2, SWN, KJR, sensitive, while the laboratory strains, B6, CAST/Ei, and and MSM avoided the dark chamber, where each animal HMI, were highly sensitive. In the tail-fl ick test, the KJR experienced an electric shock, even after spending 24 h strain proved to be insensitive, and MSM, JF1, SWN, back in its normal habituated home cage. In contrast, and BLG2 were moderately insensitive, and CAST/Ei, CAST/Ei and BLG2 showed poor performance in reten- HMI, NJL, BFM/2, and B6 were highly sensitive. tion of the memory to avoid re-entering the dark cham- ber. These results indicate that there is a strain-related Capsaicin sensitivity test difference in the learning ability. Capsaicin is the chemical component of hot chili pep- pers that causes its hot taste and stimulates the physio- logical pain system. Response to capsaicin is mediated BEHAVIOR GENETICS IN WILD MOUSE STRAINS 353 by a receptor, vanilloid receptor 1 (Trpv1), a nonselective cessfully mapped chromosomes related to behavioral cation channel in the membranes of primary sensory traits such as open-field behavior, social behavior, and nerve endings [3, 4, 5]. In the 1-bottle capsaicin (15 home-cage activity using a panel of B6-MSM consomic µM) intake tests to measure hot-taste sensitivity, the KJR strains [20, 26, 27]. Further attempts to identify the and MSM strains were less sensitive to capsaicin, and genes responsible for these behavioral phenotypes are B6 and PGN2 were highly sensitive. ongoing. However, this approach is so far only available for different behavioral traits observed between MSM Morphine sensitivity tests and B6 and is not applicable to the traits found in other Opioid drugs have been widely used for clinical pain wild-derived strains in the Mishima battery. In order to relief, and morphine is one of the commonly used anal- incorporate a wider behavioral repertoire of wild-derived gesic drugs. However, a large individual variation in strains in the genetic analysis, establishment of other sensitivity to morphine has been reported in humans. In new resources in which all the genetic diversity of the the analysis of morphine sensitivity tests using the Mishima battery has been mixed as an outbred stock will Mishima battery, a marked strain-related difference was be a great advantage [29, 31]. It is expected that these observed. MSM and KJR exhibited morphine-induced resources will comprise an ideal mouse model to inves- activation of locomotion, but B6, BFM/2, BLG2, CHD, tigate individual variation in human populations. and PGN2 showed morphine-induced suppression of locomotion [22]. In the hot-plate test, response latency Acknowledgments was significantly prolonged by morphine administration in CHD, KJR, JF1, and MSM. In the tail-flick test, This study was supported by the KAKENHI (Grant- BLG2, KJR, MSM, and JF1 exhibited higher sensitivity in-Aid for Scientific Research) and the Transdisciplinary to morphine. Overall, MSM and KJR are suggested to Research Integration Center of the Research Organiza- be highly sensitive to morphine. tion of Information and Systems.

Future Perspectives References

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