Exp. Anim. 58(5), 451–457, 2009 —Review— Review Series: Animal Bioresource in Japan Japanese Macaques as Laboratory Animals Tadashi ISA, Itaru YAMANE, Miya HAMAI, and Haruhisa INAGAKI Section for NBR Promotion, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan Abstract: The Japanese macaque (Macaca fuscata), along with rhesus and long-tailed macaques, is one of the macaca species. In Japan, it has been preferred for use as a laboratory animal, particularly in the field of neuroscience, because of its high level of intelligence and its gentle nature. In addition, the species has a relatively homogeneous genetic background and field researchers have accumulated abundant information on the social behavior of wild Japanese macaques. As future neuroscience research will undoubtedly be more focused on the higher cognitive functions of the brain, including social behavior among multiple individuals, the Japanese macaque can be expected to become even more valuable as a laboratory animal in the near future. The Ministry of Education, Culture, Sports, Science and Technology has launched a National BioResource Project (NBRP) to establish a stable breeding and supply system for Japanese macaques for laboratory use. The project is in progress and should lead to the establishment of a National Primate Center in Japan, which will support the supply of monkeys as well as social outreach and handling of animal welfare issues. Key words: bio-resource, laboratory animal, Macaca fuscata, NBRP, neuroscience Introduction ratory animals. In Japan, however, the Japanese macaque (Macaca fuscata) has been frequently employed, in part Macaque monkeys have proved to be a useful animal because Japanese macaques are native to Japan. Until model for a variety of reasons. First, they are phyloge- recently, they were regarded in many rural areas as an netically closer to humans than other animals routinely agricultural pest, and were captured and legally trans- used, e.g., mice and rats. Second, they have a similar ferred to researchers by local authorities. Now, for body structure and physiological properties to humans, various reasons, the use of animals of wild origin for and consequently have proved of value for virology, laboratory research is restricted. Nevertheless, Japanese neuroscience, and reproduction research, etc. Indeed, macaques are still the preferred choice for many types there are some types of research in which macaque mon- of laboratory research, particularly in the field of neuro- keys cannot be replaced by other animal species, such science targeting the higher brain functions. Here, we as rodents, or by cell lines. Globally, rhesus macaques describe the unique contribution of Japanese macaques (Macaca mulatta) and long-tailed macaques (Macaca to neuroscience research. fascicularis) are most commonly used primates as labo- (Received 18 June 2009 / Accepted 25 August 2009) Address corresponding: T. Isa, Section for NBR Promotion, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan 452 T. ISA, ET AL. Table 1. The research areas and the number of studies where macaca species were used Micr Neur Bioc Gene Cons HIV Phar HIV Etho Surg Endo Total Cons Phar Phys M. mulatta 102 251 36 27 13 76 106 35 35 46 39 766 M. fascicularis 38 132 26 11 6 51 16 13 36 18 12 359 M. fuscata 2 37 6 4 9 2 2 16 5 2 5 90 Total 142 420 68 42 28 129 124 64 76 66 56 1,215 Micr, microbiology. HIV, HIV/AIDS. Neur, neuroscience. Etho, ethology. Bioc, biochemistry. Surg, surgery/anatomy. Gene, genetics. Endo, endocrinology/reproduction. Cons, conservation/ecology/anthropology. Phys, physiology. Phar, pharmacology. (derived from Carlsson et al. 2004 [1]) Macaque Monkeys in Life Science Research However, in 2000, the Ministry of Environment in Japan decided to restrict the use of monkeys caught in the wild Global trend for research in response to concerns raised by prima- The number of articles published resulting from stud- tologists regarding the possibly deleterious effect on ies in which one of the macaque species was employed Japanese macaque populations. Although the numbers is shown in Table 1 (derived from Carlsson [1]). As is of wild-derived animals used in laboratories was only a clear from the table, macaque species have been used in small portion of the total number of captured monkeys, a wide range of life science studies, including microbiol- it was argued that the existence of the path for such us- ogy, neuroscience, pharmacology, and HIV/AIDS. The age might encourage levels of capture that were inap- overall proportion of studies involving Japanese ma- propriate with regard to conservation of the species. The caques (Macaca fuscata) is small in a global context as change in regulation reduced the use of wild-derived they have mainly been used by Japanese scientists. In Japanese macaques, however, a demand for the species those studies in which they have been employed, Japa- remains as many Japanese researchers regard the Japa- nese macaques have been used most frequently in neu- nese macaque as a valuable animal model, particularly roscience and HIV/AIDS research. in studies of higher brain functions. Japanese macaques have the reputation of being relatively tame and gentle Why Japanese Macaques? compared to other macaque species, such as rhesus and long-tailed macaques. In some types of neuroscience Unique situation in Japan research, macaques undergo behavioral testing in the Initially, Japanese macaques were used in Japanese laboratories after extensive training at particular tasks. laboratories because they are a native species that was The somewhat more gentle nature of Japanese macaques readily available from rural local authorities that trapped makes them more amenable to such test procedures. them as an agricultural pest. The number of Japanese Moreover, although it is less widely appreciated, ethol- macaques trapped has been reported to be about 10,000 ogists have accumulated a considerable amount of in- per year [6]. The majority of these animals were killed, formation on the behavior of Japanese macaques in the but in the past, some were transferred to researchers, wild (see the next section). In neuroscience research, mainly for use in medical studies. In neuroscience re- there is an increasing trend toward including studies of search, the number of articles published in the two lead- the neural basis of social behaviors. For such research, ing journals, the Journal of Neurophysiology and the the possibility of integrating data collected in the field Journal of Neuroscience, with Macaca fuscata as the with that gathered in laboratory studies is attractive as experimental model, dramatically increased after the mid it might provide valuable insights into many aspects of 1980s (Fig. 1). Thus, Macaca fuscata has been one of social behavior. To illustrate the potential benefits that the principal animal species used in this research field, might be gained from such studies, we briefly summarize especially among Japanese neuroscientists (Fig. 2B). the history of ethological research on Japanese macaques JAPANESE MACAQUES AS LABORATORY ANIMALS 453 Fig. 1. The number of articles published in the Journal of Neurophysiology ( ) and the Journal of Neuroscience ( ) in which Japanese macaques were used. The abscissa (“x”) axis indicates the published year. The ordinate (“y”) axis indicates the numbers of articles. Fig. 2. The comparative rates of use of different macaque species in studies published in 2008. (A) Each bar indicates the percentage of each macaca species ( M. fuscata; M. mulatta; M. fascicularis) per journal. The fi gure above each bar indicates the total number of articles. (B) The number of articles published by Japanese scientists using different macaque species. in the next section. Another little known aspect of One possible explanation for this phenomenon is that Japanese macaques is that they show considerably less only a small population of Japanese macaques initially genetic variance than other macaque species (Fig. 3). colonized the islands of Japan during the Ice Age, when 454 T. ISA, ET AL. Fig. 3. Estimated genetic variability of various species. Each bar indicates the expected average heterozygosity calculated from the mean of gene frequencies in the subpopulations of each species (Nozawa et al. 1996 [10]). The ordinate (“y”) axis indicates the value of heterozygosity. these islands were connected to the mainland, and that involving focal-animal data sampling based on indi- the modern population is derived from this relatively vidual identification. This approach led to the discovery restricted group of founders. This unique characteristic of primate “pre-culture” (i.e., sweet potato washing [4]), of Japanese macaques compared to the other macaca which is often cited as the beginning of “cultural prima- species (rhesus and long-tailed macaques) that are prev- tology”. Furthermore, such “ethnography of monkeys” alent in south-east Asian countries is of considerable also attracted public attention in Japan. Six wild popu- benefit for laboratory studies. lations were designated as National Treasures, and as resources for tourism and education, monkey watching Accumulation of ethological data at “saru-yama” (zoo enclosures) and “wild monkey From an ethological perspective, the Japanese ma- parks” (free-ranging, provisioned sites) became popular. caque is one of the most well-studied primate species. Later, from the 1970s, researchers initiated attempts to The behavior of these monkeys has been under study for habituate wild troops without provisioning to eliminate more than 50 years and there are continuous demograph- undesirable human influences on their behavior and ecol- ic records from various ecological settings. ogy. As a result of these efforts over many years, an In 1952, researchers from Kyoto University started extensive understanding of the behavior and ecology of provisioning and observing wild monkey troops at Ko- the Japanese macaque has been obtained. shima, Miyazaki and Takasakiyama, Oita, with a strong An illustration of the extent of this data gathering focus on evolution of sociality in their studies.