Laboratory rat

"Lab rat" redirects here. For other uses, see Lab rat (disambiguation).

Laboratory rats or lab rats are strains of the subspecies Rattus norvegicus domestica which are bred and kept for scientific research. While less commonly used for research than laboratory mice, rats have served as an important animal model for research in psychology and biomedical science.^[1]

The albino laboratory rat with its red eyes and white fur is an iconic model organism for scientific research in a variety of fields

Origins

 

Rat-baiting

In 18th century Europe, wild brown rats (Rattus norvegicus) ran rampant and this infestation fueled the industry of rat-catching. Rat-catchers would not only make money by trapping the rodents, but also by selling them for food or, more commonly, for rat-baiting.

Rat-baiting was a popular sport, which involved filling a pit with rats and timing how long it took for a terrier to kill them all. Over time, breeding the rats for these contests may have produced variations in color, notably the albino and hooded varieties. The first time one of these albino mutants was brought into a laboratory for a study was in 1828 for an experiment on fasting. Over the next 30 years, rats were used for several more experiments and eventually the laboratory rat became the first animal domesticated for purely scientific reasons.^[2]

 

Hooded

In Japan, there was a widespread practice of keeping rats as a domesticated pet during the Edo period and in the 18th century guidebooks on keeping domestic rats were published by Youso Tamanokakehashi (1775) and Chingan Sodategusa (1787). Genetic analysis of 117 albino rat strains collected from all parts of the world carried out by a team led by Takashi Kuramoto at Kyoto University in 2012 showed that the albinos descended from hooded rats and all the albinos descended from a single ancestor.^[3] As there is evidence that the hooded rat was known as the "Japanese rat" in the early 20th century, Kuramoto concluded that one or more Japanese hooded rats might have been brought to Europe or the Americas and an albino rat that emerged as a product of the breeding of these hooded rats was the common ancestor of all the albino laboratory rats in use today.^[3]

Use in research

 

Dissection

The rat found early use in laboratory research in five areas: W. S. Small suggested that the rate of learning could be measured by rats in a maze; a suggestion employed by John B. Watson for his Ph.D. dissertation in 1903.^[4] The first rat colony in America used for nutrition research was started in January 1908 by Elmer McCollum^[5] and then, nutritive requirements of rats were used by Thomas Burr Osborne and Lafayette Mendel to determine the details of protein nutrition. The reproductive function of rats was studied at the Institute for Experimental Biology at the University of California, Berkeley by Herbert McLean Evans and Joseph A. Long.^[6] The genetics of rats was studied by William Ernest Castle at the Bussey Institute of Harvard University until it closed in 1994. Rats have long been used in cancer research; for instance at the Crocker Institute for Cancer Research.^[7]

 

Morris water navigation test

The historical importance of this species to scientific research is reflected by the amount of literature on it: roughly 50% more than that on laboratory mice.^[2] Laboratory rats are frequently subject to dissection or microdialysis to study internal effects on organs and the brain, such as for cancer or pharmacological research. Laboratory rats not sacrificed may be euthanized or, in some cases, become pets.

 

Deprivation of REM sleep using the flowerpot technique

Domestic rats differ from wild rats (various spp. of Rodentia) in many ways: they are calmer and significantly less likely to bite, they can tolerate greater crowding, they breed earlier and produce more offspring, and their brains, livers, kidneys, adrenal glands, and hearts are smaller.

Scientists have bred many strains or "lines" of rats specifically for experimentation. Most are derived from the albino Wistar rat, which is still widely used. Other common strains are the Sprague Dawley, Fischer 344,^[8] Holtzman albino strains, Long–Evans, and Lister black hooded rats. Inbred strains are also available, but are not as commonly used as inbred mice.

Much of the genome of Rattus norvegicus has been sequenced.^[9] In October 2003, researchers succeeded in cloning two laboratory rats by nuclear transfer. This was the first in a series of developments that have begun to make rats tractable as genetic research subjects, although they still lag behind mice, which lend themselves better to the embryonic stem cell techniques typically used for genetic manipulation. Many investigators who wish to trace observations on behavior and physiology to underlying genes regard aspects of these in rats as more relevant to humans and easier to observe than in mice, giving impetus to the development of genetic research techniques applicable to rats.

Traversing complex terrain under the influence of electrode inputs to its brain

A 1972 study compared neoplasms in Sprague Dawleys from six different commercial suppliers and found highly significant differences in the incidences of endocrine and mammary tumors. There were even significant variations in the incidences of adrenal medulla tumors among rats from the same source raised in different laboratories. All but one of the testicular tumors occurred in the rats from a single supplier. The researchers found that the incidence of tumors in Sprague Dawleys from different suppliers varied as much from each other as from the other strains of rats. The authors of the study "stressed the need for extreme caution in evaluation of carcinogenicity studies conducted at different laboratories and/or on rats from different sources."^[10]

During food rationing due to World War II, British biologists had eaten laboratory rats, creamed.^{[11][12][13][14][15][16]}

Scientists have also spent time studying the thermoregulation of the rat's tail in research. The rat's tail works as a variable heat exchanger. The tail's blood flow is allows for thermoregulation to take place because it is under control of sympathetic vasoconstrictor nerves.^[17] Vasodilation occurs when the tail temperature increases, causing heat loss. Vasoconstriction occurs when the tail temperature decreases allowing heat to be conserved. Thermoregulation in the rat tail has been used to study metabolism.^[18]

Stocks and strains

For varieties bred as pets, see Fancy rat § Varieties.

A "strain", in reference to rodents, is a group in which all members are, as nearly as possible, genetically identical. In rats, this is accomplished through inbreeding. By having this kind of population, it is possible to conduct experiments on the roles of genes, or conduct experiments that exclude variations in genetics as a factor. By contrast, "outbred" populations are used when identical genotypes are unnecessary or a population with genetic variation is required, and these rats are usually referred to as "stocks" rather than "strains".^[19][20]

Wistar rat

 

The Wistar rat is an outbred albino rat. This breed was developed at the Wistar Institute in 1906 for use in biological and medical research, and is notably the first rat developed to serve as a model organism at a time when laboratories primarily used the house mouse (Mus musculus). More than half of all laboratory rat strains are descended from the original colony established by physiologist Henry Herbert Donaldson, scientific administrator Milton J. Greenman, and genetic researcher/embryologist Helen Dean King.^[21][22][23]

The Wistar rat is currently one of the most popular rats used for laboratory research. It is characterized by its wide head, long ears, and a tail length that is always less than its body length. The Sprague Dawley and Long–Evans were developed from Wistars. Wistars are more active than others like Sprague Dawleys. The spontaneously hypertensive rat and the Lewis are other well-known stocks developed from Wistars.

Long–Evans rat

The Long–Evans rat is an outbred rat developed by Long and Evans in 1915 by crossbreeding several Wistar females with a wild gray male. Long-Evans rats are white with a black hood, or occasionally white with a brown hood. They are utilized as a multipurpose model organism, frequently in behavioral research, especially in alcohol research. Long-Evans consume alcohol in a much higher rate compared to other strains, thus require less time for these behavioral studies.^{[citation needed]}

Sprague Dawley rat

 

The Sprague Dawley is an outbred, multipurpose breed of albino rat used extensively in medical and nutritional research.^{[24][25][26][27]} Its main advantage is its calmness and ease of handling.^[28] This breed of rat was first produced by the Sprague Dawley farms (later to become the Sprague Dawley Animal Company) in Madison, Wisconsin, in 1925. The name was originally hyphenated, although the brand styling today (Sprague Dawley, the trademark used by Envigo) is not. The average litter size of the Sprague Dawley rat is 11.0.^[29]

These rats typically have a longer tail in proportion to their body length than Wistars. They were involved in the Séralini affair, where the herbicide RoundUp was claimed to increase the occurrence of tumor in these rats. However, since these rats are known to grow tumors at a high (and very variable) rate, the study was considered flawed in design and its findings unsubstantiated.^[30]

Biobreeding rat

Main article: Biobreeding rat

The biobreeding rat (a.k.a. the biobreeding diabetes-prone rat or BBDP rat) is an inbred strain that spontaneously develops autoimmune type 1 diabetes. Like NOD mice, biobreeding rats are used as an animal model for Type 1 diabetes. The strain re-capitulates many of the features of human type 1 diabetes and has contributed greatly to the research of T1DM pathogenesis.^[31]

Brattleboro rat

Main article: Brattleboro rat

The Brattleboro rat is a strain that was developed by Henry A. Schroeder and technician Tim Vinton in West Brattleboro, Vermont, beginning in 1961, for Dartmouth Medical School. It has a naturally occurring genetic mutation that makes specimens unable to produce the hormone vasopressin, which helps control kidney function. The rats were being raised for laboratory use by Henry Schroeder and technician Tim Vinton, who noticed that the litter of 17 drank and urinated excessively.

Hairless rat

See also: Hairless fancy rat

Hairless laboratory rats provide researchers with valuable data regarding compromised immune systems and genetic kidney diseases. It is estimated that there are over 25 genes that cause recessive hairlessness in laboratory rats.^[32] The more common ones are denoted as rnu (Rowett nude), fz (fuzzy), and shn (shorn).

 

A Rowett nude rat

• Rowett nude rats, first identified in 1953 in Scotland, have no thymus. The lack of this organ severely compromises their immune system, with infections of the respiratory tract and eyes increasing the most dramatically.^[33]
• Fuzzy rats were identified in 1976 in a Pennsylvania lab. The leading cause of death among fz/fz rats is ultimately a progressive kidney failure that begins around the age of 1 year.^[34]
• Shorn rats were bred from Sprague Dawley rats in Connecticut in 1998.^[35] They also suffer from severe kidney problems.

Lewis rat

The Lewis rat was developed by Margaret Lewis from Wistar stock in the early 1950s. Characteristics include albino coloring, docile behavior, and low fertility.^[36] The Lewis rat suffers from several spontaneous pathologies: first, they can suffer from high incidences of neoplasms, with the rat's lifespan mainly determined by this. The most common are adenomas of the pituitary and adenomas/adenocarcinomas of the adrenal cortex in both sexes, mammary gland tumors and endometrial carcinomas in females, and C-cell adenomas/adenocarcinomas of the thyroid gland and tumors of the haemopoietic system in males. Second, Lewis rats are prone to develop a spontaneous transplantable lymphatic leukaemia. Lastly, when in advanced age, they sometimes develop spontaneous glomerular sclerosis.^[36]

Research applications include transplantation research, induced arthritis and inflammation, experimental allergic encephalitis, and STZ-induced diabetes.^[37][36]

Royal College of Surgeons rat

A Royal College of Surgeons rat undergoing visual acuity testing

The Royal College of Surgeons rat (or RCS rat) is the first known animal with inherited retinal degeneration. Although the genetic defect was not known for many years, it was identified in the year 2000 as a mutation in the gene MERTK. This mutation results in defective retinal pigment epithelium phagocytosis of photoreceptor outer segments.^[38]

Shaking rat Kawasaki

The shaking rat Kawasaki (SRK) is an autosomal recessive mutant that has a short deletion in the RELN (reelin) gene.^[39] This results in the lowered expression of reelin protein, essential for proper cortex lamination and cerebellum development. Its phenotype is similar to the widely researched reeler mouse. Shaking rat Kawasaki was first described in 1988.^[40] This and the Lewis rat are well-known stocks developed from Wistar rats.

Zucker rat

 

The Zucker rat was bred to be a genetic model for research on obesity and hypertension. They are named after Lois M. Zucker and Theodore F. Zucker, pioneer researchers in the study of the genetics of obesity. There are two types of Zucker rat: a lean Zucker rat, denoted as the dominant trait (Fa/Fa) or (Fa/fa); and the characteristically obese (or fatty) Zucker rat or Zucker diabetic fatty rat (ZDF rat), which is actually a recessive trait (fa/fa) of the leptin receptor, capable of weighing up to 1 kilogram (2.2 lb) — more than twice the average weight.^[41][42][43]

Obese Zucker rats have high levels of lipids and cholesterol in their bloodstream, are resistant to insulin without being hyperglycemic, and gain weight from an increase in both the size and number of fat cells.^[44] Obesity in Zucker rats is primarily linked to their hyperphagic nature and excessive hunger; however, food intake does not fully explain the hyperlipidemia or overall body composition.^[42][44]

Knockout rats

Main article: Knockout rat

A knockout rat (also spelled knock out or knock-out) is a genetically engineered rat with a single gene turned off through a targeted mutation. Knockout rats can mimic human diseases, and are important tools for studying gene function and for drug discovery and development. The production of knockout rats became technically feasible in 2008, through work financed by $120 million in funding from the National Institutes of Health (NIH) via the Rat Genome Sequencing Project Consortium, and work accomplished by the members of the Knock Out Rat Consortium (KORC). Knockout rat disease models for Parkinson's disease, Alzheimer's disease, hypertension, and diabetes, using zinc-finger nuclease technology, are being commercialized by SAGE Labs.

See also

• Laboratory mouse
• Animal testing on rodents
• Morris water maze
• Rat Genome Database

References

1. Vandenbergh JG (1 January 2000). "Use of House Mice in Biomedical Research". ILAR Journal. 41 (3): 133–135. doi:10.1093/ilar.41.3.133.
2. Krinke GJ, Bullock GR, Krinke G (June 15, 2000). "History, Strains and Models". The Laboratory Rat (Handbook of Experimental Animals). Academic Press (AP). pp. 3–16. ISBN 0-12-426400-X.
3. Kuramoto T (November 2012). "Origin of Albino Laboratory Rats". Bio Resource Newsletter. National Institute of Genetics. Retrieved 20 December 2013.
4. John B. Watson (1903) "Psychical development of the white rat", Ph.D. University of Chicago
5. Day HG (1974). "Elmer Verner McCollum". Biographical Memoirs of the National Academy of Sciences. 45: 263–335. PMID 11615648.
6. Long JA, Evans HM (1922). The oestrous cycle in the rat and its associated phenomena. University of California Press.
7. Suckow MA, Weisbroth SH, Franklin CL (2005). "Chapter one: Historical Foundations". The Laboratory Rat. ISBN 0080454321.
8. "43rd Annual Pathology of Laboratory Animals Course". Archived from the original on 16 August 2000. Retrieved 15 September 2008.
9. "Genome Project". Ensembl. Retrieved 17 February 2007.
10. Mac Kenzie, William; Garner, F. (1973). "Comparison of Neoplasms in Six Sources of Rats". JNCI: Journal of the National Cancer Institute. Oxford University Press (OUP). 50 (5): 1243–1257. doi:10.1093/jnci/50.5.1243. ISSN 1460-2105. PMID 4712589. National Cancer Institute.
11. Diamond JM (January 2006). Collapse: How Societies Choose to Fail or Succeed. Penguin Publishing. pp. 105ff. ISBN 978-0-14-303655-5. creamed rat.
12. Lorey DE (2003). Global Environmental Challenges of the Twenty-first Century: Resources, Consumption, and Sustainable Solutions. Rowman & Littlefield. pp. 210 ff. ISBN 978-0-8420-5049-4.
13. McComb DG (1 September 1997). Annual Editions: World History. McGraw-Hill Higher Education. p. 239. ISBN 978-0-697-39293-0.
14. Peacock KA (1996). Living with the Earth: An Introduction to Environmental Philosophy. Harcourt Brace Canada. p. 71. ISBN 978-0-7747-3377-9.
15. Spears D (29 July 2003). Improving Reading Skills: Contemporary Readings for College Students. McGraw-Hill. p. 463. ISBN 978-0-07-283070-5.
16. Sovereignty, Colonialism and the Indigenous Nations: A Reader. Carolina Academic Press. 2005. p. 772. ISBN 978-0-89089-333-3.
17. Owens, N. C.; Ootsuka, Y.; Kanosue, K.; McAllen, R. M. (2002–2009). "Thermoregulatory Control of Sympathetic Fibres Supplying the Rat's Tail". The Journal of Physiology. 543 (3): 849–858. doi:10.1113/jphysiol.2002.023770. ISSN 0022-3751. PMC 2290547. PMID 12231643.
18. Škop, Vojtěch; Liu, Naili; Guo, Juen; Gavrilova, Oksana; Reitman, Marc L. (2020-08-01). "The contribution of the mouse tail to thermoregulation is modest". American Journal of Physiology. Endocrinology and Metabolism. 319 (2): E438–E446. doi:10.1152/ajpendo.00133.2020. ISSN 0193-1849. PMC 7473913. PMID 32691633.
19. International Committee on Standardized Genetic Nomenclature for Mice / Rat Genome and Nomenclature Committee (January 2016). "Rules and Guidelines for Nomenclature of Mouse and Rat Strains". Mouse Genome Informatics. Jackson Laboratory. Retrieved 5 December 2018.
20. "Outbred Stocks". 15 February 2019.
21. Clause, B. T. (1998). "The Wistar Institute Archives: Rats (Not Mice) and History", Mendel Newsletter February, 1998. 16 December 2006 at the Wayback Machine
22. . The Wistar Institute. 2007. Archived from the original on 17 October 2008. Retrieved 9 November 2008.
23. Clause, Bonnie Tocher (1993). "The Wistar rat as a right choice: Establishing mammalian standards and the ideal of a standardized mammal". Journal of the History of Biology. 26 (2): 329–349. doi:10.1007/BF01061973. ISSN 0022-5010. PMID 11623164. S2CID 12428625.
24. Drachman RH, Root RK, Wood WB (August 1966). "Studies on the effect of experimental nonketotic diabetes mellitus on antibacterial defense. I. Demonstration of a defect in phagocytosis". The Journal of Experimental Medicine. 124 (2): 227–40. doi:10.1084/jem.124.2.227. PMC 2180468. PMID 4380670.
25. Hsu CC, Lai SC (December 2007). "Matrix metalloproteinase-2, -9 and -13 are involved in fibronectin degradation of rat lung granulomatous fibrosis caused by Angiostrongylus cantonensis". International Journal of Experimental Pathology. 88 (6): 437–43. doi:10.1111/j.1365-2613.2007.00554.x. PMC 2517339. PMID 18039280.
26. Horiuchi N, Suda T, Sasaki S, Takahashi H, Shimazawa E, Ogata E (December 1976). "Absence of regulatory effects of 1alpha25-dihydroxyvitamin D3 on 25-hydroxyvitamin D metabolism in rats constantly infused with parathyroid hormone". Biochemical and Biophysical Research Communications. 73 (4): 869–75. doi:10.1016/0006-291X(76)90202-3. PMID 15625855.
27. Sukov W, Barth DS (June 1998). "Three-dimensional analysis of spontaneous and thalamically evoked gamma oscillations in auditory cortex". Journal of Neurophysiology. 79 (6): 2875–84. doi:10.1152/jn.1998.79.6.2875. PMID 9636093.
28. . 12 December 1998. Archived from the original on 2 December 2008. Retrieved 15 December 2007.
29. . Harlan Laboratories. Archived from the original on 2012-10-26. Retrieved 2012-10-25.
30. Wallace Hayes A (March 2014). "Editor in Chief of Food and Chemical Toxicology answers questions on retraction". Food and Chemical Toxicology. 65: 394–5. doi:10.1016/j.fct.2014.01.006. PMID 24407018.
31. Mordes JP, Bortell R, Blankenhorn EP, Rossini AA, Greiner DL (1 January 2004). "Rat models of type 1 diabetes: genetics, environment, and autoimmunity". ILAR Journal. 45 (3): 278–91. doi:10.1093/ilar.45.3.278. PMID 15229375.
32. Kim H, Panteleyev AA, Jahoda CA, Ishii Y, Christiano AM (December 2004). "Genomic organization and analysis of the hairless gene in four hypotrichotic rat strains". Mammalian Genome. 15 (12): 975–81. doi:10.1007/s00335-004-2383-3. PMID 15599556. S2CID 36747187.
33. Festing MF, May D, Connors TA, Lovell D, Sparrow S (July 1978). "An athymic nude mutation in the rat". Nature. 274 (5669): 365–6. Bibcode:1978Natur.274..365F. doi:10.1038/274365a0. PMID 307688. S2CID 4206930.
34. Ferguson FG, Irving GW, Stedham MA (August 1979). "Three variations of hairlessness associated with albinism in the laboratory rat". Laboratory Animal Science. 29 (4): 459–64. PMID 513614.
35. Moemeka AN, Hildebrandt AL, Radaskiewicz P, King TR (1998). "Shorn (shn): a new mutation causing hypotrichosis in the Norway rat". The Journal of Heredity. 89 (3): 257–60. doi:10.1093/jhered/89.3.257. PMID 9656468.
36. . CRiver.com. Charles River Laboratories. 2021. Archived from the original on 24 May 2013.
37. "Lewis Rat". CRiver.com. Charles River Laboratories. Retrieved 7 June 2021.{{cite web}}: CS1 maint: url-status (link)
38. D'Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, Vollrath D (March 2000). "Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat". Human Molecular Genetics. 9 (4): 645–51. doi:10.1093/hmg/9.4.645. PMID 10699188.
39. Kikkawa S, Yamamoto T, Misaki K, Ikeda Y, Okado H, Ogawa M, Woodhams PL, Terashima T (August 2003). "Missplicing resulting from a short deletion in the reelin gene causes reeler-like neuronal disorders in the mutant shaking rat Kawasaki". The Journal of Comparative Neurology. 463 (3): 303–15. doi:10.1002/cne.10761. PMID 12820163. S2CID 21608635.
40. Aikawa H, Nonaka I, Woo M, Tsugane T, Esaki K (1988). "Shaking rat Kawasaki (SRK): a new neurological mutant rat in the Wistar strain". Acta Neuropathologica. 76 (4): 366–72. doi:10.1007/bf00686973. PMID 3176902. S2CID 5806299.
41. Kurtz TW, Morris RC, Pershadsingh HA (June 1989). "The Zucker fatty rat as a genetic model of obesity and hypertension". Hypertension. American Heart Association. 13 (6 Pt 2): 896–901. doi:10.1161/01.hyp.13.6.896. PMID 2786848. S2CID 109606.
42. Davis AJ (January 1997). . Research PennState. 18 (1). Archived from the original on 22 May 2002. Retrieved 6 December 2008.
43. Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, Masuzaki H, et al. (August 1996). "Molecular cloning of rat leptin receptor isoform complementary DNAs--identification of a missense mutation in Zucker fatty (fa/fa) rats". Biochemical and Biophysical Research Communications. 225 (1): 75–83. doi:10.1006/bbrc.1996.1133. PMID 8769097.
44. Kava R, Greenwood MR, Johnson PR (1990). "Zucker (fa/fa) Rat". ILAR Journal. Institute for Laboratory Animal Research (ILAR). 32 (3): 4–8. doi:10.1093/ilar.32.3.4.

Further reading

• Suckow MA, Weisbroth SH, Franklin CL, eds. (2005). The Laboratory Rat (2nd ed.). Academic Press. ISBN 0080454321 – via Google Books.

External links

 

Wikimedia Commons has media related to Lab rats.

• "Rat Genome", Nature
• Rat Genome Database, Medical College of Wisconsin
• Index of Inbred Rat Strains database, Jacskson Laboratory
• Rat Model Summary database, Knock Out Rat Consortium (archived copy)