Rat as a Model Organism

About Rat

The Norway rat (Rattus norvegicus), also known as brown rat, common rat, sewer rat, Hanover rat, Norwegian rat, city rat, water rat and wharf rat, is native to northern China and neighboring regions but has since spread worldwide, thriving in urban environments and close to human settlements. This medium-sized rodent, typically weighing between 250 to 500 grams, is a key species in biological and biomedical research. Adult Rattus norvegicus measure about 20 to 25 centimeters in body length, with an additional 18 to 25 centimeters for the tail. Their fur is usually coarse, with a brownish or grayish color, though albino strains are commonly used in laboratory settings.

Rattus norvegicus is highly favored in research for its larger size and more complex behavior compared to mice, serving as an excellent model for studies involving neuroscience, toxicology, and physiology. Rats reach sexual maturity at around 6 to 8 weeks, with a gestation period of approximately 21 to 23 days. Females typically produce litters of 6 to 12 pups, and they can breed year-round under optimal conditions.

The rat genome, like that of the mouse, has been fully sequenced, presenting a valuable resource for genetic studies. The Rattus norvegicus genome exhibits strong conservation with other mammals, making it a vital model organism for studying complex traits, human diseases, and therapeutic interventions.

Brief History and Key Breakthroughs

The rat (Rattus norvegicus) has a long and storied history as a model organism, significantly contributing to scientific research by deepening our knowledge of human health, disease, and biology. In this section, we describe a brief history and some of the most notable breakthroughs achieved through rat-based research.

Early Use and Emergence as a Model Organism

The Norway rat is frequently regarded as the first mammal domesticated for research purposes.¹ While rats were sporadically used in experiments before 1850, the earliest documented scientific study involving these animals was published in France in 1856, focusing on the effects of adrenalectomy.^2,3 Over time, rats became favored for research due to their small size, ease of handling, and rapid breeding.

The shift from observing animals in nature to using them in controlled laboratory settings was critical in the rat's development as a model organism. By the late 19th and early 20th centuries, rats were commonly employed in various physiological and biomedical experiments.

Establishment of Rat Strains

One of the significant milestones in the rat's history as a model organism was the establishment of inbred strains. In 1906, the Wistar Institute in Philadelphia began developing what would become the Wistar rat, one of the first standardized laboratory rat strains.³ The development of the Wistar rat allowed researchers to minimize genetic variability, which is crucial for ensuring consistent and reliable experimental results.

The establishment of inbred rat strains led to the widespread adoption of the rat as a model organism in the study of genetics, behavior, and disease. The Wistar rat, along with other strains developed later such as Sprague Dawley and Long Evans rats, became foundational in many areas of research, especially in studies related to cancer, cardiovascular diseases, and neuroscience.

Behavioral Science and Psychology

Rats have been extensively implemented in behavioral research for studying learning, memory, and addiction. Their larger brains and complex behaviors render them ideal for these studies. The development of the Skinner box by B.F. Skinner in the 1930s, which used rats to investigate operant conditioning in a controlled environment where rats could learn to perform specific behaviors in response to rewards or punishments, revolutionized behavioral psychology and demonstrated a framework for understanding the principles of behavior modification.⁴

Stress Research

In 1936, Hans Selye employed rats to develop his General Adaptation Syndrome (GAS) theory. He observed that rats exposed to various stressors exhibited a consistent set of physiological responses: enlarged adrenal glands, thymic and lymphatic atrophy, and gastric ulcers. These findings highlighted the body's short-term and long-term reactions to stress, establishing stress as a critical factor in health and disease.^5,6 Selye's work with rats laid the foundation for modern stress research, influencing fields such as endocrinology, physiology, and psychology.

Rise in Popularity and Influence

Rats gained prominence in the mid-20th century as research models for understanding human diseases. Their physiological and genetic similarities to humans, combined with their established use in research, made them indispensable in preclinical studies. Notably, rats were instrumental in the development of early models of hypertension, diabetes, and neurological disorders.

Endocrinology and Diabetes Research

Rats have been central to the study of endocrinology, particularly in diabetes research.⁷ Streptozotocin-induced diabetic rats have been a model for diabetes, leading to critical insights into the disease's mechanisms and treatments.^8,9

Neurobiology and Neuroscience

Rats have been fundamental in advancing neurobiology, particularly in learning about the brain's structure and function. The Morris water maze, introduced by Richard Morris in 1981, utilized rats to explore spatial learning and memory.¹⁰ This model has become popular in neurobiological research, especially in studies related to cognitive function, Parkinsons’ disease, Alzheimer’s disease, and other neurodegenerative disorders.¹¹

Genetic Research

With the sequencing of the rat genome in 2004, rats became even more valuable in genetic research.¹² This milestone presented researchers with comprehensive genetic information, enabling the creation of genetically modified rat models to examine gene function and disease mechanisms, and making rats indispensable in the study of complex traits and diseases.

Cancer Research

Rats have also played a crucial role in cancer research. The induction of tumors in rats has been pivotal in elucidating cancer biology, identifying carcinogens, and developing chemotherapy drugs. The rat's usage in the study of hormone-driven cancers, such as breast cancer, has shed light on cancer progression and treatment.¹³

Toxicology and Pharmacology

Rats are a standard model in toxicology for testing the safety and efficacy of drugs and chemicals.¹⁴ Their usage in these fields has provided critical data for regulatory agencies, helping to ensure the safety of pharmaceuticals and environmental chemicals before human exposure. This data is essential for hazard categorization, risk assessment, and determining safe exposure levels.

Rats have been instrumental in numerous scientific breakthroughs across disciplines by revealing major insights into human health and disease. This has led to the development of treatments and therapies with profound impacts on medicine and science.

Advantages as a Model Organism

The rat has become a cornerstone in biomedical research due to its characteristics and versatility as a model organism. Read on to learn how rats work as model organisms and the benefits of choosing them for research.

• Physiological and Genetic Similarity to Humans: Rats share approximately 90% of their genetic material with humans as well as many physiological characteristics, rendering rats as excellent models for human biology and diseases. Their cardiovascular, nervous, and endocrine systems are similar enough to human systems that findings in rats often translate well to human conditions.
• Well-Characterized and Readily Available: The rat is one of the most extensively studied mammals in biomedical research. There is a wealth of background data, well-established protocols, and a vast array of rat-specific reagents and tools, including genetic models, antibodies, and ELISA kits. This makes experimental design and data interpretation more straightforward.
• Diverse Research Applications: Rats are applied to a wide range of research areas, from behavioral studies to toxicology, cancer research, and neurobiology. Their use in developing models for hypertension, diabetes, and other chronic conditions has been impactful.
• Behavioral and Cognitive Studies: Rats exhibit complex behaviors and cognitive functions, which are ideal for studies in psychology and neuroscience. Their ability to navigate mazes, respond to operant conditioning, and exhibit social behaviors is conducive to researchers exploring learning, memory, addiction, and social interaction in a controlled environment.
• Size and Manageability: The rat's size is ideal for handling, care, and many experimental procedures. They are large enough for surgical manipulation and physiological monitoring, yet small enough to be housed in laboratory settings.
• Reproductive Efficiency: Rats have a high reproductive rate, with short gestation periods (about 21-23 days) and large litter sizes (typically 6-12 pups). This reproductive efficiency facilitates genetic studies and the maintenance of large, genetically uniform colonies, enabling researchers to conduct extensive and reproducible experiments.
• Availability of Genetic Models: The availability of inbred, outbred, and genetically modified rat strains enables researchers to study specific genetic traits and diseases. Transgenic and knockout rats have been developed to model human genetic disorders, clarifying the genetics of diseases.
• Ethical Considerations and Regulatory Support: While ethical considerations are important, rats are generally considered more acceptable for research compared to larger mammals or primates. Their usage is well-regulated, with guidelines in place to ensure humane treatment and minimize suffering, which can be a practical choice for research programs.

The rat's adaptability, physiological similarities to humans, and extensive background in research make it a powerful model organism. Its use has led to numerous scientific breakthroughs, and it continues to be a vital tool in the advancement of medical science.

Limitations as a Model Organism

Although rats (Rattus norvegicus) are common model organisms in scientific research, there are several limitations and challenges to consider.

Differences from Human Biology

• Physiological Differences: Despite many similarities, rats and humans have significant physiological differences. For instance, certain aspects of their immune system, metabolism, and disease progression do not fully replicate human conditions. This can lead to challenges in translating findings from rat studies to human applications.
• Genetic Differences: Although rats share a large percentage of their genome with humans, the differences can still impact the relevance of the findings. Certain genes and regulatory pathways may function differently, affecting how diseases manifest and how treatments work.

Ethical Concerns

• Sentience: Rats are sentient beings, capable of experiencing pain and distress. Ethical concerns arise from their usage in experiments, particularly those involving invasive procedures or long-term suffering. Researchers must balance the scientific benefits with the ethical implications, often requiring extensive justification and oversight.
• Regulatory Restrictions: The use of rats in research is subject to strict regulations aimed at minimizing suffering and ensuring humane treatment. While necessary, these regulations can limit the scope of experiments and add layers of administrative and logistical complexity.

Cost and Resource Intensity

• Maintenance Costs: Compared to smaller model organisms like fruit flies or nematodes, maintaining rat colonies is expensive. They require more space, food, and specialized care, which can be a considerable financial burden for research institutions.
• Experimental Costs: Experiments involving rats often require more resources, such as specialized equipment, surgical procedures, and advanced monitoring technologies. These costs can restrict the scale of research projects or the number of studies that can be conducted.

Limited Genetic Manipulation Tools

• Genetic Manipulation Challenges: Although significant progress has been achieved in genetic engineering techniques for rats, such as CRISPR/Cas9, they are still more challenging and less developed compared to those available for mice. This can hamper the ability to create specific genetic models or manipulate genes in precise ways.
• Longer Generation Time: Compared to other model organisms like fruit flies, rats have a longer generation time and fewer offspring per litter. This can slow down genetic studies, resulting in more time-consuming production and analysis of genetically modified lines.

Behavioral Variability

• Strain-Specific Behaviors: Different strains of rats can exhibit behavioral differences, which can affect the outcomes of experiments in studies involving cognition, emotion, and social behavior. This variability can hinder generalization of findings across different strains or to human populations.
• Environmental Sensitivity: Rats are highly sensitive to their environment, including factors like housing conditions, handling, and stress. Variations in these conditions can lead to inconsistent results, complicating experimental design and data interpretation.

Limited Suitability for Certain Research Areas

• Non-Human-Specific Pathologies: Certain human-specific diseases or conditions, such as some neurodegenerative diseases, do not have equivalent pathologies in rats. This limits their usefulness in studying these conditions or testing treatments.
• Pharmacokinetics and Toxicology: The way rats metabolize drugs and chemicals can greatly differ from humans, leading to inaccurate predictions of human responses. This can be problematic in pharmacokinetics and toxicology studies, where the goal is to assess the safety and efficacy of substances intended for humans.

Transferability Issues

• Poor Transferability of Some Findings: Some findings from rat studies do not translate well to humans in complex diseases like cancer, Alzheimer's, and psychiatric disorders. This raises concerns about the relevance and cost-effectiveness of rat models in these areas.

Addressing the Challenges

While rat model organisms present certain challenges, researchers can employ strategies to mitigate some of these issues and enhance the relevance of their studies.

Improving Translational Relevance

• Complementary Models: To bridge the physiological and genetic gaps between rats and humans, researchers often use rats alongside other models, such as mice or human cell lines.
• Humanized Rat Models: Genetic engineering techniques, like CRISPR/Cas9, are implemented to create humanized rat models that better mimic human diseases.

Ethical and Regulatory Considerations

• Refinement, Reduction, and Replacement (3Rs): Following the 3Rs principle helps minimize animal suffering while still achieving research goals.
• Enhanced Welfare Practices: Improving housing and handling techniques reduces stress and leads to more reliable results.

Cost-Effective Research

• Resource Sharing: Collaborating with other labs and sharing resources can reduce the financial burden of maintaining rat colonies.

Improving Transferability

• Integrative Data Analysis: Techniques like meta-analyses and computational modeling enhance the transferability of findings from rats to humans.

Despite their many advantages, researchers should carefully consider the challenges and limitations when designing studies and interpreting results from rat models. Rat studies often have complementary research using other model organisms or human data to enhance the robustness and applicability of scientific findings.

Research Areas

Rattus norvegicus have an essential role in biomedical research due to their physiological and genetic similarities to humans, as well as their relatively large size and ease of handling. We discuss some of the research areas where rats are model organisms below.

• Cardiovascular Research: Rats are commonly used in studies of hypertension, heart disease, and stroke. Their cardiovascular system closely resembles that of humans, making them ideal for investigating the mechanisms of heart failure, atherosclerosis, and myocardial infarction.
• Neuroscience: Rats are frequently used to study brain function, behavior, and neurological diseases. They have been instrumental in research on learning and memory, addiction, neurodegenerative diseases like Parkinson’s and Alzheimer’s, and psychiatric disorders such as depression and anxiety.
• Endocrinology: Because rats are capable of modeling human-like metabolic processes, they have been studied for hormone regulation and endocrine diseases, including diabetes, obesity, and metabolic syndrome.
• Toxicology and Pharmacology: Rats are often employed in drug testing and safety assessments, as they provide reliable data on the pharmacokinetics and toxicological effects of new compounds.
• Cancer Research: There are rat models for various cancer types, such as breast, prostate, and liver cancers. They are particularly useful for analyzing cancer progression, metastasis, and the efficacy of therapeutic interventions.
• Immunology: Rats are studied in immunological research, including studies on autoimmune diseases, transplantation, and vaccine development. Their immune system is similar to that of humans, which positions them as a good model for these studies.

In these research areas and emerging fields, scientists can leverage rats as model organisms and significantly contribute to advancements in human health and disease discoveries.

Community, Resources, and Funding Opportunities

Researchers working with rats as model organisms have access to a range of organizations, resources, conferences, and funding opportunities. In this section, we mention some of the most notable institutions and tools.

Organizations and Resources

Rat Genome Database (RGD): RGD is a comprehensive database that consists of genomic data, tools, and resources specifically focused on rats. It is an essential resource for researchers working with rat models. Website: www.rgd.mcw.edu

National BioResource Project - Rat in Japan (NBRP-Rat): NBRP-Rat presents a diverse collection of rat strains and related resources, which are essential for advancing biomedical research and supporting scientific discoveries with rat models. Website: www.anim.med.kyoto-u.ac.jp/NBR

Rat Resource & Research Center (RRRC): The RRRC provides rat strains, embryonic stem cells, and related services. Its high standards of genetic quality control and health monitoring maximize research reproducibility. Website: www.rrrc.us/

Boster Bio: Antibodies and ELISA kits are crucial resources for researchers working with rat models, especially in immunology, neuroscience, and cancer research. Boster Bio offers a range of antibodies, ELISA kits, custom antibody services, and CRO assay services for scientists working with rat samples.

International Society for Transgenic Technologies (ISTT): ISTT focuses on the development and use of transgenic technologies, including those involving rats. They provide a platform for sharing knowledge and advancements in genetic engineering. Website: www.transtechsociety.org/

Conferences

Society for Neuroscience (SfN): SfN is one of the largest organizations for neuroscientists, many of whom use rats as model organisms. The society hosts an annual conference and provides resources for researchers in neuroscience. Website: www.sfn.org

American Association for Laboratory Animal Science (AALAS) National Meeting: One of the largest conferences dedicated to the care, research, and ethics of using laboratory animals like rats. The meeting includes workshops, presentations, and networking opportunities. Website: www.aalas.org

Gordon Research Conferences (GRC) on Neural Development and Disease: GRC hosts conferences on various aspects of neuroscience, where rat models are often discussed. These conferences consist of cutting-edge research presentations and discussions. Website: www.grc.org

Transgenic Technology Meeting (TT): Organized by ISTT, this conference focuses on the latest developments in transgenic research, including advancements in rat models. Website: www.transtechsociety.org/

Funding Opportunities

National Institutes of Health (NIH): NIH is the primary funding body for biomedical research in the United States, offering various grants for studies involving rats. Specific institutes within NIH, such as the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS), often fund rat-related research. Website: www.nih.gov

National Science Foundation (NSF): The NSF funds research across a wide range of scientific disciplines, including studies involving rat models. Website: www.nsf.gov/

European Research Council (ERC): The ERC offers grants to support pioneering research projects, including those utilizing rat models for biomedical research. Website: erc.europa.eu/

Howard Hughes Medical Institute (HHMI): HHMI provides funding for biomedical research, with a focus on transformative research projects. Researchers using rats as models can apply for HHMI funding. Website: www.hhmi.org/

These resources, communities, and opportunities support researchers working with rat models, encouraging the development of new techniques, discoveries, and collaborations in the field.

Reflective Questions for Rat Research

If you’re considering rat models for your research, we have some guiding questions to help you reflect on your research objectives, ethical considerations, and experimental design.

Biological and Experimental Considerations

• Does the rat's physiology align with my research objectives? Consider whether the rat's biological systems, such as cardiovascular, neurological, or metabolic, are suitable for studying the processes you are interested in.
• Is there a relevant rat strain available for my study? Are there genetically modified or inbred rat strains that can address your research questions effectively?
• What are the advantages of choosing rats over other model organisms? Compare the benefits of using rats, such as their larger size for surgical procedures or more complex behaviors, against other potential models like mice.
• How will the rat's lifespan and reproductive cycle impact my research timeline? Consider whether the rat’s longer lifespan and breeding cycle fit within your study’s time frame and objectives.
• Can the rat's behavior and cognitive abilities enhance my study? Assess whether the rat’s capacity for learning and memory tasks will provide meaningful insights for your research.

Ethical and Welfare Considerations

• Am I prepared to address the ethical considerations of using sentient animals like rats? Reflect on the ethical implications, including the potential for suffering, and whether your research justifies the use of sentient organisms.
• Do I have the resources and knowledge to provide appropriate care and housing for rats? Ensure that you can meet the welfare needs of rats, including their social and environmental requirements, to minimize stress and ensure valid results.

Practical and Logistical Considerations

• What are the costs associated with using rats in my research? Evaluate the financial implications, including housing, feeding, and care costs, compared to other model organisms.
• Do I have access to the necessary facilities and expertise? Consider whether your institution has the required infrastructure and whether you have access to personnel with experience in rat handling and experimentation.
• What are the potential limitations of using rats in my research? Identify any constraints, such as the availability of rat-specific reagents or the applicability of rat models to your research field.
• How will the use of rats impact the scalability of my experiments? Think about whether the size and care requirements of rats will affect the number of experiments or replicates you can perform within your resources.

Scientific and Collaborative Considerations

• Is there sufficient literature and data on rats for my research area? Assess whether there is an existing body of research that can support and contextualize your findings.
• Are there opportunities for collaboration with other researchers using rat models? Consider whether using rats will facilitate collaborations with other researchers in your field, potentially enhancing the scope and impact of your work.

Reflecting on these questions can help you make an informed decision about whether rats are the appropriate model organism for your research.

References and Further Reading

1. Richter, C.P. (1959). Rats, man, and the welfare state. American Psychologist, 14(1),18-28. https://doi.org/10.1037/h0043834
2. Philipeaux, J.M. (1856). Note sur l'extirpation des capsules servenales chez les rats albios (Mus Rattus). Comptes Rendus Hebdomadaires Des Seances De l’Academie Des Sciences 43, 904–906.
3. Modlinska, K., & Pisula, W. (2020). The Natural History of Model Organisms: The Norway rat, from an obnoxious pest to a laboratory pet. eLife 9, e50651. https://doi.org/10.7554/eLife.50651
4. Papageorgi, I. (2018). Skinner Box, the. In: Shackelford, T., Weekes-Shackelford, V. (eds) Encyclopedia of Evolutionary Psychological Science. Springer, Cham. https://doi.org/10.1007/978-3-319-16999-6_1051-1
5. Selye, H. (1936). A Syndrome produced by Diverse Nocuous Agents. Nature, 138, 32. https://doi.org/10.1038/138032a0
6. Tan, S.Y., & Yip, A. (2018). Hans Selye (1907–1982): Founder of the stress theory. Singapore Medical Journal, 59(4), 170-171. https://doi.org/10.11622%2Fsmedj.2018043
7. Gray, L.E., Wilson, V., Noriega, N., Lambright, C., Furr, J., Stoker, T.E., Laws, S.C., Goldman, J., Cooper, R.L., Foster, P.M.D. Use of the Laboratory Rat as a Model in Endocrine Disruptor Screening and Testing. ILAR Journal, 45(4), 425-437. https://doi.org/10.1093/ilar.45.4.425
8. Akbarzadeh, A., Norouzian, D., Mehrabi, M. R., Jamshidi, Sh., Farhangi, A., Allah Verdi, A., Mofidian, S. M., & Lame Rad, B. (2007). Induction of diabetes by Streptozotocin in rats. Indian Journal of Clinical Biochemistry, 22, 60–64. https://doi.org/10.1007/bf02913315
9. Kottaisamy, C.P.D., Raj, D.S., Prasanth Kumar, V., & Sankaran, U. (2021). Experimental animal models for diabetes and its related complications—a review. Laboratory Animal Research, 37, 23. https://doi.org/10.1186/s42826-021-00101-4
10. Morris, R.G.M. (1981). Spatial localization does not require the presence of local cues. Learning and Motivation, 12(2), 239-260. https://doi.org/10.1016/0023-9690(81)90020-5
11. Chernyuk, D.P., Bol’shakova, A.V., Vlasova, O.L., & Bezprozvanny, I.B. (2021). Possibilities and Prospects of the Behavioral Test “Morris Water Maze”. Journal of Evolutionary Biochemistry and Physiology, 57, 289-303. https://doi.org/10.1134/S0022093021020113
12. Rat Genome Sequencing Project Consortium. (2004). Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature, 428, 493–521. https://doi.org/10.1038/nature02426
13. Mondal, P., Bailey, K.L., Cartwright, S.B., Band, V., & Carlson, M.A. (2022). Large Animal Models of Breast Cancer. Frontiers in Oncology, 12. https://doi.org/10.3389/fonc.2022.788038
14. Weber, K., Razinger, T., Hardisty, J. F., Mann, P., Martel, K. C., Frische, E. A., Blumbach, K., Hillen, S., Song, S., Anzai, T., & Chevalier, H. (2011). Differences in Rat Models Used in Routine Toxicity Studies. International Journal of Toxicology, 30(2). https://doi.org/10.1177/1091581810391818