For over 150 years, the common laboratory rat has been used as a model of human disease.
The are many cognitive and physiological characteristics that make the rat an ideal choice for laboratory studies in neurobiology, cardiobiology, immunology and toxicology.
|Metabolic Similarity||The metabolic physiology of the rat is closer to humans than in mice. This makes the rat a better species to study metabolic disorders and the pharmacokinetic/pharmacodynamic characteristics of drugs.|
|Superior Behavior Modeling||The rat is the preferred species for modeling cognition, psychotherapeutic, affective and neurological disorders.|
|Physiological Similarity||Rat physiology is better suited for the study of human toxicology, cardiovascular disease, and immunology.|
|Technical Advantages||Larger size of rats allows sophisticated surgical manipulations. The ability to harvest a larger volume of blood/CSF and tissue enables optimal experimental readouts.|
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With the development of targeted genetic manipulation of mouse ES cells 25 years ago, the mouse has overtaken the rat to become the most widely used animal model. Yet, the rat has historically been the preferred animal model for biomedical research, and, in fact, led the mouse in number of publications as recently as 2001. And in 1989, the year in which the first knockout mouse was published, there were 70% more publications in rat than in mouse.
Most in vivo assays, particularly behavioral and cardiovascular assays, were originally developed and validated in the rat and only recently adapted to the mouse. There also exists an immense archive of historical physiological data in the rat. Understanding of rat genetics is the one field where rats lag behind mice, however, this is changing with the sequencing of the rat genome and development of resources such as the rat genome database. The advent of new genomic editing tools such as zinc finger nucleases (ZFNs) has now enabled genetic manipulation of the rat, setting the stage for its resurgence as the animal model of choice.
By weight, a rat is roughly 10 times the size of a mouse. The larger size means larger tissues and samples. This can mean a reduction in the number of animals required for a study, or enable the study of molecules too low in abundance to measure in mouse. There are also more opportunities to measure multiple endpoints from the same sample, further reducing animal requirements. Small sample volumes require sensitive assays and are more prone to variability and error, while the larger sample volumes afforded by rat models lower these technical hurdles. The additional sample volume also more easily allows for archival. Rats are much more amenable to serial blood draws, enabling time-course sampling.
The larger size of the rat allows for surgeries that are much easier to perform. Technical training times are reduced with rat models reducing the time to data acquisition and publication. Easier surgeries also mean fewer errors, with increased efficiency and an accompanying savings of time, money, and animal life. Discrete substructures can be more readily studied and targeted, for example microinjection into small brain nuclei such as the arcuate nucleus of the hypothalamus is far easier to perform in the rat.
Imaging technologies are advancing rapidly with emergence of techniques such as two photon excitation microscopy, quantum dots, diffusion tensor imaging, and BOLD-fMRI among many others. The rat is an ideal model for imaging due in part to its more translational nature and closer physiology to humans. But perhaps the biggest advantage of the rat over mouse is the increase in spatial resolution due to the larger size of the rat. Spatial resolution in PET imaging has been estimated to be up to 10 fold greater in rat than mouse.
Researchers and technicians working with both mice and rats almost unilaterally prefer working with rats over mice. Compared to mice, rats are far more docile and rarely bite. Mice are frequently described as “skittish” and “erratic.” The increased handling needs of mice also make them less than ideal for behavioral studies.
In the past, researchers doing drug discovery would screen for efficacy in genetically modified mouse models and then switch models and assess safety in the rat, due to the large volume of historical safety data in the rat. This methodology relies on extrapolations of mouse dosing to rat, and the assumption that this dose would have similar efficacy in the rat. The uncertainty in this approach is less than ideal, as drug efficacy has been observed to be highly variable in different mouse strains, let alone in different species. Genetically modified rat models now solve this problem, enabling drug efficacy and safety to be performed not only in the same species (rat) but even in the same background strain.
Numerous anatomical and physiological differences have been noted between mice and rats, and rats are consistently more representative of humans. The heart rate of a mouse is ~600 bpm, while the rat is less than half of that and much closer to the 70 bpm of humans. And, also due In part to the larger heart and vessel size, rats overall are preferred as cardiovascular models. The human genome contains 2.9 billion base pairs, rats have 2.75 billion, more than the 2.6 billion of the mouse. Rats are smarter than mice and perform far more reliably on learning and memory tasks.
Traditional ES cell technology used to create genetically modified mice can take a year or more. In contrast, knockout rat models can be generated in up to less than half that amount of time—in as little as 6 months. Rat ES cells were not amenable to gene targeting until very recently, and thus researchers have had to develop new genomic editing tools that circumvent their use. Zinc finger nucleases are the most mature and characterized of these tools, and can be injected directly into fertilized embryos, eliminating the need for ES cells and removing species limitations. This technique has been demonstrated to be highly efficient in creating both rat (and mouse) knockouts as well as knock ins, and the elimination of ES cell work greatly accelerates the generation time.
Rats are far superior to mice when it comes to behavioral assays. Rats perform much more reliably and robustly than mice, and mouse behavioral assays typically require cohort sizes up to 50% larger than those needed for rats due to this increased variability. Rats are smarter than mice and perform far better than mice on assays of learning and memory and addiction. In pain assays, rats are less susceptible to anxiety-induced analgesia and again perform much more reliably; in fact, pain research is one field where mice never surpassed rats in number of publications. Rats are more social than mice and perform behaviors that mice do not. One example is juvenile play—young rats will playfully wrestle with one another much as kids do. Mice do not. In a knockout rat model of autism (lacking neuroligin 3), this play behavior is disrupted—a very translational endpoint. Lastly, rats have recently been demonstrated to exhibit very surprising sophisticated behaviors such as empathy and even processing of human speech.
In the end, an animal model must be representative of human physiology and/or disease. In vivo assays for drug discovery must be able to generate drugs with efficacy in humans. The mouse has recently come under scrutiny after several translational failures. The rat is now poised to reclaim its position as the animal model of choice because of all the reasons mentioned above.
The rat is inherently more translational than mouse with closer physiology, richer behavior, more robust and repeatable assay performance, and offers the ability to do safety studies in the same strain and species as efficacy.