By Jennifer Parla, Ph.D. and Kristen Coughlin
Rat Models of Human Disease
The history of using rats to study human disease goes back over 150 years, having been a favorite laboratory research animal, and we are all familiar with the term “lab rat.” While the use of mice in research has grown significantly over the past few decades, that increase being driven by the earlier sequencing of the mouse genome and the development of genetic engineering methods for the mouse, rats have certain characteristics that supersede mice when it comes to studying and modeling human disease.
Choose your animal model based on biology
Before the mouse genome sequencing and genetic engineering advances, rats were the predominant medical research animal, with scientific studies benefiting from the larger size of rats, the closer similarity of rat physiology to human physiology, the better cognitive and learning capabilities of rats, and the modeling of complex human diseases being more accurate in the rat. The over 100 years of research with the rat has produced a wealth of phenotypic and physiological information. The rat is a standardized physiological and toxicological model particularly in the pharmaceutical industry, and as such, most in vivo assays were originally developed and optimized in the rat. Furthermore, mice and rats are very different biologically, despite their similar appearance. There are millions of years of evolution separating the two, and thus significant differences between them, and the extensive physiological data amassed from rats are not easily adapted to mice.
The animal model of choice, for physiologists, nutritionists, biomedical researchers
Since the establishment of rats as a laboratory research animal, they have been used in the study of physiology, immunology and autoimmune diseases, neurobiology and addiction, cardiovascular diseases, endocrinology and reproduction, and cancers. Here are a few key areas where rats and mice differ when it comes to our understanding of human biology:
Substance use disorder
Rats have historically been the preferred species for behavioral investigation in substance use disorders. Intravenous drug self-administration is considered the most appropriate paradigm to study addiction-related behaviors in rodents because the behavior is voluntary and animals have been shown to self-administer the same drugs as do humans. Rats are preferred over mice for this paradigm since the surgeries required to implant intravenous catheters are easier to perform in rats. Furthermore, rats more readily acquire drug self-administration behavior compared to mice. After catheter surgery and recovery, animals are placed in operant chambers to allow them to nose poke, lever press, or touch screen in order to obtain a drug reward. Rats acquire this operant behavior without human assistance. For mice, however, interventions are sometimes needed to enable behavior, and these types of interventions can confound the interpretation of results.
In order to accurately measure addictive behavior in rodents, it is necessary to train animals for longer periods of time and for multiple hours per day. For mice this can be problematic, since they more easily develop adverse health consequences such as obstructed catheters, detrimental body weight loss, and etc. Other difficulties with mice include higher inter- and intra-subject variability and a reduced ability to adapt to modifications in experimental conditions such as variable drug doses. It is possible for mice to have side effects due to faster metabolic rates and higher energy expenditures when compared to rats, such as anorexia, sedation, and/or anxiety. An example of differences in addiction behavior can be seen in the SERT-knockout mouse and rat models. SERT-knockout and wildtype mice do not differ in their cocaine self-administration behavior. SERT-knockout rats, on the other hand, consistently self-administered higher amounts of cocaine and MDMA compared to wildtype rats, similar to what is observed in humans carrying the short allelic variant of the SERT-linked polymorphic region. This may be due to species-related differences in the acquisition of cocaine self-administration behavior, which will need to be being investigated further.
Since rats show a wider range of behaviors compared to mice, genetically modified rat models are anticipated to make major contributions when compared to mice in the field of neurodevelopmental disorders. Using the specific example of Autism, a disorder that has seen increases in diagnosis in the last decade especially, Autism spectrum disorders (ASD) cover a group of behaviorally defined conditions that are characterized by deficits in social behavior and communication, as well as restricted and repetitive behaviors, interests, and activities. Currently, reliable biomarkers for Autism have not yet been identified. The diagnostic criteria for ASD are defined purely by behavior, and the validity of rodent models for ASD strongly depends on their behavioral phenotypes. Genetic rat models for ASD exhibit several advantages in comparison to mouse models, particularly because of their wider range of social behaviors and richer acoustic communication skills. This make it easier to detect ASD-like behavioral phenotypes in rats compared to mice.
For example, juvenile rats more prominently display rough-and-tumble play when compared to mice. Also, rats have a more complex acoustic communication system used for interaction between adults and juveniles when compared to mice. Both mice and rats regulate social interactions through the emission of ultrasonic vocalizations (USVs). Both species emit USVs as pups when isolated from their mothers and Littermates, which serve as a clear communicative function as it elicits search and retrieval behavior in mothers. Differences between species become more evident when observing juvenile and adult rats, because rats emit more complex and distinct types of USVs depending on the emotional valence of the situation, which is not the case with mice. As one example, appetitive 50 kHz USVs emitted by rats during rough-and-tumble play, mating and also during cooperative behavior, induce social approach behavior suggesting that they serve as social contact calls. In mice, an affiliative function of USVs emitted during reciprocal social interactions is still missing. In support of a prosocial communicative function of rat 50 kHz USVs, it was shown that rough-and-tumble play behavior is reduced in pairs of devocalized rats and that rats selectively bred for low emission rates of 50 kHz USVs display an ASD-like behavioral phenotype.
Due to larger blood vessels, heart, blood and urine volumes, rats are a preferred model for cardiovascular research – making it possible to perform more sophisticated surgical manipulations and physiological measurements. As an example, the ability to monitor and record precise blood pressure fluctuations in research animals is vital to research for human hypertension. Blood pressure is measured in rats by telemetry devices implanted in the aorta, which is big enough to allow blood flow around the pressure sensor. In mice, the aorta is small and blood flow is impeded when transmitters are implanted, causing death.
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