Establishing appropriate animal models of disease is of vital importance in basic medical research – for which, rats and mice have become the animals of choice. Mice are considered the most important model animal for analyzing human gene functions due to its small size, low operational costs, relatively stable embryonic cells, and pliability for various genetic manipulations and gene editing. However, rats are physiologically, morphologically, and genetically closer to humans than mice, which makes rats ideal models for biomedical and clinical studies. Its larger body and organ size facilitate multiple samplings, in vivo electrophysiology, as well as neurosurgical and neuroimaging procedures. In contrast to mice, rat models are more widely used in toxicology, teratology, endocrinology, oncology, neurology, experimental gerontology, cardiovascular research, dental research, and experimental parasitology. In this review, we explore the differences between rats and mice, as well as some research applications for which rats are advantageous, to help guide the optimal use of rodent models for human disease research and medical studies.
Although the evolutionary differences between rats, mice, and humans is very small, in many respects, rats are closer to humans. At approximately 2.75 billion pairs, the rat genome is closer to the human genome, which is 2.9 billion pairs, and slightly larger than mouse genome (2.6 billion base pairs). In addition, humans have 23 pairs of chromosomes, while rats have 21 and mice have 20. These genomic differences contribute to the greater physiological similarities seen between rats and humans. For example, the heart of mouse can beat up to 600bpm (beats per minute), while the heart rate of rat is reduced to around 300bpm, which is closer to the 70bpm of humans.
The most widely employed rodent strains in biomedical research are Sprague-Dawley (SD) rats and C57 mice, which are especially useful in neurobiology studies. Recent studies have found that there are expression differences between 4,713 genes in the dendrites of hippocampal neurons in rats and mice among the 10,833 genes detected using gene chip analysis. Studying hippocampal neurons from the two most common mouse strains - C57BL/6 and BALB/c - with gene chip technology revealed only 54 genes to be differentially expressed between them. Considering the importance of the hippocampus in behavior (especially learning and memory), these findings help explain the differences in behavior between rats and mice. The researchers also compared other tissues of rats and mice (including heart, skeletal muscle, intestines, etc.). Although these tissues are quite different, these are far less apparent than the differences of gene expression in the hippocampus, which significantly contributes to the differences in experimental results between rats and mice.
Several of the major physiological and behavioral differences between mice and rats are as follows:
The use of mice as genetic model animals is no longer a necessity with the newfound availability of custom recombinant rat models. Given the wealth of physiological data for rat responses and pathways, much of the foundational research has already paved the way for improved rat models of human disease.
In recent years, in the process of preclinical to clinical translation of drug candidates, a large number of mouse-based studies have ended in failure, which has led medical researchers to reconsider the value of animal models that more closely replicate human disease pathologies. In this context, scientists have again turned their attention to the untapped potential of gene-edited rat models. Below, we cover some of the research areas that are utilizing the advantages offered by rats in studying human disease:
1) Rats are an excellent model for studying cardiovascular diseases (CVDs), especially stroke and hypertension; rat models across multiple background strains have become ideal options for these studies.
2) For breast cancer research, rat models are better than mouse models because they have a hormonal response to histopathology and have a precancerous stage that is closer to human disease.
3) Rats are the majormodels for human reproductive mechanics research.
4) For modeling of diabetes, the rat is closer to humans in some important aspects of disease pathology, including the ability of environmental factors (such as toxins, stress, diet, and vaccination) to change the course of the illness.
5) In terms of degenerative diseases, PINK1 and DJ-1 knockout (KO) rats exhibit more than 50% loss of dopaminergic neurons in the substantia nigra of the midbrain at the age of 8 months. Comparable gene KO mice exhibited insignificant phenotypic changes, leading to the genetically modified rat model providing more value in treating Parkinson's disease (PD). Additionally, this is also the first time that the loss of dopaminergic neurons has been found in a gene-edited animal model.
6) The behavioral consistency of mice is relatively poor, so the number of each group needed to produce reliable statistical results is 1.5 times that of rats. Rats are smarter than mice and perform better in learning and memory experiments, and the effects of drugs on rats are more apparent. In pain research, rats are not prone to develop pain numbness caused by anxiety, which is common in mice. In fact, pain-related literature cites rats in far greater numbers than it does mice.
7) Although past preclinical studies have evaluated drug effectiveness with mouse experiments, it is better to confirm the safety in rats before clinical testing in humans. Not only do humans share 99% of genes with rats (compared to 97.5% with mice), but the safety data of rats continues to accumulate and is increasingly referenced. With the development of advanced gene-editing in rats, both the effectiveness and safety of drugs can now be simultaneously tested in rats, saving time and often providing higher fidelity of results.
8) The large size of the rat provides many practical advantages, especially for the research of surgical interventions and spinal cord injury, for which rat models are of great transformative value. Rats also have advantages over mice in organ and tissue imaging research.
Before the first recombinant rat model was created in 2009, mice predominated applications as superior genetic models. With the expanded capabilities for developing gene-edited rats of increasing complexity, researchers now have more options than ever before when choosing a rodent model for their research.
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