A summary and overview of the mice and rats used in biomedical research, based on a survey of formal publications. Sprague-Dawley and Wistar are the main rat strains. Major research applications are in immunology, oncology, physiology, pathology, and neuroscience. CD-1 outbred, albino genetic variability positional cloning, genotypic selection, toxicology testing questionable CB17 SCID inbred, albino no T and B cells, tumor transplantation immunodeficient animal model for testing new cancer treatments and as hosts for human immune system tissues.
Figure 4. Lepr db-3J and normal mouse. Lepr db-3J mice are "obese, hyperphagic, cold intolerant, insulin resistant, and infertile". Courtesy of The Jackson Laboratory. Reprogramming to recover youthful epigenetic information and restore vision. Cerebrospinal fluid influx drives acute ischemic tissue swelling. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. An ultra-stable cytoplasmic antibody engineered for in vivo applications.
Nat Commun. Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair. Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy. PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. A non-hallucinogenic psychedelic analogue with therapeutic potential. A central master driver of psychosocial stress responses in the rat. Habenular TCF7L2 links nicotine addiction to diabetes.
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Laboratory mice born to wild mice have natural microbiota and model human immune responses. International Mouse Phenotyping Consortium. Available from: www. Immunity to commensal papillomaviruses protects against skin cancer. Brainstem nucleus incertus controls contextual memory formation. Structural and functional features of central nervous system lymphatic vessels. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter.
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In both housing systems, mice eliminated most in the location that contained food and water. One researcher who designed a cage with a focus on satisfying mouse needs also observed that mice eliminated near their food and water This researcher explained that mice tended to defaecate and urinate when they were active, especially when eating and drinking However, elimination during eating and drinking does not seem to be involuntary: in one study, mice had access to four cages each containing food and water, and despite consuming similar amounts of food and water in all cages, mice eliminated the least in the cage where they built their nest and spent the most time The choice to eliminate near food and water may be the result of an innate preference for eliminating while eating and drinking, or it could be driven by a preference for conducting all non-nest related activities in the same location and away from the nest site 25 , As in previous research, the location of food and water was confounded in our complex system.
In the standard system, however, food and water were only partially confounded. Of the three locations in the standard system, one contained neither food nor water, one contained both, and one contained only food.
These results suggest that mice may be motivated to urinate near water, a finding that should be considered in the creation of more effective housing for mice. Affiliative behaviours are considered to be associated with positive welfare because of the physiological and psychological benefits of warmth, security, and strengthening of social bonds 33 , Mice in the complex system engaged in more affiliative behaviours and displayed fewer instances of resting alone and being alone in the nest.
These findings may be the result of there being more mice in the complex system: for example, the odds of there being another mouse who wanted to rest or spend time in the nest at the same time as the focal mouse were higher when there were more possible partners. However, this cannot explain why the frequency of affiliative behaviours fluctuated more dramatically throughout the week in the standard system.
Specifically, the frequency of affiliative behaviours was similar in the two systems mid-week, but was lower in the standard system immediately after cage-change. These results suggest that cage changing may have had a greater effect on mice in the standard system. In both systems, the frequency of affiliative behaviours followed a quadratic function: affiliative behaviours decreased immediately after cage-change, then increased for three days before decreasing again in the days leading up to the next cage-change.
One explanation for this pattern might be that cage changing is disruptive, causing an immediate drop in normal patterns of behaviour; with time mice resume normal affiliative behaviour, but as cage soiling increases, this again disrupts the behaviour.
Despite better ability to segregate space in the complex system, mice must still come into contact with the dirty latrine when they feed and drink. Indeed, we found that by the end of the week, the latrine cage was more soiled in the complex system than the standard system.
A follow-up study could test if this quadratic pattern is due to soiling by cleaning the latrine cage more frequently. Mice value the segregation of nesting sites from elimination sites, but standard laboratory cages thwart this natural behaviour. A complex housing system consisting of three standard cages connected via tunnels allowed mice to set-up their nest and latrine in separate cages, and to carry bedding from clean cages into the latrine.
We conclude that mice find waste products aversive, an observation that opens avenues for new research including, for example, determining whether disgust, like pleasure and pain 47 , is highly conserved across species. Housing mice in a way that facilitates spatial segregation provides a simple way of allowing the expression of natural behaviours and improving welfare. All procedures were performed in accordance with the Canadian Council on Animal Care guidelines on care and use of mice in research.
Sixty female Swiss Webster mice aged 4—6 months were obtained as surplus breeding stock from the University of British Columbia. Before arriving at our facility, and for one month after arrival, these animals were housed in groups of four mice in standard rectangular cages. Stocking density was equivalent in the two systems. Power analysis was not performed: the magnitude of treatment differences was not known because this was the first study of its kind.
We viewed this project as an investigatory study into the idea of segregation of space. Cages were distributed on five levels of a cage rack, with one housing of each type per level. The location of each housing type was also alternated within each level left vs. Animals were marked with a permanent non-toxic animal marker Stoelting Co. Mice were housed on a reversed light cycle with lights on from 1.
Louis, MO, USA and tap water provided from a feeder and a bottle placed in a permanent location inside the cage. Cages were changed once per week. During cage changing, mice were scooped with a cupped hand the tail was held loosely for security only and transferred to a clean cage with a fixed amount of new bedding and nesting materials.
About one third of the old nest was scattered across the clean cage to provide a familiar scent in the new cage. A few treats were also provided in the clean cage sunflower seeds, shredded coconut or breakfast cereal. One mouse developed a neoplasm and was euthanised during the second week of the study, so one triad housed eight mice instead of nine from this point on.
We included latrine-only changes to explore two potential added benefits provided by the complex housing system: reduced labour and reduced disturbance to the mice.
Second, we wanted to take advantage of an additional added benefit of the complex systems: that by facilitating latrine-only changes, they produce a lower impact on the mice.
About one third of the old nest was scattered across the three cages. The position of the food and water cage middle vs. The position of these cages was changed to test the relative importance of cage function e. The decision was made not to move the red cage, as it was anticipated that mice would use this cage for nesting and we did not want to introduce too much disruption.
During latrine-only change, all mice were scooped up and given treats, but only the dirtiest cage was replaced with a clean cage with new bedding. No new nesting materials were provided; instead, the existing nest was left intact.
The position of the food and water cage was not changed. Some data were lost due to human error e. Observations were made once the cage was removed from the rack and mice removed from the cage. Each system was subdivided into three locations. In the standard system, locations were: front-right near the water bottle and part of the feeder , front-left this was the most open space in the cage , or back semi-open space behind and under part of the feeder at the back of the cage; Fig. In the complex system, locations were: food and water cage, neutral cage, or red cage.
These photographs were later arranged into pairs i. Two independent observers, blind to date and cage position except in the case of red cages, which were only in the complex system, never in the middle of the triad and never containing the food and water scored each pair of photographs for soiling level and bedding coverage. Therefore, each standard housing unit each cage had one soiling and one bedding coverage score, while each complex housing unit each triad had three soiling and three bedding coverage scores one for each cage in the triad.
Observers could not be blinded to treatment because cages from the standard housing system did not have tunnel connector ports. However, no statistical comparisons were made between the two treatments on soiling level or bedding coverage these were within system analyses.
Each pair of photographs was scored by two independent observers. To investigate the use of space for various behaviours in each system, mice were observed over a three-week period via instantaneous scan sampling starting three weeks after they were placed in their respective housing systems. On 12 different days, the behaviour of each of these mice was instantaneously scan-sampled three times always at least 2.
If the mouse appeared to be influenced by the observer e. To score behaviours, an ethogram based on 46 , 48 , 49 was adapted to include behaviours particular to this study e.
We used generalised linear multilevel models GLMMs , which allow for normal and non-normally distributed outcomes and crossed-random effects 50 , 51 , to account for both repeated observations by cage-system, session, and mouse. In general, we allowed all parameters intercepts and slopes to vary by cage-system, session, and mouse when we had sufficient observations for the model to run i. All models contained at least a random intercept by cage-system.
All models were univariate i. The only time we found indication of a non-linear relationship was the effect of days since cage-change on the probability of affiliative behaviour, which appeared to follow a curvilinear path. For this behaviour only, therefore, we tested the quadratic curvilinear effect of days since cage-change on probability of affiliative behaviour.
For example, if a complex system contained no nesting material score of 1 in the food and water cage, flat nesting material score of 2 in the middle cage, and high domed nest score of 4 in the red cage, the system would receive a tally of 1 nest. Bedding coverage was modelled with a normal GLMM identity link, Gaussian error distribution and evaluated with t-statistics using Satterthwaite-corrected degrees of freedom. The effect of location type three types of locations in each system; see Methods on the probability of finding a urine spot or a nest was assessed with a Likelihood Ratio Test LRT model comparison: the null model without the location factor vs.
All data manipulation, plotting, and statistical analyses were conducted in R 52 , using Rstudio 53 and the following packages: tidyverse 54 , psych 55 , lme4 56 , lmerTest All data generated or analysed during this study are included in this published article and its Supplementary Information files.
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The pathogens were all similar to those that often infect children in developing countries. The researchers gave the mice the infections one at a time and allowed the animals time to recover before administering the next infection — in much the same way as humans get an infection, recover, then get another. Another group of mice received mock inoculations with saline. The final immune challenge was a vaccination against yellow fever, which uses a live but weakened form of the virus.
They differed in their gene-expression profiles and in their response to the vaccination: at first, both groups had the same antibody responses, but a month later, the co-infected mice had lower antibody levels.
Still, he hopes that these dirtier models will lead to greater mechanistic understanding of the immune system. Other researchers have bypassed the pet shop in their quest for dirty mice. Rosshart had joined the lab of NIDDK immunologist Barbara Rehermann in , and the two began poring over the literature on the microbiome, the collection of microorganisms that live on and in a larger organism.
The studies showed that the microbiome has a huge influence on the immune system, but most of the papers they found were based on a comparison of two types of lab mouse: some with a lab-derived microbiome and others with no microbiome at all. What would happen, Rosshart wondered, if he gave a lab mouse a wild microbiome?
But Rosshart could not be dissuaded. So each morning, he drove to between 3 and 10 barns, emptied more than mouse traps and drove back to NIH with the mice.
He then dissected them and preserved their tissue and faeces. In the evening, he retraced his route, collecting even more mice and baiting new traps with peanut butter. He followed this routine seven days a week for two months. By the end, Rosshart had handled more than mice. He and his colleagues selected three with the right genetics and no sign of pathogens.
When those mice gave birth, they passed this microbiome to their pups. The team compared this group with germ-free mice that had a microbiome derived from the sanitized lab environment. The wild-microbiome mice also developed less-severe disease when the researchers exposed them to chemicals that cause colon cancer. Last month, Andrea Graham, an evolutionary ecologist at Princeton University in New Jersey, and her colleagues showed that letting lab mice re-wild themselves makes them more susceptible to worm infections 5.
Graham gave her lab mice free run of eight outdoor enclosures. When she released the first batch, they immediately began exploring the enclosure, digging burrows and sampling new food.
The researchers are still trying to unpack why that might be, which could help to reveal how the immune system works in a more natural environment. Perhaps the system prioritizes fighting deadly microbes — viruses and bacteria — over less-fatal infections such as worms, says Rosshart. The dirty models have generated a great deal of excitement. Eleanor Riley, an immunologist at the University of Edinburgh, UK, says none of these models can fully replicate what happens in nature 6.
Wild mice differ from lab mice in many ways: diet could play a part, or sex, daylight or temperature. Even recreating such a simplistic version of the wild in a lab is a headache, says Virgin. Whether dirty mouse models represent the human condition better than standard lab mice — and provide a better testing ground for drugs — also remains to be seen.
The ideal experiment would involve taking a therapy that failed in clinical trials and retesting it in the new models to see whether the results match what happened in humans.
One has a therapy that failed in human studies, and the company would like to know whether the dirty mice could have predicted that failure. Another asked Masopust to use his mice to test a candidate therapy that works well in clean mice. The preliminary data suggest that it does not have much of an effect in dirty mice.
Colonies of dirty mice are springing up in other places. He and his colleagues want to test treatments they have developed for autoimmunity, in which the immune system starts attacking healthy tissues. Therapies for such conditions seem to work well in pathogen-free mice.
Campbell thinks dirty mice, which have a more developed immune system than standard lab mice, might be a more realistic model in which to test those therapies.
For example, they might allow researchers to better detect unwanted side effects. Campbell says that getting the co-housing model up and running has been challenging, but he thinks the results will be worth the trouble.
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