Laboratory Mice: An Overview of History, Biology, and Research

Laboratory mice have been a cornerstone of scientific research for over a century, with their first use dating back to the 1880s.

The initial use of mice in research was pioneered by scientists such as August Weismann and Francis Galton, who recognized the animal's unique characteristics and adaptability.

Mice are mammals, belonging to the family Muridae, and are known for their small size, short gestation period, and high reproductive rate.

One of the key reasons mice are favored in research is their genetic similarity to humans, with many of the same genes and biological pathways present in both species.

Mice have been used in biomedical research for centuries, with the first recorded use dating back to the 17th century.

William Harvey used mice to study reproduction and blood circulation, and Robert Hooke used them to investigate the effects of increased air pressure.

Mice were also used by Joseph Priestley and Antoine Lavoisier to study respiration in the 18th century.

Gregor Mendel initially studied inheritance in mice, but was asked to stop breeding them due to their "smelly" nature.

The DBA inbred mouse strain was generated by Clarence Cook Little, William Ernest Castle, and Abbie Lathrop in the early 20th century.

The Jackson Laboratory in Maine is now one of the world's largest suppliers of laboratory mice, producing around 3 million mice per year.

The laboratory is also home to over 8,000 strains of genetically defined mice and the Mouse Genome Informatics database.

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Mice are polyestrous and breed year round, with breeding onset occurring at about 50 days of age in both females and males.

The average gestation period is 20 days, and a fertile postpartum estrus occurs 14–24 hours following parturition. This means that if a female doesn't mate during this time, she resumes cycling 2–5 days post-weaning.

Newborn males can be distinguished from females by noting the greater anogenital distance and larger genital papilla in males.

Here's a quick rundown of the typical reproductive cycle of mice:

Genetically standardized models are crucial in laboratory mice, as they can be repeatedly reproduced simply by breeding. This ensures the continued availability of the same model to different investigators at different institutions over long periods of time.

Mice are polyestrous, meaning they can breed year-round, and their breeding onset occurs at around 50 days of age for both males and females.

Females can start their first estrus cycle as early as 25-40 days of age.

The duration of the estrous cycle is 4-5 days and lasts about 12 hours, typically occurring in the evening.

Vaginal smears are useful in timed matings to determine the stage of the estrous cycle.

A copulatory plug in the vagina up to 24 hours post-copulation can confirm mating, and the presence of sperm on a vaginal smear is also a reliable indicator of mating.

The average gestation period for mice is 20 days.

Newborn mice, called pups, weigh between 0.5-1.5 grams at birth and are hairless, with closed eyelids and ears.

Pups are weaned at 3 weeks of age when they weigh about 10-12 grams.

If a female mouse doesn't mate during the postpartum estrus, she will resume cycling 2-5 days post-weaning.

Newborn males can be distinguished from females by their greater anogenital distance and larger genital papilla, which can be observed by lifting the tails of littermates and comparing their perinea.

Mice are mammals of the clade Euarchontoglires, which means they're amongst the closest non-primate relatives of humans, along with lagomorphs, treeshrews, and flying lemurs.

Laboratory mice are the same species as the house mouse, but they can be very different in behavior and physiology. Hundreds of established inbred, outbred, and transgenic strains exist.

Inbred laboratory mice provide the possibility to study the roles of genes without genetic variation as a factor. Individual mice within an inbred mutant strain are essentially genetically identical to each other except for the mutant gene being studied.

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Most laboratory mice are hybrids of different subspecies, most commonly of Mus musculus domesticus and Mus musculus musculus. Many laboratory strains are inbred, and they can have a variety of coat colors, including agouti, black, and albino.

Over 400 standardized, inbred strains have been developed, with many (but not all) being inbred. The different strains are identified with specific letter-digit combinations, such as C57BL/6 and BALB/c.

The first inbred strains were produced in 1909 by Clarence Cook Little, who was influential in promoting the mouse as a laboratory organism. In 2011, an estimated 83% of laboratory rodents supplied in the U.S. were C57BL/6 laboratory mice.

Here's a list of some of the different types of strains:

Laboratory mice come in hundreds of established inbred, outbred, and transgenic strains.

These strains are created through inbreeding, which makes all members of the group genetically identical. This is ideal for conducting experiments that exclude genetic variation as a factor.

Inbred mice have several traits that make them ideal for research purposes. They are isogenic, meaning that all animals are nearly genetically identical, and approximately 98.7% of the genetic loci in the genome are homozygous.

The top 10 most popular inbred strains according to Jackson Laboratories include C3HeB/FeJ, NOD/ShiLtJ, DBA/1J, BALB/cByJ, DBA/2J, C3H/HeJ, C57BL/6J, SJL/J, FVB/NJ, and 129S1/SvImJ.

Here are some key characteristics of these strains:

BALB/c is a popular inbred strain that has been used in over 200 generations of breeding since 1920. It's known for displaying high levels of anxiety and for being relatively resistant to diet-induced atherosclerosis.

The Jackson Labs DO project is a mouse breeding program that creates genetically diverse mice for scientific research. These mice are designed for fine genetic mapping and have been used to identify genetic factors for diseases like obesity, cancer, diabetes, and alcohol use disorder.

One of the key benefits of the DO project is that it captures a large portion of the genetic diversity of the mouse genome. This makes it an invaluable resource for researchers studying genetics and disease.

The DO project uses a group of founder strains, each with its own unique characteristics. Let's take a look at some of these strains:

These strains have been used in a wide range of research applications, from studying cancer and immunology to obesity and genetic mapping.

Laboratory mice have retained many of the physical and behavioural characteristics of house mice. They've been bred in such a way that some of these characteristics now vary significantly.

Their physical characteristics can vary markedly due to the large number of strains of laboratory mice. This makes it impractical to comprehensively describe the appearance of all of them.

Despite the variation, laboratory mice can be described for two of the most commonly used strains.

Laboratory mice have retained many of the physical and behavioural characteristics of house mice.

Their appearance can vary markedly due to artificial selection, but they generally resemble house mice in many ways.

Some strains of laboratory mice have been bred to have distinct physical characteristics, such as different coat colors or sizes.

These physical variations can make it difficult to describe the appearance of all laboratory mice, as there are many strains to consider.

Despite the variations, laboratory mice still exhibit many of the same behaviors as house mice, such as social interaction and exploration.

Their behavior can be influenced by their genetic makeup, which is why different strains may exhibit different behavioral traits.

The ob/ob mouse is a mutant mouse that eats excessively and becomes profoundly obese.

It's a genetic mutation that affects the production of leptin, a hormone that signals to the brain when an animal has had enough to eat.

This mouse is a model of type II diabetes and develops high blood sugar, despite an enlargement of the pancreatic islets and increased levels of insulin.

Mutant mice like the ob/ob mouse are phenotypically indistinguishable from their unaffected littermates at birth.

They gain weight rapidly throughout their lives, reaching a weight three times that of unaffected mice.

Nude mice were first discovered in 1962, and they're quite unique in appearance, lacking body hair.

Their genetic mutation on the FOXN1 gene causes a deteriorated or absent thymus, which makes them unable to generate mature T lymphocytes.

This leads to a repressed immune system, making them valuable to research.

Nude mice can receive many different types of tissue and tumour grafts because they can't produce the immune response required for tissue rejection.

They're commonly used to test new methods of imaging and treating tumours, and they can even receive grafts from other mice or even different species.

However, researchers have found other genes or methods of repressing the immune system more efficiently, making nude mice less popular in research today.

When handling laboratory mice, it's essential to consider their well-being. Traditionally, mice have been picked up by the base of the tail, but this type of handling increases anxiety and aversive behaviour.

Handling mice using a tunnel or cupped hands is a more recommended approach. Tunnel-handled mice show a greater willingness to explore and investigate test stimuli.

In behavioural tests, tail-handled mice tend to be less responsive, whereas tunnel-handled mice exhibit robust responses to test stimuli.

Handling laboratory mice requires care and attention to detail. Traditionally, mice have been picked up by the base of the tail, but this method can increase anxiety and aversive behaviour.

Tail-handling can lead to mice showing less willingness to explore and investigate test stimuli. In contrast, mice handled using a tunnel or cupped hands are more likely to readily explore and respond to test stimuli.

Using a tunnel or cupped hands is advocated as a more humane and effective way to handle mice. This method helps to reduce stress and anxiety, making the mice more receptive to testing.

In laboratory mice, injections are typically administered through subcutaneous, intraperitoneal, and intravenous routes. Intramuscular administration is not recommended due to their small muscle mass.

For subcutaneous injections, the recommended site is the dorsum, between the scapula. A 25-26 gauge needle is suitable for this route, with a maximum injected volume of 2-3 ml at a single site.

Intraperitoneal injections are best given in the left lower quadrant, using a 25-27 gauge needle, with a maximum volume of 2-3 ml.

Intravenous injections require a 27-28 gauge needle and can only be 0.2 ml at a time, typically administered in the lateral tail vein. To facilitate this, mice can be warmed under heat lamps to vasodilate the vessels.

Here are the recommended injection sites for each route:

Anaesthesia is a crucial aspect of handling mice, and understanding the options available is essential for their well-being. A common regimen for general anesthesia in house mice is ketamine plus xylazine, injected intraperitoneally.

The dosage for ketamine is 100 mg per kg body weight, while xylazine is administered at 5–10 mg per kg. This combination has a duration of effect of about 30 minutes.

Intraperitoneal injection is the preferred method for administering this anesthetic combination.

Laboratory mice are typically fed commercial pelleted mouse feed, which is a necessary step to avoid biological variation in their diet.

In the wild, mice are usually herbivores, consuming a wide range of fruit or grain.

Food intake for laboratory mice is approximately 15 g per 100 g of body weight per day.

Water intake for laboratory mice is about 15 ml per 100 g of body weight per day, which is a crucial aspect of their care.

Mice need a balanced diet to stay healthy, and their food intake should be monitored regularly to ensure they're getting the nutrients they need.

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Laboratory mice are genetically identical inbred strains, developed through inbreeding to minimize genetic variation and ensure consistent results. This allows researchers to conduct experiments that isolate the effects of specific genes or mutations.

Inbred strains are identified by specific letter-digit combinations, such as C57BL/6 and BALB/c. Over 400 standardized inbred strains have been developed, with the C57BL/6 strain being the most commonly used in the US, accounting for an estimated 83% of laboratory rodents supplied in 2011.

Genetic monitoring is crucial to maintaining genetically defined strains, and involves monitoring for genetic contamination and mutations. This can be done by screening biochemical and DNA markers in progenitor breeding pairs, as well as monitoring mice chosen randomly from the expansion colony.

The mouse genome is about three billion base pairs long, similar in size to the human genome, and contains an estimated 23,139 primary coding genes. The genome is easily manipulated to create models of specific diseases, making the laboratory mouse a valuable tool for researchers.

Researchers have created mice that can glow in the dark by adding the Green Fluorescent Protein (GFP) gene to their genome, allowing for the tracking of specific molecules and cells in the mice. This has revolutionized cell biology, enabling the imaging of nearly any protein at submicrometer spatial resolution and subsecond time resolution in a live cell or organism.

Laboratory mice have a relatively short lifespan, typically living between 1-2 years, which can make it challenging to study certain aspects of their behavior and well-being.

Their small size and high metabolism also mean they require specialized care and housing to ensure their physical and mental health.

In addition, laboratory mice are prone to stress and anxiety, which can affect their behavior and overall well-being, especially in high-density environments.

Despite these limitations, researchers have developed various strategies to mitigate these issues and promote the well-being of laboratory mice.

Euthanasia is a crucial aspect of laboratory animal care, and it's essential to understand the approved procedures for ending the life of animals in a humane manner. Compressed CO2 gas is one such method, which has been deemed optimal for euthanasing laboratory mice.

The American Veterinary Medical Association issued new guidelines in 2013, specifying that a flow rate of 10% to 30% volume/min is ideal for CO2 induction. This precise rate is crucial for ensuring a quick and painless death.

Limitations can be a significant barrier to achieving well-being.

Research suggests that people who experience more limitations tend to have lower levels of well-being, with a study finding that 75% of participants reported lower well-being when faced with significant limitations.

Limitations can be a result of various factors, including physical health issues. For example, chronic pain can significantly limit a person's ability to engage in activities they enjoy.

A study found that 60% of people experiencing chronic pain reported feeling limited in their daily lives.

Limitations can also be a result of mental health issues, such as depression. People with depression often report feeling overwhelmed and unable to complete tasks.

According to a study, 80% of people with depression reported feeling limited in their daily lives due to their mental health.

In some cases, limitations can be a result of societal expectations and pressures. For instance, the societal expectation to be productive can lead to burnout and feelings of being overwhelmed.

A study found that 70% of people reported feeling pressure to be productive, which can lead to feelings of burnout and being overwhelmed.

Assessing animal well-being requires a holistic approach that considers multiple factors, including nutrition, environment, and social interaction.

Adequate nutrition is essential for animal well-being, with a balanced diet providing the necessary nutrients for optimal health.

Nutritional deficiencies can lead to a range of health problems, including stunted growth, weakened immune systems, and increased susceptibility to disease.

Inadequate shelter and environmental conditions can also have a significant impact on animal well-being, with factors such as temperature, humidity, and exposure to predators playing a crucial role.

Social interaction is another critical factor, with animals that are socially isolated or deprived of interaction with their own kind often experiencing stress and anxiety.

Studies have shown that animals that are provided with adequate social interaction and enrichment activities are less likely to exhibit abnormal behaviors, such as pacing or self-mutilation.

By considering these factors and taking a proactive approach to animal well-being, we can help ensure that animals are living in a way that promotes their physical and emotional health.

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Laboratory mice are a mainstay of biomedical research, but they have several major limitations. They have been instrumental for many discoveries in the field of immunology.

Divergent microbiota among research facilities contribute to variable and sometimes contradictory experimental results obtained from genetically identical animals. This can lead to conflicting results between institutions.

A standardized microbiota has been proposed to address this issue, but feasibility concerns and the absence of an evidence-based rationale for choosing a suitable standard have hindered its implementation.

Research has shown that laboratory mice are genetically similar to humans, with a 99% similarity in DNA. This makes them an ideal model for studying human diseases.

Their small size and short lifespan, typically 1-2 years, also make them a convenient choice for researchers. They can be bred in large numbers and housed in relatively small spaces.

Mice are highly social animals and live in colonies in the wild, which is why researchers often keep them in groups in the lab. This helps to reduce stress and promote normal behavior.

Researchers have developed a wide range of techniques for studying mice, including surgical procedures and behavioral tests. These methods allow scientists to study specific traits and diseases in great detail.

The development of genetically modified mice has also been a major breakthrough in laboratory research. By introducing specific genetic mutations, researchers can study the effects of these changes on the animal's behavior and physiology.

Laboratory mice are a mainstay of biomedical research, and have been instrumental for many discoveries in the field of immunology.

The current mouse models have several major limitations, including conflicting results rooted in divergent microbiota among research facilities.

Divergent microbiota contribute to variable and sometimes contradictory experimental results obtained from genetically identical animals in different academic and commercial vivaria.

Scientific journal editors have recently called for the mandatory documentation of all factors that may influence the microbiome, including pH and treatment of drinking water, diet, and bedding and nesting material.

A standardized microbiota to be shared among institutions has been proposed to address the issue of divergent laboratory microbiota, but feasibility concerns and lack of an evidence-based rationale have hindered its implementation.

Conventional laboratory microbiota lack resilience and change in composition upon even minor disturbances, making standardization with low-resilience conventional microbiota ineffective.

Laboratory mice also have limited translational research value, primarily attributed to differences in physiology and genetics between mice and humans.

The "natural microbiota" approach, which engrafts a naturally co-evolved but pathogen-free microbiota from wild mice into laboratory mice, has been proposed to improve the translational research value of mouse models.

This approach has shown potential in increasing resilience and translational research value, making it a promising solution to the limitations of current mouse models.