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Laboratory rat

The laboratory rat, a domesticated strain of the Norway rat (Rattus norvegicus), is a foundational model organism in biomedical research, valued for its physiological and genetic similarities to humans, rapid reproductive cycle, and adaptability to laboratory conditions.^[1] Originating from wild populations in northern China around 620,000–644,000 years ago, the species spread globally, often via shipping routes, before being selectively bred for scientific purposes starting in the mid-19th century.^[1] The first documented use in experimentation occurred in 1856 in France, where researchers studied the effects of adrenalectomy, marking the beginning of over 150 years of its application in fields such as physiology, toxicology, neuroscience, and oncology.^[2] Today, laboratory rats constitute approximately 7.5% of animals used for scientific purposes in the European Union as of 2022 and are preferred for studies involving complex behaviors, surgical interventions, and disease modeling due to their size (typically 250–500 grams as adults), short gestation period of 21–23 days, and litter sizes of 6–12 pups.^[1]^[3] Key strains have been developed to suit specific research needs, enhancing the precision of experiments. The Wistar rat, an outbred albino strain established in 1906 at the Wistar Institute, is widely used in infectious disease and general surgical studies for its docile temperament and well-documented physiology.^[4] The Sprague Dawley rat, another outbred albino line introduced in 1925, excels in behavioral, endocrine, and cancer research owing to its rapid growth and low tumor incidence in controls.^[4] In contrast, the inbred Brown Norway rat, developed in 1958, features pigmented fur and is favored for immunological and cardiovascular studies due to its genetic uniformity and hypertension-prone traits.^[1] These strains, along with genetically modified variants, benefit from a 90% genetic homology with humans and the availability of extensive genomic resources, including the full rat genome sequence published in 2004, which has accelerated insights into human diseases like diabetes, hypertension, and neurological disorders.^[2] Despite these advantages, ethical considerations govern their use, emphasizing the 3Rs principle (replacement, reduction, refinement) to minimize animal welfare impacts in research protocols.^[5]

Biology

Taxonomy and origins

The laboratory rat is classified as Rattus norvegicus domestica, a domesticated subspecies derived from the wild Norway rat (Rattus norvegicus), belonging to the family Muridae within the order Rodentia.^[6] This taxonomy places it in the kingdom Animalia, phylum Chordata, class Mammalia, with the species Rattus norvegicus first formally named in 1769 by John Berkenhout based on specimens from Britain.^[7] The nomenclature reflects its close relation to the wild form, though the "norvegicus" epithet is a historical misnomer, as the species did not originate in Norway.^[1] The species R. norvegicus originated in northern China and adjacent regions during the Pleistocene epoch, where it likely emerged from wild populations in the temperate grasslands of the region, with the genus Rattus having deeper roots in southeast Asia dating to the early Pleistocene; the earliest archaeological evidence dates to the Neolithic period approximately 7,000–9,000 years ago.^[6] From there, it spread globally via human trade routes, particularly on ships during the 18th century, reaching Europe by the mid-1700s and North America shortly after, facilitated by its commensal adaptation to human environments.^[6] Genetic analyses indicate divergence from sibling species like the Himalayan field rat (Rattus nitidus) approximately 620,000–644,000 years ago, with domestication processes beginning in Asia as early as the 15th century in China for fancy rats, with further development in Japan during the 17th century, leading to selective breeding that produced the laboratory form.^[1]^[8] Domestication has resulted in notable genetic divergence from wild ancestors, characterized by selection for traits that enhance suitability for captivity, including reduced aggression toward conspecifics and other species.^[1] A key genetic marker is the Arg299His missense mutation in the Tyrosinase (Tyr) gene, responsible for albinism prevalent in many laboratory strains such as Wistar and Sprague-Dawley, which arose from a single origin in early domesticated stocks and is absent in wild R. norvegicus.^[9] These changes reflect broader genomic signatures of selection on metabolism, locomotion, and stress response, with laboratory rats exhibiting limited genetic variation compared to diverse wild populations.^[7] The subspecies R. norvegicus domestica gained formal recognition alongside the development of dedicated breeding lines in the 19th and early 20th centuries, with initial European fancy rat programs in the 1820s and the establishment of the Wistar Institute strain in 1906 marking key milestones in nomenclature standardization for laboratory use.^[6] By the mid-20th century, the term "domestica" was widely adopted in scientific literature to distinguish captive-bred lines, and genomic studies through 2024 have revealed multiple domestication events across Asia and Europe, with laboratory rat strains primarily deriving from 19th-century European fancy rat lineages that trace back to earlier Asian origins.^[7]

Physical and physiological characteristics

Laboratory rats (Rattus norvegicus) are medium-sized rodents, with adult body lengths typically ranging from 15 to 25 cm excluding the tail, and weights between 200 and 500 grams depending on age, sex, and strain. The tail adds another 15 to 25 cm to the total length. Sexual dimorphism is pronounced, with males generally 50% larger than females in body weight and size, reflecting differences in growth rates and hormonal influences.^[10]^[11] In terms of sensory systems, laboratory rats exhibit dichromatic vision with poor color discrimination, relying primarily on rod cells for low-light detection rather than cones for color. Their olfaction is highly acute, supported by a large olfactory bulb and over 1,000 olfactory receptor genes, enabling precise odor detection and discrimination essential for foraging and social cues. Hearing is also well-developed, with sensitivity to frequencies up to 70 kHz, far exceeding human range, though they are less responsive to very high frequencies compared to mice. Physiologically, resting heart rates average 300-400 beats per minute, and blood volume is approximately 64 ml/kg body weight, facilitating rapid cardiovascular responses in experimental settings.^[12]^[13]^[14] Laboratory rats have a captive lifespan of 2-3 years, reaching sexual maturity around 6-8 weeks of age. Their reproductive physiology includes a short estrous cycle of 4-5 days, with estrus lasting about 12-24 hours, allowing for frequent breeding. Litters average 6-12 pups (typically around 10), born after a gestation period of 21-23 days, with neonates weighing 4-6 grams at birth. These traits contribute to high reproductive efficiency in colony maintenance.^[15]^[16]^[17] Compared to mice, laboratory rats display a faster metabolism relative to humans but slower than mice, with basal metabolic rates scaling allometrically with body size. Their renal function closely mirrors human glomerular filtration and tubular reabsorption processes, while cardiovascular physiology, including blood pressure regulation and heart responses, provides relevant analogies for studying human diseases, though with species-specific differences in force-frequency relationships.^[18]^[19]

Behavioral traits

Laboratory rats exhibit complex social structures characterized by dominance hierarchies, which form through agonistic interactions such as biting, chasing, and submissive postures.^[20] In group settings, males typically establish stable linear hierarchies, with dominant individuals gaining priority access to resources like food and water, while subordinates experience higher stress levels evidenced by elevated corticosterone and reduced body weight.^[20] Females show weaker or less consistent hierarchies, often lacking clear dominance unless competing directly for resources.^[20] These rats display a strong preference for group housing, as solitary confinement can lead to increased anxiety and disrupted social behaviors compared to communal living in enriched environments.^[21] Maternal care in laboratory rats involves instinctive behaviors such as retrieving pups to the nest, licking and grooming, nest building, and nursing in a kyphotic posture, with these actions peaking in the first postpartum week and declining as offspring mature.^[22] Variations in maternal licking and grooming occur naturally, correlating with differences in pup sensitization latency and estrogen-inducible oxytocin receptor expression in brain regions like the medial preoptic area.^[23] Activity patterns in laboratory rats are primarily nocturnal or crepuscular, with peak locomotion and exploratory foraging occurring during the dark phase, reflecting their wild ancestry but adapted to controlled light cycles in captivity.^[1] They engage in investigative foraging, sniffing and manipulating objects to assess novelty, though domestication has notably reduced neophobia—the innate aversion to unfamiliar foods or environments—compared to wild rats, allowing quicker adaptation to novel stimuli in lab settings.^[24] This behavioral shift, evident in multi-strain comparisons, stems from selective breeding and stable food availability, enabling laboratory rats to sample new items more readily than their cautious wild counterparts.^[24] Laboratory rats demonstrate robust learning and cognitive abilities, particularly in spatial tasks like maze navigation, where they form cognitive maps to efficiently locate rewards through trial-and-error exploration.^[25] They readily acquire conditioned responses, such as associating cues with rewards or aversive stimuli in fear conditioning paradigms, showing rapid extinction when contingencies change.^[25] Stress indicators include ultrasonic vocalizations (USVs), with 22-kHz calls emitted during anxiety-provoking situations like foot-shock anticipation, serving as a measurable readout of emotional states modulated by anxiolytics.^[26] These vocalizations link to physiological stress responses, such as elevated corticosterone, providing a non-invasive proxy for affective processing in cognitive experiments.^[26] Captivity influences laboratory rat behavior by diminishing territoriality relative to wild populations, where rats defend burrows and foraging areas aggressively; in controlled environments, this aggression wanes due to reduced resource competition and increased tameness from domestication.^[27] However, barren housing can provoke stereotypic behaviors, such as repetitive bar-biting or route-tracing, arising from thwarted natural motivations like exploration and social interaction, potentially signaling chronic stress from environmental restriction.^[28]

History

Domestication from wild populations

The brown rat (Rattus norvegicus), the progenitor of the laboratory rat, originated in northern China and spread to Europe as a commensal species in human settlements during the 18th century, arriving via trade routes from Asia through Russia.^[29] These rats thrived in urban environments, exploiting food resources from human activities, but were primarily viewed as pests due to their role in spreading diseases and damaging property.^[29] Initial human interactions involved capturing wild rats for pest control efforts, with early studies focusing on their behavior and physiology to improve eradication methods, marking the transition from vermin to subjects of scientific interest.^[29] In the 19th century, the use of rats expanded into phrenology and early psychological research, where they served as models for studying brain function and behavior.^[30] This period saw informal selection pressures favoring tameness, as aggressive wild traits hindered experimental utility, laying the groundwork for domestication through repeated capture and breeding of calmer specimens.^[29] A key milestone occurred in 1856 when French physiologist Jean-Baptiste Philipeaux conducted the first documented surgical experiment on albino rats, removing their adrenal glands to study physiological responses; this highlighted the emergence of the albino mutation, likely a spontaneous genetic variant in captive populations that was noted for its visibility in research.^[31] By the early 1900s, wild rats were imported to the United States for comparative studies with emerging domestic lines, allowing researchers at institutions like the University of Chicago to examine behavioral and genetic differences between feral and captive populations.^[32] The domestication process imposed genetic bottlenecks on early laboratory rat lines, as small founder populations from wild captures led to reduced genetic diversity and inbreeding depression, manifesting in decreased variability and heightened susceptibility to certain disorders by the 1920s.^[29] These effects underscored the rapid evolutionary changes driven by human selection, distinguishing domestic rats from their wild Norway rat ancestors while highlighting the need for careful management to preserve research utility.^[29]

Development of laboratory breeding programs

The development of laboratory breeding programs for rats began in the early 20th century with efforts to create standardized colonies that ensured genetic and physiological uniformity for reliable scientific experimentation. In 1906, the Wistar Institute in Philadelphia established the first such colony under the direction of Henry Herbert Donaldson and Helen Dean King, using albino mutants derived from wild-caught Norway rats (Rattus norvegicus) to produce the Wistar rat strain, an outbred stock selected for docility and ease of handling.^[1] This initiative addressed the variability in wild or pet rats previously used in research, marking a shift toward controlled domestication specifically for biomedical purposes.^[33] Breeding techniques emphasized closed colonies to minimize genetic drift and external contamination, with the Wistar Institute designing specialized cages, diets, and facilities to support large-scale production.^[1] By the 1910s, strategies differentiated between outbreeding—maintaining genetic diversity through rotational mating to mimic natural populations—and inbreeding via brother-sister pairings to generate homozygous lines for genetic studies, laying the groundwork for future strain development.^[34] Distribution efforts accelerated in the 1920s and 1930s, with the Wistar Institute supplying rats to other institutions starting in 1912, and the U.S. Public Health Service (predecessor to the National Institutes of Health) establishing breeding colonies to meet demands for standardized animals in federally sponsored research and testing.^[1]^[35] Post-World War II, these programs expanded globally to support growing research needs, with the UK Medical Research Council founding the Laboratory Animals Bureau in 1947 to develop national production standards and distribute pathogen-tested rodents across Europe.^[36] By the 1950s, international standardization initiatives, including those coordinated by bodies like the International Committee on Laboratory Animals, promoted uniform breeding protocols to facilitate cross-institutional reproducibility.^[37] Early challenges included recurrent disease outbreaks, such as salmonellosis epidemics in the 1920s that devastated colonies due to bacterial transmission from contaminated feed or wild rodents, prompting the adoption of quarantine measures and the establishment of pathogen-free facilities by the mid-20th century.^[38]^[39] These efforts transformed the laboratory rat into a cornerstone model organism, with millions bred annually under rigorous controls.^[29]

Research Applications

Historical uses in experimentation

The laboratory rat emerged as a pivotal model organism in early 20th-century biomedical research, enabling foundational discoveries in nutrition, physiology, behavior, and toxicology due to its physiological similarities to humans, ease of breeding, and short generation time. Pioneering nutrition studies in the 1900s highlighted the rat's utility in elucidating essential dietary components. In 1912, Frederick Gowland Hopkins conducted feeding experiments with young rats maintained on artificial diets composed of purified casein, starch, sugar, lard, and mineral salts; these rats exhibited stunted growth and weight loss, but the addition of small quantities of milk—providing unknown "accessory factors"—restored normal growth rates, laying the groundwork for the discovery of vitamins such as vitamin A and B1. This work earned Hopkins the 1929 Nobel Prize in Physiology or Medicine and established rats as a standard for nutritional deficiency studies.^[40] In physiology and endocrinology, rats contributed to breakthroughs in metabolic research, including the isolation of insulin. Around 1921, Frederick Banting, Charles Best, and colleagues utilized dogs to test pancreatic extracts for antidiabetic effects, with rabbits used for standardization, confirming insulin's role in regulating blood glucose and advancing treatments for diabetes mellitus.^[41] Behavioral psychology further solidified the rat's role through controlled learning experiments. Edward Thorndike's 1898 puzzle box studies with animals demonstrated trial-and-error learning, influencing subsequent rat-based research; by the 1930s, B.F. Skinner refined this into operant conditioning paradigms using rats in enclosed chambers (later called Skinner boxes), where lever-pressing behaviors were shaped through reinforcement schedules, revealing principles of voluntary behavior modification that underpin modern behavioral analysis.^[42]^[43] Toxicology and pharmacology saw the rat's adoption for safety assessments following pivotal events. The 1937 Elixir Sulfanilamide disaster, in which diethylene glycol as a solvent caused over 100 deaths due to untested toxicity, prompted the U.S. Food, Drug, and Cosmetic Act of 1938, mandating preclinical animal safety testing; this spurred the widespread use of rats in median lethal dose (LD50) assays to quantify drug toxicity thresholds, standardizing pharmacological evaluations.^[44] In cancer research, Takaoki Sasaki and Tomizo Yoshida's 1932 experiments induced the first artificial liver cancer in rats by feeding o-aminoazotoluene, providing early evidence of chemical carcinogenesis in internal organs and influencing oncological methodologies.^[45] During World War II, animal models, such as mice, supported urgent medical advancements, particularly in wound healing and infection control. Researchers employed animal models to evaluate antibiotics like penicillin and topical agents for accelerating tissue repair in contaminated wounds, simulating battlefield injuries; these studies demonstrated enhanced granulation and epithelialization rates, informing clinical protocols that reduced infection mortality among soldiers. Such applications underscored the rat's versatility in high-stakes, time-sensitive experimentation, cementing its status as an indispensable tool for translational research.

Contemporary fields of study

In the 21st century, laboratory rats have remained central to advancing biomedical research, particularly in modeling complex human conditions through sophisticated genetic and physiological manipulations. Post-2000 studies have leveraged their neuroanatomical similarities to humans for investigating neurological disorders, while their metabolic pathways facilitate pharmacological evaluations. Recent innovations, such as optogenetics and humanized strains, have enhanced precision in these applications, enabling targeted interventions that bridge basic science and therapeutic development.^[46] In neuroscience, laboratory rats serve as key models for addiction and pain research, allowing dissection of neural circuits underlying compulsive behaviors and sensory processing. For addiction, outbred rat strains exhibit divergent cocaine-seeking behaviors, enabling genomic analyses to identify vulnerability factors like striatal gene expression patterns that predict addiction liability.^[47] In pain studies, rats with induced inflammatory or neuropathic conditions reveal how prelimbic cortex ensembles encode spontaneous pain signals, informing non-opioid analgesic strategies.^[48] Optogenetic techniques have further refined these models; for instance, 2024 investigations used light-activated opsins in rat subthalamic nucleus to modulate deep brain stimulation circuits, restoring motor function in Parkinson's disease models by altering BOLD signals in basal ganglia regions.^[49] Pharmacological research utilizes laboratory rats to assess drug metabolism and efficacy, capitalizing on their cytochrome P450 enzyme systems that parallel human Phase I reactions. Humanized CYP1A2 rat models, engineered via CRISPR/Cas9, accurately predict clearance of substrates like caffeine and theophylline, outperforming traditional rodent assays for translating pharmacokinetic data to clinical dosing.^[50] In immuno-oncology, emerging humanized rat platforms—featuring engrafted human immune components—support evaluation of checkpoint inhibitors against patient-derived xenografts, with market projections indicating their growing role in preclinical immunotherapy testing by 2025.^[51] Toxicology employs laboratory rats to evaluate endocrine disruptors and reproductive hazards, adhering to standardized protocols that detect subtle hormonal perturbations. Chlorobenzenes, as model disruptors, alter arginine vasopressin and oxytocin signaling in exposed rats, leading to impaired social behaviors and highlighting neuroendocrinal risks.^[52] For reproductive toxicity, OECD Test Guideline 421 uses rat cohorts to screen chemicals for fertility and developmental effects, incorporating endpoints like anogenital distance and estrous cyclicity to identify endocrine-active substances since its 2015 update.^[53] Recent trends reflect a regulatory push toward alternatives, yet laboratory rats retain validation roles in cardiovascular research amid the 2025 FDA roadmap to reduce animal testing via AI and in vitro methods. The FDA's initiative prioritizes non-animal approaches for monoclonal antibodies but emphasizes rat models for confirming AI-predicted toxicities in complex systems.^[54] In hypertension studies, spontaneously hypertensive rats simulate essential hypertension, revealing how high-salt diets exacerbate vascular remodeling, thus guiding antihypertensive drug validation.^[55]

Advantages and limitations as a model organism

Laboratory rats (Rattus norvegicus) offer several advantages as model organisms in biomedical research, particularly due to their physiological and genetic similarities to humans. They share approximately 90% of their genetic material with humans, enabling the study of disease-associated genes and pathways that are highly conserved across mammalian evolution.^[2] This genetic homology, combined with nearly all human disease-related genes having rat counterparts, makes rats valuable for modeling complex human conditions.^[56] Physiologically, rats exhibit human-like features in cardiovascular, nervous, and endocrine systems, facilitating translational research.^[2] For instance, their sleep architecture shows conserved patterns with humans, including similar electroencephalographic changes during aging and consolidated sleep-wake cycles, which aids in studying sleep disorders.^[57] The larger body size of rats (typically 250-500 g) compared to mice provides practical benefits for experimental procedures. This size facilitates surgical interventions, such as implanting devices or performing neurosurgery, where the rat's brain—roughly eight to ten times larger than a mouse's—allows for higher spatial resolution in imaging techniques like fMRI and PET, and easier electrode placement.^[58] In drug response studies, rats demonstrate closer parallels to human physiology; for example, they are preferred over mice for hypertension models due to spontaneous hypertensive strains like the SHR rat, which better recapitulate human cardiovascular responses to treatments.^[59] Relative to non-human primates, rats are significantly cheaper to maintain and breed rapidly (gestation 21-23 days, litters of 6-12 pups), offering ethical and logistical advantages for high-throughput studies while reducing the need for more resource-intensive primate models.^[60] Rats also excel in behavioral research, displaying greater complexity than mice, such as enhanced social interactions (e.g., 79% interaction time vs. 22% in mice during 15-minute observations) and reduced handling stress, which improves data reliability in cognitive, affective, and addiction studies.^[58] These traits make rats particularly suitable for modeling human-like social behaviors and neurotransmitter systems, like higher striatal 5-HT6 receptor levels akin to humans.^[58] Despite these strengths, laboratory rats have notable limitations. Their maintenance costs are higher than mice due to greater food and space requirements, potentially straining budgets for large-scale genetic or screening studies.^[58] Ethical concerns arise from their extensive use, with an estimated 111.5 million mice and rats employed annually in U.S. research alone, raising questions about welfare and the moral implications of such volumes in sentient animals.^[61] Outbred rat stocks introduce variability in genetic makeup and phenotypes, which can complicate reproducibility and increase experimental noise compared to more uniform inbred strains or mice.^[62] Additionally, while advancing, genetic manipulation tools in rats lag behind those in mice, with fewer knockout lines historically available, though technologies like CRISPR/Cas are bridging this gap.^[63] Some physiological differences, such as immune and metabolic responses, limit direct translation to humans in certain diseases like cancer.^[2]

Husbandry and Welfare

Standard housing and care protocols

Laboratory rats are typically housed in solid-bottom or ventilated cages that provide adequate space for movement and social interaction, with minimum floor area recommendations varying by body weight to ensure welfare and experimental consistency. For rats weighing 100-200 g, the Guide for the Care and Use of Laboratory Animals specifies a minimum of 23 in² (148 cm²) per animal, while larger groups in standard cages often utilize at least 800 cm² total floor space to accommodate 2-5 adults depending on size.^[64] Housing facilities maintain a temperature range of 20-26°C and relative humidity of 30-70%, with a standard 12-hour light/dark cycle to mimic natural rhythms and support physiological health.^[64] Diet consists of ad libitum access to commercially prepared, nutritionally complete pelleted chow, typically containing 18-24% crude protein to meet maintenance and growth needs, provided in feeders designed to minimize waste and contamination.^[64]^[65] Clean water is available ad libitum via bottles or automatic systems. Hygiene protocols include changing bedding and cleaning cages at least weekly for static microisolator systems to control ammonia levels and prevent disease, with more frequent spot changes if soiled conditions arise.^[64]^[66] Breeding protocols emphasize pair (one male, one female) or trio (one male, two females) housing in enlarged cages providing at least 800 cm² floor space for the female and litter, with weaning occurring at approximately 21 days of age to separate pups and prevent overcrowding.^[64] New arrivals undergo a quarantine period of at least 14 days in isolated facilities, including health screening for pathogens before integration into colonies.^[67] Veterinary monitoring involves daily visual inspections by trained personnel for signs of illness, such as lethargy or weight loss, with the attending veterinarian overseeing preventive care, including vaccinations if applicable, and prompt intervention for any health issues.^[64]^[68] All practices comply with the Guide for the Care and Use of Laboratory Animals (8th edition, 2011), which serves as the primary regulatory standard in the United States, enforced through Institutional Animal Care and Use Committees (IACUCs) under the Public Health Service Policy and Animal Welfare Act; no major updates to core protocols have been issued as of 2025.^[64]

Environmental enrichment and ethical considerations

Environmental enrichment (EE) for laboratory rats involves providing stimuli that promote physical, social, cognitive, and sensory engagement to improve welfare beyond standard housing. Physical enrichment includes items such as tunnels, running wheels, and nesting materials, which encourage natural behaviors like burrowing and exercise. Social enrichment typically entails group housing of 3 to 5 rats to mimic social structures observed in wild populations, reducing isolation-related stress. Cognitive enrichment features puzzles or foraging devices that require problem-solving, enhancing mental stimulation. A 2025 review of studies on murine models highlighted that these enrichment types—particularly physical and social—significantly reduce anxiety-like behaviors and improve overall physiological responses, with enriched rats showing lower cortisol levels and enhanced exploratory activity in open-field tests.^[69]^[70] Poor housing conditions in conventional laboratory cages, characterized by limited space and minimal stimulation, have been linked to increased morbidity and mortality in rats, including higher rates of respiratory infections, obesity, and abnormal behaviors such as stereotypic bar-biting. A 2022 meta-analysis in BMC Biology analyzed over 100 studies and found that rats in standard barren cages exhibited 1.5 to 2 times higher disease incidence compared to those in enriched environments, potentially confounding research outcomes. In contrast, EE positively impacts welfare by boosting exploratory behavior and neuroplasticity; for instance, wheel access increases voluntary activity and reduces anxiety in novel environments, leading to more reliable behavioral data in experiments.^[71]^[72] Ethical considerations in laboratory rat research are guided by the 3Rs principle—Replacement, Reduction, and Refinement—introduced by Russell and Burch in 1959 and now a cornerstone of international guidelines to minimize animal suffering. Replacement seeks non-animal alternatives like in vitro models; Reduction aims to lower the number of rats used through statistical optimization; and Refinement focuses on enhancing procedures and housing to avoid or alleviate pain. Humane endpoints, predefined criteria such as 20% body weight loss, severe lethargy, or tumor burdens exceeding 10% of body weight, require intervention like euthanasia to prevent unnecessary distress, ensuring experiments terminate early when welfare thresholds are met.^[73]^[74] Recent advancements emphasize refinement and replacement to reduce rat usage. In April 2025, the U.S. Food and Drug Administration (FDA) announced a roadmap to phase out mandatory animal testing for monoclonal antibodies and other drugs, promoting AI-based computational models, organ-on-a-chip systems, and digital twins that simulate human physiology for toxicity predictions, significantly reducing the reliance on animal testing in preclinical stages. These technologies, as part of ongoing pilot studies initiated in 2025, offer higher predictive accuracy for human responses than traditional rat models in some endpoints like liver metabolism.^[54]^[75] Regulatory frameworks enforce these ethical standards. In the United States, Institutional Animal Care and Use Committees (IACUCs) provide oversight by reviewing protocols, inspecting facilities semiannually, and ensuring compliance with the Animal Welfare Act to safeguard rat welfare. In the European Union, Directive 2010/63/EU mandates the 3Rs and minimum housing standards, with 2024 updates from the European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) emphasizing validated non-animal methods. Ethical debates on rat sentience have intensified following 2024 neuroscientific evidence of their complex affective and cognitive capacities, including empathy-like behaviors, prompting calls for expanded legal recognitions of sentience in research policies to further prioritize welfare.^[76]^[77]^[78]

Stocks and Strains

Outbred stocks

Outbred stocks of laboratory rats are populations maintained through random mating to preserve genetic diversity and heterozygosity, resulting in non-isogenic animals with a limited inbreeding coefficient of less than 1% per generation.^[79]^[80] This breeding strategy contrasts with inbred lines by promoting variability in traits and responses, which better mimics the genetic heterogeneity observed in human populations and is particularly valuable for preclinical studies in toxicology, pharmacology, and general physiology where uniform genetics could mask diverse outcomes.^[81]^[82] The Wistar rat, an albino outbred stock, was developed in 1906 at the Wistar Institute in Philadelphia by researcher Henry H. Donaldson through selective breeding from wild-derived Rattus norvegicus populations.^[83]^[84] Characterized by its white fur, pink eyes, and docile temperament, this strain has become one of the most widely used in biomedical research, comprising over half of all laboratory rats globally and serving as a standard model for studies in general physiology, metabolism, and infectious diseases due to its standardized traits and ease of handling.^[84]^[34] The Sprague Dawley rat, another prominent outbred stock, originated in the 1920s when Robert W. Dawley crossed Wistar females with wild gray males or hybrids to create a larger, more robust line.^[85] This strain typically exhibits faster growth rates and greater body size compared to the Wistar, with adult males often reaching 400–600 grams versus 300–500 grams for Wistar counterparts, making it suitable for studies requiring substantial tissue samples.^[86]^[87] It is commonly employed in teratology, reproductive toxicology, and nutritional research owing to its metabolic profile and responsiveness to dietary manipulations.^[88] The Long-Evans rat, a hooded outbred stock with black pigmentation over a white base coat, was established in 1915 by researchers J.A. Long and H.H. Evans through crosses between Wistar albino females and wild gray males captured in California.^[89] The pigmentation enhances visibility during surgical procedures and supports research involving contrast-sensitive observations, while the strain's superior visual acuity—due to intact retinal pigmentation—makes it ideal for behavioral, neurological, and vision studies, including learning, aging, and sensory processing.^[90]^[91] Comparisons between Wistar and Sprague Dawley rats reveal notable differences in growth and disease susceptibility that influence their selection for specific applications. Wistar rats generally exhibit slower growth rates and lower body weights, contributing to higher survival in long-term studies, whereas Sprague Dawley rats grow more rapidly and attain larger sizes, which can accelerate experimental timelines but may increase metabolic demands.^[86]^[92] Regarding tumor susceptibility, Wistar rats display lower overall incidences of spontaneous neoplasms, particularly mammary and pituitary tumors, compared to Sprague Dawley rats, which show higher rates of these conditions in chronic carcinogenicity assays, potentially affecting interpretations of oncogenic risks.^[93]^[94]

Inbred and congenic strains

Inbred strains of laboratory rats are developed through continuous brother-sister mating for at least 20 generations, resulting in greater than 98% homozygosity across the genome and genetic uniformity among individuals.^[95]^[96] Congenic strains, in contrast, are created by backcrossing a donor strain to a recipient inbred strain for 10 or more generations while selecting for a specific genetic locus or chromosomal segment from the donor, yielding an otherwise genetically identical background with targeted allelic differences.^[97]^[98] These strains are particularly valuable for disease modeling, as their uniformity minimizes environmental and genetic variability, enabling precise studies of phenotype-genotype relationships in autoimmune, metabolic, and neurological conditions. The Lewis rat (RT1^l haplotype) originated in the 1950s from Wistar stock through inbreeding initiated by Dr. Margaret Lewis, reaching F20 by 1954.^[99] This strain's major histocompatibility complex (MHC) haplotype predisposes it to experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis characterized by T-cell-mediated demyelination and inflammation in the central nervous system.^[100] Similarly, Lewis rats are highly susceptible to adjuvant-induced arthritis, serving as a model for rheumatoid arthritis with reliable joint inflammation and autoantibody production upon immunization.^[101] The Zucker rat emerged in the early 1960s from a spontaneous autosomal recessive mutation (fa/fa) in the leptin receptor gene within an outbred colony, as first described by Lois and Theodore Zucker in 1961. Homozygous fa/fa individuals develop hyperphagia, obesity, hyperlipidemia, and insulin resistance by 4-8 weeks of age, making this strain a cornerstone for studying type 2 diabetes and associated metabolic syndrome complications like nephropathy and cardiovascular disease.^[102] The BioBreeding (BB) rat strain was identified in 1974 within an outbred Wistar colony at BioBreeding Laboratories in Ottawa, Canada, where approximately 10% of offspring spontaneously developed hyperglycemia due to autoimmune destruction of pancreatic beta cells.^[103] The diabetes-prone BB (BB-DP) subline, maintained through selective breeding, exhibits lymphopenia and insulin-dependent diabetes by 60-100 days of age, closely mimicking human type 1 diabetes and facilitating research on immune dysregulation and beta-cell autoimmunity.^[104] The Royal College of Surgeons (RCS) rat, developed before 1965 from a London colony exhibiting inherited retinal dystrophy, carries a mutation in the Mertk gene that impairs phagocytosis of photoreceptor outer segments by retinal pigment epithelium.^[105]^[106] This leads to progressive rod and cone degeneration starting at 3-4 weeks of age, culminating in near-total photoreceptor loss by 3 months, and serves as a key model for retinitis pigmentosa and evaluating retinal transplantation or gene therapies.^[107] The Shaking rat Kawasaki (SRK), an autosomal recessive mutant discovered in the late 1980s within a Wistar colony, harbors a deletion in the reelin gene causing impaired neuronal migration and lamination in the cerebellum and hippocampus.^[108] Affected rats display tremors, ataxia, and seizures from weaning, with early mortality, providing a model for epilepsy and reeler-like neurodevelopmental disorders including aberrant cortical layering and hypomyelination.^[109] A primary advantage of inbred and congenic rat strains is their highly reproducible phenotypes, which allow consistent experimental outcomes and facilitate quantitative trait locus (QTL) mapping to identify genes underlying disease susceptibility without confounding genetic heterogeneity.^[95]^[110]

Genetically modified strains

Genetically modified laboratory rats have been engineered using targeted genome editing techniques to create precise alterations for studying human diseases. Early methods included zinc-finger nucleases (ZFNs), which emerged in the 2000s and enabled the first targeted knockouts in rats by 2009, allowing specific gene disruptions for functional studies.^[111] Subsequent advancements involved transcription activator-like effector nucleases (TALENs) in the early 2010s, which improved specificity for multiplex editing in rat embryos. The breakthrough came with CRISPR-Cas9, first applied to generate rat knockouts in 2013, revolutionizing the field by simplifying the creation of heritable mutations with high efficiency.^[112] Knockout rats produced via these techniques have been pivotal in modeling infectious and neurodegenerative diseases. In 2024, humanized ACE2 knock-in rats were developed to study SARS-CoV-2 infection, permitting viral entry through human ACE2 expression in a rat physiological context.^[113] Genetically modified rats offer advantages over mice for applications such as large-scale brain imaging due to their larger size, which permits higher-resolution optical and MRI techniques in behaving animals. However, ethical concerns persist regarding off-target effects in CRISPR-edited rats, including unintended mutations that could alter behavior or physiology, necessitating rigorous validation and welfare monitoring in research protocols.^[114]

References

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