Laboratory Rat Strains Research Articles

Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

SummaryLarge numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models.PaperClip

Rederivation by embryo transfer in strains of laboratory mice and rats

Rederivation enables one to decontaminate colonies of laboratory mice and rats from specific pathogens and to convert them to the SPF (specified pathogen free) state. In this study the results of the rederivation of two unique rat strains that were selected at the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, viz., tame Norway rats, rats with inherited stress-induced arterial hypertension (ISIAH), and the ICR mouse strain, are presented. The SPF state of the rederivated rats was confirmed by indicator animals, which are also called sentinel animals. An optimized rederivation model of laboratory animals is suggested in the article, which includes a series of embryotechnological methods, viz., freezing and cryopreservation of embryos, their decontamination by washing in sterile media, cultivation for 48 h, and, finally, transfer to recipients (with the SPF state). As a result of the application of this model to the ICR strain mice, it was possible to obtain 39 offspring that were born in the conditions of an SPF animal facility. It is worth mentioning that the efficacy of the procedure is in agreement with international standards, with all three lines representing a specific phenotype after undergoing all the procedures of rederivation.

Circadian Rhythm of Outside-Nest Activity in Wild (WWCPS), Albino and Pigmented Laboratory Rats

The domestication process of the laboratory rat has been going on for several hundred generations in stable environmental conditions, which may have affected their physiological and behavioural functions, including their circadian system. Rats tested in our ethological experiments were laboratory-bred wild Norway rats (WWCPS), two strains of pigmented laboratory rats (Brown Norway and Long Evans), and two strains of albino rats (Sprague-Dawley and Wistar). Rats were placed in purpose-built enclosures and their cycle of activity (time spent actively outside the nest) has been studied for one week in standard light conditions and for the next one in round-the-clock darkness. The analysis of circadian pattern of outside-nest activity revealed differences between wild, pigmented laboratory, and albino laboratory strains. During daytime, albino rats showed lower activity than pigmented rats, greater decrease in activity when the light was turned on and greater increase in activity when the light was switched off, than pigmented rats. Moreover albino rats presented higher activity during the night than wild rats. The magnitude of the change in activity between daytime and nighttime was also more pronounced in albino rats. Additionaly, they slept outside the nest more often during the night than during the day. These results can be interpreted in accordance with the proposition that intense light is an aversive stimulus for albino rats, due to lack of pigment in their iris and choroid, which reduces their ability to adapt to light. Pigmented laboratory rats were more active during lights on, not only in comparison to the albino, but also to the wild rats. Since the difference seems to be independent of light intensity, it is likely to be a result of the domestication process. Cosinor analysis revealed a high rhythmicity of circadian cycles in all groups.

What can we learn on rodent fearfulness/anxiety from the genetically heterogeneous NIH-HS rat stock?

The “National Institutes of Health” genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, WN/N, WKY/N, M520/N, F344/N, ACI/N, BN/SsN and BUF/N strains) which were readily available at that time. Hansen and Spuhler [1] developed a more naturalistic, genetically heterogeneous rat stock with the aim of optimizing the distribution of genotypic frequencies and recombination and under the hypothesis that the NIH-HS stock could yield a broad-range distribution of responses (broader than commonly used laboratory rat strains) to experimental conditions, and thus serve as a base population for selection studies. Along the last decade, in a series of studies we have phenotypically characterized the NIH-HS rat stock (a colony exists at our laboratory since 2004) for their anxiety/fearfulness profiles (using a battery of both unconditioned and conditioned tests/tasks), as well as regarding their stress-induced hormonal responses, coping style under inescapable stress and spatial learning ability. We have also compared the phenotypic profiles of NIH-HS rats with those of the low anxious RHA-I and the high anxious RLA-I rat strains. The NIH-HS rat stock is, as a population, a rather anxious type of rat, with predominantly reactive/passive coping style in unlearned and learned anxiety/fear tests, and elevated stress hormone responses (as well as enhanced “depressive” symptoms in the forced swimming test). Genetic studies currently under way have thus far revealed that the genetically heterogeneous NIH-HS rat stock constitutes a unique tool for fine mapping of QTL (for multiple behavioural and biological complex traits) to megabase resolution levels, thus enabling candidate gene identification. We give some examples of this in the present paper, while also highlighting that microarray gene expression studies reveal that HPA-axis- and prolactin-related genes (among others) in the amygdala appear to be related with (or associated to) the coping style and anxiety/fearfulness responses of NIH-HS rats.

Fundamental interstrain differences in cortical activity between Wistar and Sprague–Dawley rats during global ischemia

Four-vessel occlusion (4VO), a frequently used model of global cerebral ischemia in rats, results in a dysfunction in wide brain areas, including the cerebral cortex and hippocampus. However, there are pronounced differences in response to global ischemia between the laboratory rat strains used in these studies. In the present work, the immediate acute effects of 4VO-induced global ischemia on the spontaneous electrocorticogram (ECoG) signals were analyzed in Wistar and Sprague–Dawley rats. The ECoG was isoelectric during the 10min of global cerebral ischemia in Wistar rats and the first burst (FB) was seen 10–13min after the start of reperfusion. In Sprague–Dawley rats, the FB was detected immediately after the start of 4VO or a few seconds later. The burst suppression ratio (BSR) in Wistar rats decreased to 45% in 5min after FB, and after 25min it was approximately 40%. In Sprague–Dawley rats, the BSR was 55% immediately after the FB and it decreased steeply to reach 0% by 10min. There was also a significant difference between the two strains in the frequency composition of the ECoG pattern. The power spectral densities of the two strains differed virtually throughout the post-ischemic state. The histological results (Evans Blue, Cresyl Violet and Fluoro Jade C stainings) supplemented the electrophysiological data: the neuronal damage in the CA1 pyramids in Wistar rats was severe, whereas in the Sprague–Dawley animals it was only partial. These observations clearly demonstrate that the use of different rat strains (e.g. Wistar vs. Sprague–Dawley) can be a source of considerable variability in the results of acute experiments on global ischemia and it is important that the laboratory rats used in such experiments should be carefully chosen.

Origins of Albino and Hooded Rats: Implications from Molecular Genetic Analysis across Modern Laboratory Rat Strains

Albino and hooded (or piebald) rats are one of the most frequently used laboratory animals for the past 150 years. Despite this fact, the origin of the albino mutation as well as the genetic basis of the hooded phenotype remained unclear. Recently, the albino mutation has been identified as the Arg299His missense mutation in the Tyrosinase gene and the hooded (H) locus has been mapped to the ∼460-kb region in which only the Kit gene exists. Here, we surveyed 172 laboratory rat strains for the albino mutation and the hooded (h) mutation that we identified by positional cloning approach to investigate possible genetic roots and relationships of albino and hooded rats. All of 117 existing laboratory albino rats shared the same albino missense mutation, indicating they had only one single ancestor. Genetic fine mapping followed by de novo sequencing of BAC inserts covering the H locus revealed that an endogenous retrovirus (ERV) element was inserted into the first intron of the Kit gene where the hooded allele maps. A solitary long terminal repeat (LTR) was found at the same position to the ERV insertion in another allele of the H locus, which causes the so called Irish (hi) phenotype. The ERV and the solitary LTR insertions were completely associated with the hooded and Irish coat patterns, respectively, across all colored rat strains examined. Interestingly, all 117 albino rat strains shared the ERV insertion without any exception, which strongly suggests that the albino mutation had originally occurred in hooded rats.

Species Specific Behavioural Patterns (Digging and Swimming) and Reaction to Novel Objects in Wild Type, Wistar, Sprague-Dawley and Brown Norway Rats

BackgroundThe purpose of the present study was to analyse species-specific forms of behaviour (digging and swimming) and response to novelty in laboratory rats and their wild type counterparts at a very early stage of laboratorization. Three behavioural phenomena were taken into account: burrowing, spontaneous swimming, and neophobic behaviour.Principal FindingsWild-type rats and three strains of laboratory rats were involved in experiments: Warsaw-Wild-Captive-Pisula-Stryjek (WWCPS), Wistar, Sprague-Dawley, and Brown Norway rats were compared in spontaneous swimming test, while WWCPS and Wistar rats were studied in burrowing and neophobia experiments. Wild rats were found to be faster at building tunnels than Wistar rats and at constructing more complex burrow systems. The experiment on neophobia showed that Wistar rats exhibited less neophobic responses and were more often trapped. WWCPS rats showed highly neophobic behaviour and were rarely trapped in this experiment. The experiment on swimming showed that WWCPS rats showed more complex water tank related activity than their laboratory counterparts. They swam and explored under surface environment.ConclusionsThe three experiments showed profound behavioural differences in quasi-natural forms of behaviour between wild type rats (WWCPS) and three laboratory strains frequently used in behavioural studies.

Lymphocyte phenotypes in wild-caught rats suggest potential mechanisms underlying increased immune sensitivity in post-industrial environments

The immune systems of wild rats and of laboratory rats can been utilized as models of the human immune system in pre-industrial and post-industrial societies, respectively. In this study, lymphocyte phenotypes in wild rats were broadly characterized, and the results were compared to those obtained by us and by others using cells derived from various strains of laboratory rats. Although not expected, the production of regulatory T cells was not apparently different in wild rats compared to laboratory rats. On the other hand, differences in expression of markers involved in complement regulation, adhesion, signaling and maturation suggest increased complement regulation and decreased sensitivity in wild-caught rats compared to laboratory rats, and point toward complex differences between the maturation of T cells. The results potentially lend insight into the pathogenesis of post-industrial epidemics of allergy and autoimmune disease.

Favoured genetic background for testing anxiolytics in the fear-potentiated and light-enhanced startle paradigms in the rat

The fear-potentiated startle (FPS) and the light-enhanced startle (LES) paradigms are rodent tests of fear and anxiety, which combine face validity with predictive validity for clinically effective anxiolytic drugs. However, systematic strain comparisons aimed at identifying a rat strain that shows robust and reliable fear and anxiety responses in both models are missing. Here, we investigated four commonly used laboratory rat strains: Wistar, Sprague Dawley, Long-Evans and F344. Following strong cued fear conditioning training [60 conditioned stimulus–unconditioned stimulus (CS–US) pairings], all strains except Wistar exhibited significant FPS responses. F344 rats showed the strongest FPS response. Following milder cued fear conditioning protocols, designed to reduce the underlying component of contextual fear conditioning (by context pre-exposure or less CS–US pairings), also Wistar rats were able to show significant FPS, albeit still to a lesser extent than F344 rats tested under identical conditions. When tested in the LES protocol (light intensity ∼1500 lx), all strains except Long-Evans displayed significant light-enhanced startle responses. F344 and Wistar showed the strongest LES responses, which were of similar magnitude. The most sensitive strain in both paradigms, F344, was chosen for further pharmacological validation. The clinically active anxiolytic alprazolam (0.3, 1, 3 mg/kg p.o.) dose-dependently reduced both fear-like responses in the FPS paradigm and anxiety-like responses in the LES paradigm at non-myorelaxant dosages. We propose that the F344 rat strain is particularly suited for the predictability assessment of novel anxiolytic drugs in both startle paradigms.

Genetic Quality Control of the Rat Strains at the National Bio Resource Project-Rat

Abstract The National Bio Resource Project-Rat (NBRP-Rat) comprises the largest bank of laboratory rat ( Rattus norvegicus ) strains in the world. Its main focus is to develop infrastructure that will facilitate the systematic collection, preservation, and provision of rat strains. As of the end of September, 2010, more than 600 strains have been collected and preserved. Among them, 180 are maintained as living animal stocks. It is necessary to carry out a fast and reliable genetic diagnosis of mutations that each animal possesses to breed it effectively. In addition, a genetic monitoring system is needed to ensure its genetic quality. Here, we show the genetic control system of the NBRP-Rat in which a systematic set of genetic diagnoses and genetic monitoring is established. Genetic monitoring is performed by using 20 polymorphic markers. Monitoring is carried out when a living animal stock is re-established by using cryopreserved embryos or sperm or when a rat strain is first introduced to the NBRP-Rat by a depositor. Additional monitoring is then carried out on each strain every two years and each resulting genetic profile is compared with the original profile. Genetic diagnosis is performed largely by employing the Amp-FTA method. Protocols which detail how to perform a genetic diagnosis of 11 transgenes and 24 mutations have been made. Among the mutations, nine can be detected by simple gel electrophoresis of the PCR products, 11 by restriction enzyme treatment of the PCR products, and four by direct PCR product sequencing. As of the end of March, 2010, a total of 288 genetic profiles from 154 strains had been obtained and 16,812 samples had been subjected to genetic diagnosis. Furthermore, we reported on identifying a coat color mutation and a hairless mutation that is harbored by the mutant strains which are preserved at the NBRP-Rat. Using this genetic control system, the NBRP-Rat can guarantee the genetic quality of its rat strains. These rat strains are excellent model systems for biomedical research.

Superovulatory Response, Oocyte Spontaneous Activation, and Embryo Development in WMN/Nrs Inbred Rats

WMN/Nrs inbred rats have been widely used in radiation biology for years. However, their reproductive profile has never been examined. We examined various reproductive characteristics of WMN/Nrs inbred rats such as superovulatory response, oocytes spontaneous activation (OSA), and embryo development in vitro and in vivo. Superovulation was induced in 3- to 9-week-old females by injection of 150 IU/kg PMSG and 150 IU/Kg hCG by 48 h apart. Only 8- and 9-week-old animals superovulated averaging 31.4 and 43.9 oocytes, respectively, and superovulation did not depend on estrous cycle. Animals 3-7 weeks of age did not superovulate. Because Wistar strains have been known to show a high incidence of OSA, factors expected to affect OSA in WMN/Nrs, including the time interval of various steps from euthanasia to oocyte recovery, incubation media, estrous cycle, and anesthetic treatments, were examined. The time from animal euthanasia to oviduct excision was the only factor shown to affect OSA. We also compared in vitro and in vivo embryo developmental competence between embryos obtained by natural ovulation and superovulation. Although percent in vitro development of 2-cell embryos to blastocysts was similar for embryos obtained by natural ovulation (63.7%) and superovulation (69.7%), fetus development after oviductal transfer of 2-cell embryos was significantly lower in embryos obtained by superovulation than in those obtained by natural ovulation (60.2% vs. 87.5%, P=0.02). Our results provide important normative data regarding future applications of rat assisted reproductive technologies (ARTs) such as in vitro fertilization and cryopreservation in WMN/Nrs strain and may be applicable to other strains of laboratory rats.

Spontaneous Hibernomas in Sprague-Dawley Rats

Hibernomas are rare neoplasms originating in brown adipose tissue of humans and other animal species, including laboratory animals. Background incidence values for these tumors in all common strains of laboratory rats are generally accepted as being <0.1%. Between April 2000 and April 2007, however, sixty-two hibernomas (an overall prevalence of 3.52%) were observed in a total of 1760 Sprague-Dawley rats assigned to three carcinogenesis bioassays at two separate research laboratories. All rats were obtained from Charles River's breeding facilities in either Portage, Michigan, or Raleigh, North Carolina. Tumors (twenty-nine benign and thirty-three malignant) were randomly distributed among test article-treated and control groups and were considered to be spontaneous. Most tumors originated in the thoracic cavity, and they were usually described as soft, mottled to tan masses with nodular to lobulated profiles. Immunohistochemical procedures for uncoupling protein 1 (UCP1) confirmed brown adipose tissue as the site of origin rather than white fat. The marked increase in hibernomas in our studies suggests that greater numbers of spontaneous hibernomas may be sporadically encountered in future carcinogenesis studies with Sprague-Dawley rats. The increased potential for hibernomas to arise as spontaneous neoplasms has important implications in studies involving peroxisome proliferators-activated receptor (PPAR) drugs, lipophilic environmental chemicals (e.g., polychlorinated biphenyls), and other molecules or physiologic processes (e.g., beta-adrenergic stimulation) that may target brown fat adipocytes.

Basic indices of spleen immune activity in natural populations of Norway rats (Rattus norvegicus berkenhout, 1769) in Serbia

Basic parameters of spleen immune activity (spleen weight, histomorphology of splenic compartments, and mitogen-induced splenocyte proliferative capacity in vitro) were evaluated in adult individuals of wild Norway rats from urban habitats and compared to the same data obtained in laboratory rat strains. A wider range of relative spleen mass and differential histomorphological characteristics, together with differences in the level and pattern of responsiveness of splenocytes to exogenous stimulation, were noted in spleens of wild Norway rats. Evidence of both enhanced and low-level immune-relevant spleen activity in wild rats demonstrates the complexity of changes in spleen immune activity in rats from natural populations.

Effect of Aging on Brain-Derived Neurotrophic Factor, proBDNF, and Their Receptors in the Hippocampus of Lou/C Rats

The interest in understanding healthy aging has prompted scientist to look for animal models presenting this feature. Lou/C rats, an inbred strain of Wistar origin, is an animal model of successful aging with a longer lifespan and preserved memory capacities than most laboratory rat strains. In an attempt to shed light on this remarkable aging feature, we investigated the hippocampal patterns (mRNA and proteins) of some protective and plasticity-related molecules, i.e., brain-derived neurotrophic factor (BDNF), its precursor proBDNF, and its receptors (i.e., TrkB.FL, TrkB.T1, TrkB.T2, and p75). Using different experimental approaches, we compared these characteristics in young and aged Lou/C versus matched Wistar rats (the most appropriate controls). Data showed that young and aged Lou/C rats had higher amounts of BDNF and proBDNF content than Wistar rats. In contrast, proBDNF content was reduced in aged Lou/C rats and increased in aged Wistar rats. With aging, Lou/C rats showed a weaker decrease in TrkB.FL receptors than Wistar rats and no changes in TrkB.T1 receptors, which, contrarily, were increased in aged Wistar rats. Overall, these observations could account for the preserved cognitive performances and memory-dependent mechanisms, such as the unaltered long-term potentiation (LTP), throughout the lifespan recently reported in the Lou/C strain. Data suggest that boosting the expression or activity of these endogenous protective systems may be a promising alternative for combating some age-related cognitive declines. Therefore, Lou/C rats represent an interesting model of healthy aging for studying plasticity-related processes that evolve from youthfulness to aging.

SNP and haplotype mapping for genetic analysis in the rat

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

Reply to: Schreuder

reply: In aging male Wistar rats, renal injury develops spontaneously ([2][1]). It is gratifying that Dr. Schreuder is intrigued by our recent finding of a protective effect of early postnatal protein restriction (i.e., during lactation) on the spontaneous development of renal injury in male Wistar

Susceptibility to the anticoagulants bromadiolone and coumatetralyl in wild Norway rats ( Rattus norvegicus ) from the UK and Germany*

A new blood clotting response test was used to determine the susceptibility, to coumatetralyl and bromadiolone, of laboratory strains of Norway rat from Germany and the UK (Hampshire), and wild rats trapped on farms in Wales (UK) and Westphalia (Germany). Resistance factors were calculated in relation to the CD strain of Norway rat. An outbred strain of wild rats, raised from rats trapped in Germany, was found to be more susceptible to coumatetralyl by a factor of 0.5 – 0.6 compared to the CD strain. Homozygous and heterozygous animals of a strain of resistant rats from Westphalia were cross-resistant to coumatetralyl and bromadiolone, with a higher resistance factor for bromadiolone than that found in both UK strains. Our results show that the degree of altered susceptibility and resistance varies between strains of wild rat and between resistance foci. Some wild rat strains may be more susceptible than laboratory rat strains. Even in a well-established resistance area, it may be difficult to find infestations with resistance high enough to suspect control problems with bromadiolone, even after decades of use of this compound.

Strain and locomotor speed affect over-ground locomotion in intact rats

A variety of animal models for neurological disease and injury exist and locomotor performance is an important outcome parameter in studies employing these models. The CatWalk, an automated quantitative gait analysis method is a method to study over-ground locomotor performance in large groups of animals. In the present study, we used the CatWalk which allowed us to investigate strain differences in over-ground locomotion in three commonly used strains of laboratory rat (i.e. Lewis, Wistar and Sprague–Dawley rats) based on objective data-analysis in a large number of animals. The present results revealed marked strain differences on the static paw parameters; base-of-support, and the relative paw position. Furthermore, strain differences were noted on the static parameter stride length and the dynamic parameters stance-, swing- and stepcycle duration, which are due logically to morphological differences between strains. The parameters related to coordination did not reveal any differences between the strains. Furthermore, the swing duration and the cruciate and alternate patterns i.e. regular step patterns Ca (“cruciate” pattern type a) and Ab (“alternate” pattern type b) were shown to be differentially affected by the locomotor speed. We conclude that differences in gait traits exist between the three laboratory rat strains investigated and several of the examined gait parameters showed strain dependent interdependency with locomotor speed.

Genetic strain differences in platelet aggregation and thrombus formation of laboratory rats

Rats are employed to investigate the role of platelets in thrombus formation under flow conditions in vivo and to evaluate the pre-clinical potential of antiplatelet drugs. While Wistar and Sprague-Dawley (SD) strains are commonly used in thrombosis models, a number of rat strains have been established. Each strain possesses genetically unique characteristics such as hypertension, hyperglycemia or hyperlipidemia. The appropriate selection of a strain might have advantages for physiological and pharmacological studies. Comparative investigation of platelet aggregation among laboratory strains of rats is useful for the development of thrombosis models. In the present study, platelet aggregation response in eight laboratory rat strains, ACI, Brown Norway (BN), Donryu, Fischer 344 (F344), LEW, SD, Wistar and WKAH, were compared. Considerable strain differences were observed in ADP-, collagen- and TRAP-induced platelet aggregation. SD and BN are high-platelet-aggregation strains, while F344 and ACI are low-response strains. In the arteriovenous shunt thrombosis model, SD formed larger thrombi than F344 and Wistar rats. In the FeCl(3)-induced thrombosis model with the carotid artery, the time to occlusion of SD was significantly shorter than of F344 and ACI rats. F344 and ACI rats had significantly increased bleeding times compared with SD rat. The present study demonstrates that there are considerable strain differences in platelet aggregation among laboratory rats, which reflect thrombus formation.

Functional Polymorphisms of the Lss and Fdft1 Genes in Laboratory Rats

We previously identified mutant alleles of the lanosterol synthase (Lss) and farnesyl diphosphate farnesyl transferase 1 (Fdft1) genes, which function in the cholesterol biosynthesis pathway, as determinants for hereditary cataracts in the SCR rat strain. Lss(S) and Fdft1(S) were established as hypomorphic alleles with missense nucleotide substitutions, while Lss(l) is a null allele with nucleotide deletion/insertion mutations. Here we report a more detailed characterization of the rat Lss and Fdft1 genes. Screening of various laboratory rat strains revealed that the hypomorphic Lss(S) and Fdft1(S) alleles are not specific to the SCR strain, but are widely prevalent in other laboratory rat strains. Meanwhile, Lss(l) was not found in any rat strains examined. It was also found that functional inter-strain polymorphisms are present in the Lss upstream regulatory region. The BN strain had a higher potential for expression of Lss transcripts than ACI and SCR under conditions where cholesterol synthesis is necessary. SCR was less efficient than BN and ACI in suppressing Lss transcription in circumstances when cholesterol synthesis should be halted. These findings not only imply that there is a genetic polymorphism for cholesterol homeostasis in laboratory rats, but also point to the possibility that rat strains with different Lss alleles exhibit different responses to measures intervening in cholesterol metabolism.