Inbred Rat Strains Research Articles

Three decades of rat genomics: approaching the finish(ed) line.

The rat, Rattus norvegicus, has provided an important model for investigation of a range of characteristics of biomedical importance. Here we survey the origins of this species, its introduction into laboratory research and the emergence of genetic and genomic methods that utilize this model organism. Genomic studies have yielded important progress and provided new insight into several biologically important traits. However, some studies have been impeded by the lack of a complete and accurate reference genome for this species. New sequencing and genome assembly methods applied to the rat have resulted in a new reference genome assembly, GRCr8, which is a near telomere-to-telomere assembly of high base level accuracy that incorporates several elements not captured in prior assemblies. As genome assembly methods continue to advance and production costs become a less significant obstacle, genome assemblies for multiple inbred rat strains are emerging. These assemblies will allow a rat pangenome assembly to be constructed which captures all the genetic variation in strains selected for their utility in research and will overcome reference bias, a limitation associated with reliance on a single reference assembly. By this means, the full utility of this model organism to genomic studies will begin to be revealed.

Difference in immune responses to Candida albicans in two inbred strains of male rats

ObjectiveTo investigate the influence of strain differences in immune response on the pathogenesis of oral candidiasis in Dark Agouti (DA) and Albino Oxford (AO) inbred strains of rats. DesignSeventy male 8-weeks old DA and AO rats were inoculated with Candida albicans to induce three different experimental models of oral candidiasis, one immunocompetent and two immunocompromised models. The animals were sacrificed after 16 days from the beginning of the experiment followed by collecting the samples of the tongue dorsum and blood for histopathological (PAS and H&E staining), immunohistochemical, qRT-PCR, and oxidative stress analyses. ResultsHistopathological and immunohistochemical analyses revealed lower levels of epithelial colonization, epithelial damage, and inflammatory infiltration in DA compared to AO strain of rats. DA rats had fewer CD45, CD68, and CD3 positive cells but more HIS 48 positive cells than AO rats. The expressions of IL-1β, TNFα, IFN-γ, IL-10 and TGF-β1 were consistently higher in DA strain across all experimental models. However, the expressions of IL-4 and IL-17 differed inconsistently between DA and AO strain in various experimental models. Strain differences were observed in levels of prooxidative hydrogen peroxide and lipid peroxidation, with higher levels presented in AO rats compared to DA rats, while antioxidative parameters presented little yet inconsistent difference between strains. ConclusionDA strain of rats consistently presented lower susceptibility to oral infection with C. albicans compared to AO strain with robust Th1/Th17 immune response indicating the importance of the genetic background on the development of oral candidiasis.

Low prepulse inhibition predicts lower social interaction, impaired spatial working memory, reference memory and cognitive flexibility in genetically heterogeneous rats

The “Genetically Heterogeneous National Institutes of Health (NIHHS)” stock rat (hereafter HS) shows a wide phenotypic variation, as a result of having been derived from eight inbred rat strains. Thus, these rats may be a conceivable parallel model of a healthy human sample. In order to evaluate whether HS rats have face validity as an animal model of schizophrenia-relevant features, it should be demonstrated that they present behavioural traits that may model negative and cognitive symptoms of the disorder. Previous studies on HS rats have shown that prepulse inhibition (PPI, a measure of sensorimotor gating processes), which is impaired in schizophrenic patients, is correlated with their working memory performance. In this study, we evaluated whether low PPI in the HS stock rat predicts impairments of spatial working memory (SWM), spatial reference memory and cognitive flexibility in the Morris water maze (MWM) test, and we evaluated HS rats for social interaction (SI) in a social investigation task. HS rats were stratified into 2 different groups according to their PPI scores, i.e. low- and high-PPI. In the SI task, low-PPI rats showed decreased social behaviour compared to high-PPI rats. In addition, relative to high-PPI HS rats, the low-PPI group displayed poorer SWM performance, impaired cognitive flexibility (in a reversal task) and worsened long-term spatial memory. Such differential behaviours in social and cognitive paradigms provide evidence on the face validity of low-PPI HS rats as a model of negative-like and cognitive schizophrenia-relevant traits.

Radiation cataract in Heterogeneous Stock mice after γ-ray or HZE ion exposure

Health effects of space radiation are a serious concern for astronauts on long-duration missions. The lens of the eye is one of the most radiosensitive tissues in the body and, therefore, ocular health risks for astronauts is a significant concern. Studies in humans and animals indicate that ionizing radiation exposure to the eye produces characteristic lens changes, termed “radiation cataract,” that can affect visual function. Animal models of radiation cataractogenesis have previously utilized inbred mouse or rat strains. These studies were essential for determining morphological changes and dose-response relationships between radiation exposure and cataract. However, the relevance of these studies to human radiosensitivity is limited by the narrow phenotypic range of genetically homogeneous animal models. To model radiation cataract in genetically diverse populations, longitudinal cataract phenotyping was nested within a lifetime carcinogenesis study in male and female heterogeneous stock (HS/Npt) mice exposed to 0.4 Gy HZE ions (n = 609) or 3.0 Gy γ-rays (n = 602) and in unirradiated controls (n = 603). Cataractous change was quantified in each eye for up to 2 years using Merriam-Focht grading criteria by dilated slit lamp examination. Virtual Optomotry™ measurement of visual acuity and contrast sensitivity was utilized to assess visual function in a subgroup of mice. Prevalence and severity of posterior lens opacifications were 2.6-fold higher in HZE ion and 2.3-fold higher in γ-ray irradiated mice compared to unirradiated controls. Male mice were at greater risk for spontaneous and radiation associated cataracts. Risk for cataractogenesis was associated with family structure, demonstrating that HS/Npt mice are well-suited to evaluate genetic determinants of ocular radiosensitivity. Last, mice were extensively evaluated for cataract and tumor formation, which revealed an overlap between individual susceptibility to both cancer and cataract.

The Wistar Kyoto Rat: A Model of Depression Traits.

There is an ongoing debate about the value of animal research in psychiatry with valid lines of reasoning stating the limits of individual animal models compared to human psychiatric illnesses. Human depression is not a homogenous disorder; therefore, one cannot expect a single animal model to reflect depression heterogeneity. This limited review presents arguments that the Wistar Kyoto (WKY) rats show intrinsic depression traits. The phenotypes of WKY do not completely mirror those of human depression but clearly indicate characteristics that are common with it. WKYs present despair- like behavior, passive coping with stress, comorbid anxiety, and enhanced drug use compared to other routinely used inbred or outbred strains of rats. The commonly used tests identifying these phenotypes reflect exploratory, escape-oriented, and withdrawal-like behaviors. The WKYs consistently choose withdrawal or avoidance in novel environments and freezing behaviors in response to a challenge in these tests. The physiological response to a stressful environment is exaggerated in WKYs. Selective breeding generated two WKY substrains that are nearly isogenic but show clear behavioral differences, including that of depression-like behavior. WKY and its substrains may share characteristics of subgroups of depressed individuals with social withdrawal, low energy, weight loss, sleep disturbances, and specific cognitive dysfunction. The genomes of the WKY and WKY substrains contain variations that impact the function of many genes identified in recent human genetic studies of depression. Thus, these strains of rats share characteristics of human depression at both phenotypic and genetic levels, making them a model of depression traits.

The Difference between Male and Female Rats in Terms of Freezing and Aversive Ultrasonic Vocalization in an Active Avoidance Test

We examined sex differences in behavioral responses to fear-related learning through ultrasonic vocalization. Adult male and female rats of two inbred rat strains (WAG/Rij rats with genetic predisposition absence epilepsy, n = 25; and the minor substrain NEW with non-epileptic phenotype, n = 32) were examined in the two-way active avoidance task (50 trials). Three behavioral responses were defined: successful learning, unsuccessful learning, and freezing (motionless behavior). We found that males were more likely to experience freezing (40%) than females (3.7%). Females performed significantly better than males: 93% of females showed “successful learning”, while only 43.2% of males did. Long-lasting 22 kHz ultrasonic calls, so-called aversive ultrasonic vocalizations aUSVs, were recorded in 26% of females (only successful learners) and in 50% of males. The density of aUSVs in females was lower than in males. WAG/Rij males performed much poorer than the NEW males. In general, males, in contrast to females, showed significantly poorer avoidance learning, more frequently experienced freezing, and produced more aversive USVs. Males thus experienced a negative emotional state, rather than exhibiting poor cognitive abilities. Perhaps, WAG/Rij rats and a minor NEW substrain showed an increased emotionally in fear-related tasks, because they are prone to emotional disorders or emotional exhaustion. Sex differences in freezing and in aUSVs might result from the poorly understood neuromodulatory effects of the cholinergic system.

LAMP2A, and other chaperone-mediated autophagy related proteins, do not decline with age in genetically heterogeneous UM-HET3 mice.

Chaperone-mediated autophagy (CMA) selectively degrades proteins that are crucial for glycolysis, fatty acid metabolism, and the progression of several age-associated diseases. Several previous studies, each of which evaluated males of a single inbred mouse or rat strain, have reported that CMA declines with age in many tissues, attributed to an age-related loss of LAMP2A, the primary and indispensable component of the CMA translocation complex. This has led to a paradigm in the field of CMA research, stating that the age-associated decline in LAMP2A in turn decreases CMA, contributing to the pathogenesis of late-life disease. We assessed LAMP2A levels and CMA substrate uptake in both sexes of the genetically heterogeneous UM-HET3 mouse stock, which is the current global standard for the evaluation of anti-aging interventions. We found no evidence for age-related changes in LAMP2A levels, CMA substrate uptake, or whole liver levels of CMA degradation targets, despite identifying sex differences in CMA.

S-22-7: GENOMIC ANALYSES OF HYPERTENSION-ASSOCIATED DISEASES ACROSS ETHNIC GROUPS AND SPECIES

To explore genetic architecture of hypertension and end-organ damages, we performed integrative genomic analyses in both humans and inbred hypertensive rat strains. In humans, noting that hypertension is more prevalent and contributes to the increased risk of stroke in people of East Asian ancestry, we performed a multi-stage GWAS for blood pressure (BP) principally in East Asians and meta-analysis in East Asians and Europeans. We reported 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. Some of the ancestry-specific association signals are influenced by a selective sweep. These data provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP. In rats, we also performed genomic analyses of BP and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP). By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n = 1415) and fine congenic mapping (maximum n = 8704) plus comparative analysis with human, transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY). We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this analysis, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein-kinin/renin-angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. Furthermore, to unravel the mechanisms underlying antihypertensive drug-induced amelioration of end-organ damages, we performed transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred rat strains (SHRSP and WKY). Noticeable changes of mRNA expression were induced particularly by RAS blockade, for example, for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the KKS/RAS (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. Taken together, we provide genetic epidemiological evidence for ethnic differences in hypertension susceptibility and also in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, likely across species.

The Level of Individual Biochemical Constants of the Brain of in the Krushinsky-Molodkina Inbred Rat Strain against the Background of Radon Inhalation During Epilepsy

Introduction: The elucidation of the mechanism of action of radon on antioxidant processes needs further research, however, based on the results of the experiment, it can be concluded that studies on experimental animals have shown that, while inhaling Tskhaltubo water, the phenomenon of hormesis develops.
 Methods: we placed 10 experimental animals (KM rats) in Radon contained mineral water spa`s sauna. Inhalation of radon-water was administered through the nose, for 10 minutes, once a day, in conditions of high humidity (about 90%) for 10 days.
 Results: Hormesis regulates oxidative processes in the brain due to the activation of antioxidants expressed in a decrease in existing epileptic seizures and is expressed in the activation of Na / K-ATPase and specific glutaminergic neurons of the "attack center" of the hypothalamus but also with the activation of the entire adaptive-compensatory system.
 Conclusion: Inhalation of radon contained water can be considered as a method of treatment with an anticonvulsant effect confirmed by experimental studies.

Evaluation and characterization of expression quantitative trait analysis methods in the Hybrid Rat Diversity Panel.

The Hybrid Rat Diversity Panel (HRDP) is a stable and well-characterized set of more than 90 inbred rat strains that can be leveraged for systems genetics approaches to understanding the genetic and genomic variation associated with complex disease. The HRDP exhibits substantial between-strain diversity while retaining substantial within-strain isogenicity, allowing for the precise mapping of genetic variation associated with complex phenotypes and providing statistical power to identify associated variants. In order to robustly identify associated genetic variants, it is important to account for the population structure induced by inbreeding. To this end, we investigate the performance of four plausible approaches towards modeling quantitative traits in the HRDP and quantify their operating characteristics. In particular, we investigate three approaches based on genome-wide mixed model analysis, and one approach based on ordinary least squares linear regression. Towards facilitating study planning and design, we conduct extensive simulations to investigate the power of genetic association analyses in the HRDP, and characterize the impressive attained power. In simulation of eQTL data in the HRDP, we find that a mixed model approach that leverages leave-one-chromosome-out kinship estimation attains the highest power while controlling type I error.

Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways.

P2RX7, an ionotropic receptor for extracellular adenosine triphosphate (ATP), is expressed on immune cells, including macrophages, monocytes, and dendritic cells and is upregulated on nonimmune cells following injury. P2RX7 plays a role in many biological processes, including production of proinflammatory cytokines such as interleukin (IL)‐1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knockout (KO) inbred rat strain and, taking advantage of the human‐resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A‐438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its ‘off‐target’ properties. We identified a novel ATP/P2RX7/K+ efflux‐independent and caspase‐1/8‐dependent pathway for the production of IL‐1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off‐target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an ‘alternative inflammasome’ pathway to produce IL‐1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Hybrid Rat Diversity Program (HRDP): A rat resource for mapping complex traits

Rats are a major model for studying complex disease mechanisms, behavioral phenotypes, environmental factors, and for drug development and discovery. Inbred rat strains control for genetic background and allow for repeated, reproducible molecular, cellular, and whole animal phenotyping. Genetic susceptibility to disease, sensitivity to environmental elements, and pharmacogenomics are critical components of the concepts of precision medicine. The Hybrid Rat Diversity Program (HRDP) is a resource that combines the power of genetic stability within strains, power for genomic mapping strategies, and strength in an animal model that mirrors many human disease traits. The HRDP was designed to include 96 inbred rat strains with genomic and physiological diversity to maximize power to detect specific genetic loci associated with complex traits while maximizing the genetic diversity among strains. The 96 strain panel consists of 33 genetically diverse inbred strains and two panels of recombinant inbred panels: FEXL/LEXF (33 strains, Japan) and HXB/BXH (30 strains, Czech Republic). Embryo resuscitation and breeding is well underway at the Medical College of Wisconsin (MCW) with 55 strains available. Whole genome sequencing for 54 of the 96 strains is complete, having been generated on am Illumina NovaSeq S4 to achieve 30X coverage. An additional 14 related substrains have been sequenced. Liver and brain transcriptome analysis is underway through PhenoGen (http://phenogen.ucdenver.edu) at the University of Colorado. Genomic, phenotype, and strain information will be made available through the Hybrid Rat Diversity Panel portal at the Rat Genome Database (http://rgd.mcw.edu). The HRDP will provide a genetically stable population of rat strains with fully sequenced genomes, transcriptomes for brain and liver, and general phenotypic characterization to be used for systems genetic studies and fine mapping of complex traits.

Influence of Age and Genetic Background on Ethanol Intake and Behavioral Response Following Ethanol Consumption and During Abstinence in a Model of Alcohol Abuse.

Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40–70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction.

Cap analysis of gene expression reveals alternative promoter usage in a rat model of hypertension.

The role of alternative promoter usage in tissue-specific gene expression has been well established; however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) sequencing from the left ventricle of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, Brown Norway to understand the role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites in the rat left ventricle, including 1,970 novel cardiac transcription start sites. We identified 28 genes with alternative promoter usage between SHR and Brown Norway, which could lead to protein isoforms differing at the amino terminus between two strains and 475 promoter switching events altering the length of the 5' UTR. We found that the shift in Insr promoter usage was significantly associated with insulin levels and blood pressure within a panel of HXB/BXH recombinant inbred rat strains, suggesting that hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.

Transcriptomic Response in the Heart and Kidney to Different Types of Antihypertensive Drug Administration.

Certain classes of antihypertensive drug may exert specific, blood pressure (BP)-independent protective effects on end-organ damages such as left ventricular hypertrophy, although the overall evidence has not been definitive in clinical trials. To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains (ie, hypertensive and normotensive) of rats. We chose 6 antihypertensive classes: enalapril (angiotensin-converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating β-blocker), and hydralazine. In the tested rat strains, 4 of 6 drugs, including 2 renin-angiotensin system inhibitors, were effective for BP lowering, whereas the remaining 2 drugs were not. Besides BP lowering, there appeared to be some interdrug heterogeneity in phenotypic changes, such as suppressed body weight gain and body weight-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by renin-angiotensin system blockade, for example, for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the renin-angiotensin system/kallikrein-kinin system (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. The research resources constructed here will help corroborate occasionally inconclusive evidence in clinical settings.

Periapical lesions in two inbred strains of rats differing in immunological reactivity.

To investigate the influence of strain differences in immune responses on the pathogenesis of experimental periapical lesions in Dark Agouti (DA) and Albino Oxford (AO) inbred strains of rats. Periapical lesions were induced in male DA and AO rats by pulp exposure of the first mandibular right molars to the oral environment. Animals were killed 21days after pulp exposure. The mandibular jaws were retrieved and prepared for radiographic, pathohistological, immunohistochemical analysis, real-time PCR and flow cytometry. Blood samples and the supernatant of periapical lesions were collected for measurement of cytokines and oxidative stress marker levels. Statistical analysis was performed using the Kruskal-Wallis H and Mann-Whitney U non-parametric tests or parametric One-Way anova and Independent Samples T-test to determine the differences between groups depending on the normality of the data. A significant difference was considered when p values were <.05. DA rats developed significantly larger (p<.05) periapical lesions compared to AO rats as confirmed by radiographic and pathohistological analysis. The immunohistochemical staining intensity for CD3 was significantly greater in periapical lesions of DA rats compared to AO rats (p<.05). In DA rats, periapical lesions had a significantly higher (p<.05) percentage of CD3+ cells compared to AO rats. Also, the percentage of INF-γ, IL-17 and IL-10 CD3+CD4+ cells was significantly higher in DA rats (p<.05). DA rats had a significantly higher Th17/Th10 ratio. RT-PCR expression of IL-1β, INF-γ and IL-17 genes was significantly higher in periapical lesions of DA compared to AO rats (p<.05). The receptor activator of nuclear factor kappa-Β ligand/osteoprotegerin ratio was higher in DA compared to AO rats with periapical lesions (p<.05). Systemic levels of TNF-α and IL-6 were significantly higher in DA compared to AO rats (p<.05). Levels of lipid peroxidation measured as thiobarbituric acid reactive substances and reduced glutathione were significantly higher (p<.05) in the supernatant in the periapical lesions of DA rats. After pulp exposure, DA rats developed much larger periapical lesions compared to AO rats. Genetically determined differences in immunopathology have been demonstrated to be a significant element defining the severity of periapical lesions.

Coding variants in mouse and rat model organisms: mousepost and ratpost.

Mice and rats are the most commonly used vertebrate model organisms in biomedical research. The availability of a reference genome in both animals combined with the deep sequencing of several doze of popular inbred lines also provides rich sequence variation data in these species. In some cases, such sequence variants can be linked directly to a distinctive phenotype. In previous work, we created the mouse and rat online searchable databases ("Mousepost" and "Ratpost") where small variant information for protein coding transcripts in mouse and rat inbred strains can be easily retrieved at the amino acid level. These tools are directly useful in forward genetics strategies or as a repository of existing sequence variations. Here, we perform a comparison between the "Mousepost" and "Ratpost" databases and we couple these two tools to a database of human sequence variants ClinVar. We investigated the level of redundancy and complementarity of known variants in protein coding transcripts and found that the large majority of variants is species-specific. However, a small set of positions is conserved in an inbred line between both species. We conclude that both databases are highly complementary, but this may change with further sequencing efforts in both species.

Comparison of Ovarian Morphology and Follicular Disturbances between Two Inbred Strains of Cotton Rats (Sigmodon hispidus).

Simple SummaryMulti-oocyte follicles have been reported in several mammals, especially in rabbits and hamsters, although their significance remains unclear. The present study compared ovarian histology, focusing on folliculogenesis, between two inbred cotton rat strains maintained at Hokkaido Institute of Public Health and the University of Miyazaki. Abundant multi-oocyte follicles and double-nucleated oocytes were observed in the Hokkaido strain, whereas Miyazaki had fewer multi-oocyte follicles and lacked double-nucleated oocytes. These findings indicate that early folliculogenesis events such as oocyte nest breakdown and oocyte vitality, rather than proliferation and cell death in each oocyte, affect the unique ovarian phenotypes found in cotton rats, including multi-oocyte follicles or double-nucleated oocytes, and their differences between strains. Therefore, these results can clarify mammalian folliculogenesis and its abnormal processes.Most mammalian ovarian follicles contain only a single oocyte having a single nucleus. However, two or more oocytes and nuclei are observed within one follicle and one oocyte, respectively, in several species, including cotton rat (CR, Sigmodon hispidus). The present study compared ovarian histology, focusing on folliculogenesis, between two inbred CR strains, HIS/Hiph and HIS/Mz. At 4 weeks of age, ovarian sections from both the strains were analyzed histologically. Multi-oocyte follicles (MOFs) and double-nucleated oocytes (DNOs) were observed in all stages of developing follicles in HIS/Hiph, whereas HIS/Mz had MOFs up to secondary stages and lacked DNOs. The estimated total follicles in HIS/Mz were almost half that of HIS/Hiph, but interstitial cells were well developed in HIS/Mz. Furthermore, immunostaining revealed no clear strain differences in the appearance of oocytes positive for Ki67, PCNA, and p63 in MOF or DNOs; no cell death was observed in these oocytes. Ultrastructural analysis revealed more abundant mitochondrial clouds in oocytes of HIS/Hiph than HIS/Mz. Thus, we clarified the strain differences in the CR ovary. These findings indicate that early events during folliculogenesis affect the unique ovarian phenotypes found in CRs, including MOFs or DNOs, and their strain differences.

Ratpost: a searchable database of protein-inactivating sequence variations in 40 sequenced rat-inbred strains.

Rat-inbred strains are essential as scientific tools. We have analyzed the publicly available genome sequences of 40 rat-inbred strains and provide an overview of sequence variations leading to amino acid changes in protein-coding genes, premature STOP codons or loss of STOP codons, and short in-frame insertions and deletions of all protein-coding genes across all these inbred lines. We provide an overview of the predicted impact on protein function of all these affected proteins in the database, by comparing their sequence with the sequences of the rat reference strain BN/SsNHsdMcwi. We also investigate the flaws of the protein-coding sequences of this reference strain itself, by comparing them with a consensus genome. These data can be retrieved via a searchable website (Ratpost.be) and allow a global, better interpretation of genetic background effects and a source of naturally defective alleles in these 40 sequenced classical and high-priority rat-inbred strains.

Пифитрин-альфа тормозит дифференцировку вновь образованных клеток субгранулярной зоны зубчатой извилины у крыс линии Крушинского–Молодкиной при аудиогенном киндлинге

One of the main goal of modern neurobiology is search for approaches to prevent structural violations in the brain. In particular, damage to the hippocampus after epileptic activity. Epilepsy leads to an increase in proliferation in the hippocampal neurogenic niche - subgranular cells layer of dental gyrus. In recent years, there is a prevalent idea that new-born cells contribute to epileptogenesis to a greater extent than prevent neurodegenerative damage. We suggested that proapoptotic protein p53 can be one of possible therapeutic targets for epilepsy and neurodegenerative consequences of this disease.In present work, we used The Krushinsky - Molodkina (KM) inbred rat strain. This strain is genetically prone to audiogenic seizures (AGS). Audiogenic kindling induced epileptiform activity in the limbic system and the cortex. It has been shown that in initial stages of epileptogenesis 4 AGS lead to increase in proliferation, aberrant migration in hilus and acceleration of differentiation of newborn cells. We did not show any disturbance in apoptosis nor autophagy in early development of limbic epilepsy. Pifitrin-α (chemical inhibitor of p53) did not lead to changes in apoptosis and autophagy but caused increase in proliferation and migration of newborn cells in granular cell layer and hilus of dental gyrus. However, in a week after the last seizure the number of differentiated cells decreased despite a significant increase in the number of newborn cells in the group with inactivation of p53 compared to the vehicle control group. Decreased number of differentiated cells tells that pifitrin -α may be used as a potential therapeutic agent for reduction in neurodegeneration which is associated with epilepsy.