• metabolism
• peptide hormones

• Animals
• Insulin Receptor Substrate Proteins/metabolism
• Insulin Receptor Substrate Proteins/genetics
• Insulin Resistance/genetics
• Liver/metabolism
• Signal Transduction
• Rats
• Muscle, Skeletal/metabolism
• Insulin/metabolism
• Male
• Phosphorylation
• Down-Regulation
• Gene Deletion

• 22K05488 Japan Society for the Promotion of Science

• Astrocytes
• Brain
• Microglia
• Neuroinflammation
• Ultrasound bio-effects

• Animals
• Rats
• Rats, Wistar
• Brain/diagnostic imaging
• Neuroinflammatory Diseases/diagnostic imaging
• Male

• Anti-inflammatory cytokine
• Inflammatory cytokine
• Rotator cuff tear
• Subacromial bursa
• Tendon healing

• Animals
• Rotator Cuff Injuries/pathology
• Rotator Cuff Injuries/metabolism
• Rats
• Disease Models, Animal
• Rotator Cuff/metabolism
• Rotator Cuff/pathology
• Rats, Sprague-Dawley
• Bursa, Synovial/metabolism
• Bursa, Synovial/pathology
• Male
• Tendons/metabolism
• Tendons/pathology
• Wound Healing
• Gene Expression Regulation

• Cardiac magnetic resonance
• Myocardial strain
• Plateau
• Tissue tracking
• Ventricular function

• Animals
• Male
• Ventricular Function, Left
• Altitude
• Stroke Volume
• Rats, Sprague-Dawley
• Altitude Sickness/physiopathology
• Altitude Sickness/diagnostic imaging
• Predictive Value of Tests
• Magnetic Resonance Imaging, Cine
• Magnetic Resonance Imaging
• Time Factors
• Ventricular Dysfunction, Left/physiopathology
• Ventricular Dysfunction, Left/diagnostic imaging
• Ventricular Dysfunction, Left/etiology
• Rats
• Hypoxia/physiopathology

• FCD IIb
• FCD rats
• NMDAR
• TSC
• α-syn

• dopamine transporter
• dopamine transporter knockout rodents
• hyperdopaminergia
• hypodopaminergia
• locomotor hyperactivity

• Animals
• Rodentia/metabolism
• Dopamine Plasma Membrane Transport Proteins/metabolism
• Corpus Striatum/metabolism
• Dopamine/metabolism
• Synaptic Transmission

• EGCG
• Lepr KO rats
• diglycerides
• glycerophospholipid
• lipidomics
• obesity-related complications

• Animals
• Rats
• Animals, Newborn
• Matrix Metalloproteinase 2/genetics
• Chromatography, Liquid
• Tandem Mass Spectrometry
• Collagen
• Extracellular Matrix Proteins
• Cell Proliferation
• Fibroblasts

• Deanship of Research, Jordan University of Science and Technology
• Deanship of Scientific Research, King Saud University

• Blastocyst
• Chimera
• Embryo transfer
• Embryonic stem cells
• NSET
• Rat
• Transgenesis

• PDE10A inhibitors
• Parkinson’s disease
• dopamine transporter knockout rat
• hypodopaminergia
• locomotor activity

• Animals
• Rats
• Carbidopa
• Catalepsy/complications
• Catalepsy/drug therapy
• Dopamine
• Levodopa/pharmacology
• Levodopa/therapeutic use
• Parkinson Disease/drug therapy
• Parkinson Disease/etiology

• Aged rodents
• Cognitive decline
• Environmental enrichment
• Experimental variables
• Standardization

• autism
• behavior
• developmental
• genetic
• genetic disorder
• intellectual disability
• models
• mouse models
• neurodevelopmental disorder
• social
• syndrome

• ADHD model
• dopamine transporter knockout rats
• long-term memory
• novelty
• recognition memory

• Autoimmunity
• Lacrimal glands
• Salivary glands
• Sjögren’s syndrome

Mice and rats are widely used to explore mechanisms of mammalian social behavior in health and disease, raising the question whether they actually differ in their social behavior. Here we address this question by directly comparing social investigation behavior between two mouse and rat strains used most frequently for behavioral studies and as models of neuropathological conditions: C57BL/6 J mice and Sprague Dawley (SD) rats. Employing novel experimental systems for behavioral analysis of both subjects and stimuli during the social preference test, we reveal marked differences in behavioral dynamics between the strains, suggesting stronger and faster induction of social motivation in SD rats. These different behavioral patterns, which correlate with distinctive c-Fos expression in social motivation-related brain areas, are modified by competition with non-social rewarding stimuli, in a strain-specific manner. Thus, these two strains differ in their social behavior, which should be taken into consideration when selecting an appropriate model organism.

Laboratory rat and mouse strains serve as animal models to explore brain mechanisms underlying social behavior. Here, the authors describe differences in social behavior between commonly used rat and mouse strains, which may reflect distinct dynamics of social motivation.

• CRISPR/Cas9
• CSB
• Cockayne syndrome rat model
• neurodevelopmental disorder
• transcription dysregulation

Spermatogonial stem cells (SSCs) transmit genetic information to the next progeny in males. Thus, SSCs are a potential target for germline modifications to generate transgenic animals. In this study, we report a technique for the generation of transgenic rats by in vivo manipulation of SSCs with a high success rate. SSCs in juvenile rats were transduced in vivo with high titers of lentivirus harboring enhanced green fluorescent protein and mated with wild-type females to create founder rats. These founder rats expressed the transgene and passed on the transgene with an overall success rate of 50.0%. Subsequent generations of progeny from the founder rats both expressed and passed on the transgene. Thus, direct modification of SSCs in juvenile rats is an effective means of generating transgenic rats through the male germline. This technology could be adapted to larger animals, in which existing methods for gene modification are inadequate or inapplicable, resulting in the generation of transgenic animals in a variety of species.

• germline modification
• lentivirus
• spermatogonial stem cell
• testis
• transgenic animal

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose well to some extent, each has its own limitations. To help overcome this, clustered regularly interspaced short palindromic repeat (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field.

• CRISPR
• Duchenne muscular dystrophy
• animal models
• dystrophin
• in vivo testing
• mutant generation

• Animals
• CRISPR-Cas Systems
• Disease Models, Animal
• Gene Editing/methods
• Haplorhini
• Murinae
• Muscular Dystrophy, Duchenne/genetics
• Muscular Dystrophy, Duchenne/pathology
• Rabbits
• Swine

• FDN 143251 CIHR

• Chromosome transfer
• Human artificial chromosome
• Human chromosome fragment
• Humanized animal
• Mouse artificial chromosome
• Transchromosomic animal

• Achilles tendon
• amniotic membrane
• collagenase
• regenerative medicine
• tendinopathy

• Amnion/cytology
• Animals
• Biomarkers
• Biopsy
• Collagenases/adverse effects
• Disease Models, Animal
• Female
• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Pregnancy
• Rats
• Severity of Illness Index
• Tendon Injuries/etiology
• Tendon Injuries/pathology
• Tendon Injuries/therapy
• Time Factors
• Treatment Outcome

Genomically humanized animals overcoming species differences are invaluable for biomedical research. Although rats would be preferred over mice for several applications, generation of a humanized model is restricted to mice due to the difficulty of complex genetic manipulations in rats. In this study, we successfully generated humanized rats with megabase-sized gene clusters via combination of chromosome transfer using mouse artificial chromosome vector and genome editing technologies. In the humanized UGT2 and CYP3A transchromosomic rats described in this paper, the expression of the human genes, as well as the pharmacokinetics and metabolism of relevant probe substrates, accurately mimic the situation in humans. Thus, the advanced technologies can be used to generate fully humanized rats useful for biomedical research.

Although “genomically” humanized animals are invaluable tools for generating human disease models as well as for biomedical research, their development has been mainly restricted to mice via established transgenic-based and embryonic stem cell-based technologies. Since rats are widely used for studying human disease and for drug efficacy and toxicity testing, humanized rat models would be preferred over mice for several applications. However, the development of sophisticated humanized rat models has been hampered by the difficulty of complex genetic manipulations in rats. Additionally, several genes and gene clusters, which are megabase range in size, were difficult to introduce into rats with conventional technologies. As a proof of concept, we herein report the generation of genomically humanized rats expressing key human drug-metabolizing enzymes in the absence of their orthologous rat counterparts via the combination of chromosome transfer using mouse artificial chromosome (MAC) and genome editing technologies. About 1.5 Mb and 700 kb of the entire UDP glucuronosyltransferase family 2 and cytochrome P450 family 3 subfamily A genomic regions, respectively, were successfully introduced via the MACs into rats. The transchromosomic rats were combined with rats carrying deletions of the endogenous orthologous genes, achieved by genome editing. In the “transchromosomic humanized” rat strains, the gene expression, pharmacokinetics, and metabolism observed in humans were well reproduced. Thus, the combination of chromosome transfer and genome editing technologies can be used to generate fully humanized rats for improved prediction of the pharmacokinetics and drug–drug interactions in humans, and for basic research, drug discovery, and development.

• chromosome transfer
• genome editing
• humanized animal model
• mouse artificial chromosome
• transchromosomic rat

• IL-6
• Microglia
• Placenta
• Poly I:C
• Wistar rat
• mIA (maternal immune activation)

• Brain
• Development
• LINE-1
• Rat
• Retrotransposition

• APP/PS1
• Alzheimer’s disease
• blueberry
• brain-derived neurotrophic factor
• transgenic mice

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.

• CRISPR/Cas9
• Cre reporter
• Cre-loxP
• Rosa26
• rat

• Animals
• CRISPR-Cas Systems
• Crosses, Genetic
• Dependovirus/genetics
• Dependovirus/metabolism
• Embryo, Mammalian
• Female
• Gene Editing/methods
• Gene Expression Regulation
• Gene Knock-In Techniques
• Gene Targeting
• Genes, Reporter
• Genetic Loci
• Genetic Vectors/chemistry
• Genetic Vectors/metabolism
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• Integrases/genetics
• Integrases/metabolism
• Liver/metabolism
• Luminescent Proteins/genetics
• Luminescent Proteins/metabolism
• Male
• Myocardium/metabolism
• RNA, Guide, CRISPR-Cas Systems/genetics
• RNA, Guide, CRISPR-Cas Systems/metabolism
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism
• Rats
• Rats, Transgenic
• Red Fluorescent Protein

• Animal model
• Anxiety
• Approach-avoidance test
• Home cage behaviour
• Light spot
• SCA17

• Animals
• Anxiety/physiopathology
• Avoidance Learning/physiology
• Behavior, Animal/physiology
• Behavioral Research/instrumentation
• Behavioral Research/methods
• Disease Models, Animal
• Female
• Housing
• Light
• Rats
• Rats, Sprague-Dawley
• Rats, Transgenic
• Spinocerebellar Ataxias/genetics
• Spinocerebellar Ataxias/physiopathology

As concerns increase about adenovirus type 5 (Ad5) being a safe gene transfer vector, it is important to evaluate its distribution, residence time, and possible toxicity in immunodeficient populations. To characterize the potential risk associated with different Ad5 vector delivery modes, we used immunocompetent and immunodeficient Rag2^−/− animals to establish mouse and rat models that could be monitored with bioluminescent imaging following intramuscular or intravascular infection with an engineered replication-incompetent Ad5 virus carrying the firefly luciferase gene (Ad5-Fluc). The Ad5 vector was less well-tolerated by Rag2^−/− animals than by wildtype ones, with delayed residence time, wider virus dissemination, less weight gain, and relatively severe pathological changes. In intravascularly Ad5-Fluc-infected Rag2^−/− mice, systemic virus dissemination extended from the abdomen to the limbs and head on day 9 post-infection. Additionally, significant increases in plasma TNF-α and IFN-γ, which may be important factors in the heightened immunopathology in the liver and brain, were detected in the Rag2^−/− mice 30 days after intravascular delivery. The Ad5 vector was better tolerated after intramuscular delivery than after intravascular delivery. Ad5-Fluc/Rag2^−/− mice and rats can be used as reliable models of an immunodeficient population in which to evaluate the safety of Ad5-vectored vaccines or gene therapy products.

The gene that encodes tumor protein p53, Tp53, is mutated or silenced in most human cancers and is recognized as one of the most important cancer drivers. Homozygotic Tp53 knockout mice, which develop lethal cancers early in their lives, are already used in cancer prevention studies, and now Tp53 knockout rats have also been generated. This study assessed feasibility of using homozygous Tp53 knockout rats to evaluate the possible outcome of cancer chemoprevention.

A small colony of Tp53 knockout rats with a Wistar strain genetic background was initiated and maintained in the animal house at our institution. Tp53 heterozygotic females were bred with Tp53 homozygous knockout males to obtain a surplus of knockout homozygotes. To evaluate the reproducibility of their lifespan, 4 groups of Tp53 homozygous knockout male rats born during consecutive quarters of the year were kept behind a sanitary barrier in a controlled environment until they reached a moribund state. Their individual lifespan data were used to construct quarterly survival curves.

The four consecutive quarterly survival curves were highly reproducible. They were combined into a single “master” curve for use as a reference in intervention studies. The average lifespan of untreated male Tp53 homozygous knockout rats was normally distributed, with a median of 133 days. Sample size vs. effect calculations revealed that confirming a 20% and 30% increase in the lifespan would respectively require a sample size of 18 and 9 animals (when assessed using the t-test with a power of 80% and alpha set at 0.05). As an example, the Tp53 homozygous knockout rat model was used to test the chemopreventive properties of carnosine, a dipeptide with suspected anticancer properties possibly involving modulation of the mTOR pathway. The result was negative.

Further evaluation of the Tp53 homozygous knockout male rat colony is required before it can be confirmed as a viable tool for assessing new methods of cancer prevention or treatment.

• Cancer
• Chemoprevention
• Survival curve
• Tp53 knockout rats

Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor-associated microglia- and bone marrow-derived macrophages, and the formation of stem-like cell niches within the tumor. This transgenic rat model may enable detailed interspecies comparisons of fundamental cancer pathways and clinically relevant experimental imaging procedures and interventions that are limited by the smaller size of the mouse brain.

The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene (Slc6a3_N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity.

Summary: The first systematic RDoc study of a disease mechanism proposes dopamine transporter DAT mutant rats as a model for drug development, targeting a hyperdopaminergic state.

• In vivo microdialysis
• Molecular modeling
• RDoC matrix
• Rat mutagenesis
• mGluR2/3 antagonist LY341495

• breast cancer
• carbonyl reductase 1
• cardiotoxicity
• chemotherapy
• doxorubicin
• doxorubicinol

• CRISPR/Cas9
• Conditional knockout
• Cre/loxP
• Homologous recombination
• Rat

• Animals
• Bacterial Proteins/genetics
• Bacterial Proteins/metabolism
• CRISPR-Associated Protein 9
• CRISPR-Cas Systems
• Clustered Regularly Interspaced Short Palindromic Repeats
• Endonucleases/genetics
• Endonucleases/metabolism
• Founder Effect
• Gene Knock-In Techniques
• Gene Silencing
• Gene Targeting/methods
• Genome
• Homologous Recombination
• Integrases/genetics
• Integrases/metabolism
• RNA, Guide, CRISPR-Cas Systems/genetics
• RNA, Guide, CRISPR-Cas Systems/metabolism
• Rats
• Rats, Transgenic
• Zygote/growth & development
• Zygote/metabolism

• blood
• cadmium
• feces
• liver

• Achilles Tendon/drug effects
• Achilles Tendon/metabolism
• Achilles Tendon/pathology
• Animals
• Collagen/metabolism
• Collagenases/administration & dosage
• Disease Models, Animal
• Disease Progression
• Dose-Response Relationship, Drug
• Humans
• Injections
• Male
• Neovascularization, Pathologic/chemically induced
• Neovascularization, Pathologic/diagnosis
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Rats
• Rats, Sprague-Dawley
• Tendinopathy/chemically induced
• Tendinopathy/diagnosis
• Tendinopathy/metabolism
• Tendinopathy/pathology
• Time Factors
• Wound Healing/physiology

• IGEA SpA Clinical Biophysics

BAC transgenic mammalian systems offer an important platform for recapitulating human gene expression and disease modeling. While the larger body mass, and greater genetic and physiologic similarity to humans render rats well suited for reproducing human immune diseases and evaluating therapeutic strategies, difficulties of generating BAC transgenic rats have hindered progress. Thus, an efficient method for BAC transgenesis in rats would be valuable. Immunodeficient mice carrying a human SIRPA transgene have previously been shown to support improved human cell hematopoiesis. Here, we have generated for the first time, human SIRPA BAC transgenic rats, for which the gene is faithfully expressed, functionally active, and germline transmissible. To do this, human SIRPA BAC was modified with elements to work in coordination with genome engineering technologies-piggyBac, CRISPR/Cas9 or TALEN. Our findings show that piggyBac transposition is a more efficient approach than the classical BAC transgenesis, resulting in complete BAC integration with predictable end sequences, thereby permitting precise assessment of the integration site. Neither CRISPR/Cas9 nor TALEN increased BAC transgenesis. Therefore, an efficient generation of human SIRPA transgenic rats using piggyBac opens opportunities for expansion of humanized transgenic rat models in the future to advance biomedical research and therapeutic applications.

• animal model
• hemolytic anemia
• red cell disorders
• thrombosis