Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

PubMed

Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

2015-09-01

The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans.

The association between expression of IFIT1 in podocytes of MRL/lpr mice and the renal pathological changes it causes: An animal study.

PubMed

Hu, Weiping; Niu, Guodong; Li, Hongbo; Gao, Hanyuan; Kang, Rudian; Chen, Xiaoqing; Lin, Ling

2016-11-22

Renal damage is the major cause of SLE associated mortality, and IFIT1expression was elevated in SLE cases in accordance of previous studies. Therefore, we conducted an animal study to identify the role of IFIT1 expression in renal pathological changes.18 female MRL/lpr mice and same number of female BALB/c mice were enrolled in present study. Quantitative analysis of urine protein, Complement C3 and C4, and anti-ds DNA antibody were conducted. HE and PAS staining and TEM analysis were employed to observe the pathological changes in renal tissue. Significant elevation on urine protein and anti-dsDNA and reduction on Complement C3 and C4 were observed in MRL/lpr mice when comparing the controls in same age. Staining and TEM analysis observed several pathological changes in glomerulus among MRL/lpr mice, including cellular enlargement, basement membrane thickening, and increased cellularcasts. The linear regression analysis found the optical density of IFIT1 was inversely associated with F-actin, Nephrin, and Podocin, but not Synatopodin. In summary, IFIT1 expression is associated with podocytes damage, and capable of suppressing some proteins essential to glomerular filtration.

Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction.

PubMed

Yu, Tao; Guo, Ming; Garza, Jacob; Rendon, Samantha; Sun, Xue-Li; Zhang, Wei; Lu, Xin-Yun

2011-04-01

Human depression is associated with cognitive deficits. It is critical to have valid animal models in order to investigate mechanisms and treatment strategies for these associated conditions. The goal of this study was to determine the association of cognitive dysfunction with depression-like behaviour in an animal model of depression and investigate the neural circuits underlying the behaviour. Mice that were exposed to social defeat for 14 d developed depression-like behaviour, i.e. anhedonia and social avoidance as indicated by reduced sucrose preference and decreased social interaction. The assessment of cognitive performance of defeated mice demonstrated impaired working memory in the T-maze continuous alternation task and enhanced fear memory in the contextual and cued fear-conditioning tests. In contrast, reference learning and memory in the Morris water maze test were intact in defeated mice. Neuronal activation following chronic social defeat was investigated by c-fosin-situ hybridization. Defeated mice exhibited preferential neural activity in the prefrontal cortex, cingulate cortex, hippocampal formation, septum, amygdala, and hypothalamic nuclei. Taken together, our results suggest that the chronic social defeat mouse model could serve as a valid animal model to study depression with cognitive impairments. The patterns of neuronal activation provide a neural basis for social defeat-induced changes in behaviour.

Dietary Animal Plasma Proteins Improve the Intestinal Immune Response in Senescent Mice.

PubMed

Miró, Lluïsa; Garcia-Just, Alba; Amat, Concepció; Polo, Javier; Moretó, Miquel; Pérez-Bosque, Anna

2017-12-11

Increased life expectancy has promoted research on healthy aging. Aging is accompanied by increased non-specific immune activation (inflammaging) which favors the appearance of several disorders. Here, we study whether dietary supplementation with spray-dried animal plasma (SDP), which has been shown to reduce the activation of gut-associated lymphoid tissue (GALT) in rodents challenged by S. aureus enterotoxin B (SEB), and can also prevent the effects of aging on immune system homeostasis. We first characterized GALT in a mouse model of accelerated senescence (SAMP8) at different ages (compared to mice resistant to accelerated senescence; SAMR1). Second, we analyzed the SDP effects on GALT response to an SEB challenge in SAMP8 mice. In GALT characterization, aging increased the cell number and the percentage of activated Th lymphocytes in mesenteric lymph nodes and Peyer's patches (all, p < 0.05), as well as the expression of IL-6 and TNF-α in intestinal mucosa (both, p < 0.05). With respect to GALT response to the SEB challenge, young mice showed increased expression of intestinal IL-6 and TNF-α, as well as lymphocyte recruitment and activation (all, p < 0.05). However, the immune response of senescent mice to the SEB challenge was weak, since SEB did not change cell recruitment or the percentage of activated Th lymphocytes. Mice supplemented with SDP showed improved capacity to respond to the SEB challenge, similar to the response of the young mice. These results indicate that senescent mice have an impaired mucosal immune response characterized by unspecific GALT activation and a weak specific immune response. SDP supplementation reduces non-specific basal immune activation, allowing for the generation of specific responses.

Animal Study on Primary Dysmenorrhoea Treatment at Different Administration Times

PubMed Central

Pu, Bao-Chan; Fang, Ling; Gao, Li-Na; Liu, Rui; Li, Ai-zhu

2015-01-01

The new methods of different administration times for the treatment of primary dysmenorrhea are more widely used clinically; however, no obvious mechanism has been reported. Therefore, an animal model which is closer to clinical evaluation is indispensable. A novel animal experiment with different administration times, based on the mice oestrous cycle, for primary dysmenorrhoea treatment was explored in this study. Mice were randomly divided into two parts (one-cycle and three-cycle part) and each part includes five groups (12 mice per group), namely, Jingqian Zhitong Fang (JQF) 6-day group, JQF last 3-day group, Yuanhu Zhitong tablet group, model control group, and normal control group. According to the one-way ANOVAs, results (writhing reaction, and PGF2α, PGE2, NO, and calcium ions analysis by ELISA) of the JQF cycle group were in accordance with those of JQF last 3-day group. Similarly, results of three-cycle continuous administration were consistent with those of one-cycle treatment. In conclusion, the consistency of the experimental results illustrated that the novel animal model based on mice oestrous cycle with different administration times is more reasonable and feasible and can be used to explore in-depth mechanism of drugs for the treatment of primary dysmenorrhoea in future. PMID:25705236

Assessing the welfare of laboratory mice in their home environment using animal-based measures--a benchmarking tool.

PubMed

Spangenberg, Elin M F; Keeling, Linda J

2016-02-01

Welfare problems in laboratory mice can be a consequence of an ongoing experiment, or a characteristic of a particular genetic line, but in some cases, such as breeding animals, they are most likely to be a result of the design and management of the home cage. Assessment of the home cage environment is commonly performed using resource-based measures, like access to nesting material. However, animal-based measures (related to the health status and behaviour of the animals) can be used to assess the current welfare of animals regardless of the inputs applied (i.e. the resources or management). The aim of this study was to design a protocol for assessing the welfare of laboratory mice using only animal-based measures. The protocol, to be used as a benchmarking tool, assesses mouse welfare in the home cage and does not contain parameters related to experimental situations. It is based on parameters corresponding to the 12 welfare criteria established by the Welfare Quality® project. Selection of animal-based measures was performed by scanning existing published, web-based and informal protocols, and by choosing parameters that matched these criteria, were feasible in practice and, if possible, were already validated indicators of mouse welfare. The parameters should identify possible animal welfare problems and enable assessment directly in an animal room during cage cleaning procedures, without the need for extra equipment. Thermal comfort behaviours and positive emotional states are areas where more research is needed to find valid, reliable and feasible animal-based measures. © The Author(s) 2015.

Of mice and men: how animal models advance our understanding of T-cell function in RA.

PubMed

Kobezda, Tamás; Ghassemi-Nejad, Sheida; Mikecz, Katalin; Glant, Tibor T; Szekanecz, Zoltán

2014-03-01

The involvement of autoreactive T cells in the pathogenesis of rheumatoid arthritis (RA) as well as in autoimmune animal models of arthritis has been well established; however, unanswered questions, such as the role of joint-homing T cells, remain. Animal models of arthritis are superb experimental tools in demonstrating how T cells trigger joint inflammation, and thus can help to further our knowledge of disease mechanisms and potential therapies. In this Review, we discuss the similarities and differences in T-cell subsets and functions between RA and mouse arthritis models. For example, various T-cell subsets are involved in both human and mouse arthritis, but differences might exist in the cytokine regulation and plasticity of these cells. With regard to joint-homing T cells, an abundance of synovial T cells is present in humans compared with mice. On the other hand, local expansion of type 17 T-helper (TH17) cells is observed in some animal models, but not in RA. Finally, whereas T-cell depletion therapy essentially failed in RA, antibody targeting of T cells can work, at least preventatively, in most arthritis models. Clearly, additional human and animal studies are needed to fill the gap in our understanding of the specific contribution of T-cell subsets to arthritis in mice and men.

A novel small animal model to study the replication of simian foamy virus in vivo.

PubMed

Blochmann, Rico; Curths, Christoph; Coulibaly, Cheick; Cichutek, Klaus; Kurth, Reinhard; Norley, Stephen; Bannert, Norbert; Fiebig, Uwe

2014-01-05

Preclinical evaluation in a small animal model would help the development of gene therapies and vaccines based on foamy virus vectors. The establishment of persistent, non-pathogenic infection with the prototype foamy virus in mice and rabbits has been described previously. To extend this spectrum of available animal models, hamsters were inoculated with infectious cell supernatant or bioballistically with a foamy virus plasmid. In addition, a novel foamy virus from a rhesus macaque was isolated and characterised genetically. Hamsters and mice were infected with this new SFVmac isolate to evaluate whether hamsters are also susceptible to infection. Both hamsters and mice developed humoral responses to either virus subtype. Virus integration and replication in different animal tissues were analysed by PCR and co-cultivation. The results strongly indicate establishment of a persistent infection in hamsters. These studies provide a further small animal model for studying FV-based vectors in addition to the established models. © 2013 Elsevier Inc. All rights reserved.

Studies on induction of lamotrigine metabolism in transgenic UGT1 mice

PubMed Central

Argikar, U. A.; Senekeo-Effenberger, K.; Larson, E. E.; Tukey, R. H.; Remmel, R. P.

2010-01-01

A transgenic ‘knock-in’ mouse model expressing a human UGT1 locus (Tg-UGT1) was recently developed and validated. Although these animals express mouse UGT1A proteins, UGT1A4 is a pseudo-gene in mice. Therefore, Tg-UGT1 mice serve as a ‘humanized’ UGT1A4 animal model.Lamotrigine (LTG) is primarily metabolized to its N-glucuronide (LTGG) by hUGT1A4. This investigation aimed at examining the impact of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR) activators on LTG glucuronidation in vivo and in vitro. Tg-UGT1 mice were administered the inducers phenobarbital (CAR), pregnenolone-16α-carbonitrile (PXR), WY-14643 (PPAR-α), ciglitazone (PPAR-γ), or L-165041 (PPAR-β), once daily for 3 or 4 days. Thereafter, LTG was administered orally and blood samples were collected over 24 h. LTG was measured in blood and formation of LTGG was measured in pooled microsomes made from the livers of treated animals.A three-fold increase in in vivo LTG clearance was seen after phenobarbital administration. In microsomes prepared from phenobarbital-treated Tg-UGT1 animals, 13-fold higher CLint (Vmax/Km) value was observed as compared with the untreated transgenic mice. A trend toward induction of catalytic activity in vitro and in vivo was also observed following pregnenolone-16α-carbonitrile and WY-14643 treatment. This study demonstrates the successful application of Tg-UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of UGT1A4 substrates. PMID:19845433

Detection of Corynebacterium bovis infection in athymic nude mice from a research animal facility in Korea.

PubMed

Kim, Tae-Hyoun; Kim, Dong-Su; Han, Ju-Hee; Chang, Seo-Na; Kim, Kyung-Sul; Seok, Seung-Hyeok; Kim, Dong-Jae; Park, Jong-Hwan; Park, Jae-Hak

2014-12-01

Corynebacterium (C.) bovis infection in nude mice causes hyperkeratosis and weight loss and has been reported worldwide but not in Korea. In 2011, nude mice from an animal facility in Korea were found to have white flakes on their dorsal skin. Histopathological testing revealed that the mice had hyperkeratosis and Gram-positive bacteria were found in the skin. We identified isolated bacteria from the skin lesions as C. bovis using PCR and 16S rRNA sequencing. To the best of our knowledge, this is the first report of C. bovis infection in nude mice from Korea.

Animal models of physiologic markers of male reproduction: genetically defined infertile mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chubb, C.

The present report focuses on novel animal models of male infertility: genetically defined mice bearing single-gene mutations that induce infertility. The primary goal of the investigations was to identify the reproductive defects in these mutant mice. The phenotypic effects of the gene mutations were deciphered by comparing the mutant mice to their normal siblings. Initially testicular steroidogenesis and spermatogenesis were investigated. The physiologic markers for testicular steroidogenesis were steroid secretion by testes perifused in vitro, seminal vesicle weight, and Leydig cell histology. Spermatogenesis was evaluated by the enumeration of homogenization-resistant sperm/spermatids in testes and by morphometric analyses of germ cellsmore » in the seminiferous epithelium. If testicular function appeared normal, the authors investigated the sexual behavior of the mice. The parameters of male sexual behavior that were quantified included mount patency, mount frequency, intromission latency, thrusts per intromission, ejaculation latency, and ejaculation duration. Females of pairs breeding under normal circumstances were monitored for the presence of vaginal plugs and pregnancies. The patency of the ejaculatory process was determined by quantifying sperm in the female reproductive tract after sexual behavior tests. Sperm function was studied by quantitatively determining sperm motility during videomicroscopic observation. Also, the ability of epididymal sperm to function within the uterine environment was analyzed by determining sperm capacity to initiate pregnancy after artificial insemination. Together, the experimental results permitted the grouping of the gene mutations into three general categories. They propose that the same biological markers used in the reported studies can be implemented in the assessment of the impact that environmental toxins may have on male reproduction.« less

DEVELOPMENTAL TOXICOGENOMIC STUDIES OF PFOA AND PFOS IN MICE.

EPA Science Inventory

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are developmentally toxic in rodents. To better understand the mechanism(s) associated with this toxicity, we have conducted transcript profiling in mice. In an initial study, pregnant animals were dosed througho...

Myeloproliferative Neoplasm Animal Models

PubMed Central

Mullally, Ann; Lane, Steven W.; Brumme, Kristina; Ebert, Benjamin L.

2012-01-01

Synopsis Myeloproliferative neoplasm (MPN) animal models accurately re-capitulate human disease in mice and have been an important tool for the study of MPN biology and therapy. Transplantation of BCR-ABL transduced bone marrow cells into irradiated syngeneic mice established the field of MPN animal modeling and the retroviral bone marrow transplantation (BMT) assay has been used extensively since. Genetically engineered MPN animal models have enabled detailed characterization of the effects of specific MPN associated genetic abnormalities on the hematopoietic stem and progenitor cell (HSPC) compartment and xenograft models have allowed the study of primary human MPN-propagating cells in vivo. All models have facilitated the pre-clinical development of MPN therapies. JAK2V617F, the most common molecular abnormality in BCR-ABL negative MPN, has been extensively studied using retroviral, transgenic, knock-in and xenograft models. MPN animal models have also been used to investigate additional genetic lesions found in human MPN and to evaluate the bone marrow microenvironment in these diseases. Finally, several genetic lesions, although not common, somatically mutated drivers of MPN in humans induce a MPN phenotype in mice. Future uses for MPN animal models will include modeling compound genetic lesions in MPN and studying myelofibrotic transformation. PMID:23009938

Preclinical animal acute toxicity studies of new developed MRI contrast agent based on gadolinium

NASA Astrophysics Data System (ADS)

Nam, I. F.; Zhuk, V. V.

2015-04-01

Acute toxicity test of new developed MRI contrast agent based on disodium salt of gadopentetic acid complex were carried out on Mus musculus and Sprague Dawley rats according to guidelines of preclinical studies [1]. Groups of six animals each were selected for experiment. Death and clinical symptoms of animals were recorded during 14 days. As a result the maximum tolerated dose (MTD) for female mice is 2.8 mM/kg of body weight, male mice - 1.4 mM/kg, female rats - 2.8 mM/kg, male rats - 5.6 mM/kg of body weight. No Observed Adverse Effect Dose (NOAEL) for female mice is 1.4 mM/kg, male mice - 0.7 mM/kg, male and female rats - 0.7 mM/kg. According to experimental data new developed MRI contrast agent based on Gd-DTPA complex is low-toxic.

Population sensitivities of animals to chronic ionizing radiation-model predictions from mice to elephant.

PubMed

Sazykina, Tatiana G

2018-02-01

Model predictions of population response to chronic ionizing radiation (endpoint 'morbidity') were made for 11 species of warm-blooded animals, differing in body mass and lifespan - from mice to elephant. Predictions were made also for 3 bird species (duck, pigeon, and house sparrow). Calculations were based on analytical solutions of the mathematical model, simulating a population response to low-LET ionizing radiation in an ecosystem with a limiting resource (Sazykina, Kryshev, 2016). Model parameters for different species were taken from biological and radioecological databases; allometric relationships were employed for estimating some parameter values. As a threshold of decreased health status in exposed populations ('health threshold'), a 10% reduction in self-repairing capacity of organisms was suggested, associated with a decline in ability to sustain environmental stresses. Results of the modeling demonstrate a general increase of population vulnerability to ionizing radiation in animal species of larger size and longevity. Populations of small widespread species (mice, house sparrow; body mass 20-50 g), which are characterized by intensive metabolism and short lifespan, have calculated 'health thresholds' at dose rates about 6.5-7.5 mGy day -1 . Widespread animals with body mass 200-500 g (rat, common pigeon) - demonstrate 'health threshold' values at 4-5 mGy day -1 . For populations of animals with body mass 2-5 kg (rabbit, fox, raccoon), the indicators of 10% health decrease are in the range 2-3.4 mGy day -1 . For animals with body mass 40-100 kg (wolf, sheep, wild boar), thresholds are within 0.5-0.8 mGy day -1 ; for herbivorous animals with body mass 200-300 kg (deer, horse) - 0.5-0.6 mGy day -1 . The lowest health threshold was estimated for elephant (body mass around 5000 kg) - 0.1 mGy day -1 . According to the model results, the differences in population sensitivities of warm-blooded animal species to ionizing radiation are generally

Study of the pathogenesis and treatment of diabetes mellitus through animal models.

PubMed

Brito-Casillas, Yeray; Melián, Carlos; Wägner, Ana María

2016-01-01

Most research in diabetes mellitus (DM) has been conducted in animals, and their replacement is currently a chimera. As compared to when they started to be used by modern science in the 17th century, a very high number of animal models of diabetes is now available, and they provide new insights into almost every aspect of diabetes. Approaches combining human, in vitro, and animal studies are probably the best strategy to improve our understanding of the underlying mechanisms of diabetes, and the choice of the best model to achieve such objective is crucial. Traditionally classified based on pathogenesis as spontaneous or induced models, each has its own advantages and disadvantages. The most common animal models of diabetes are described, and in addition to non-obese diabetic mice, biobreeding diabetes-prone (BB-DP) rats, streptozotocin-induced models, or high-fat diet-induced diabetic C57Bl/6J mice, new valuable models, such as dogs and cats with spontaneous diabetes, are described. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

Mice selected for high versus low stress reactivity: a new animal model for affective disorders.

PubMed

Touma, Chadi; Bunck, Mirjam; Glasl, Lisa; Nussbaumer, Markus; Palme, Rupert; Stein, Hendrik; Wolferstätter, Michael; Zeh, Ramona; Zimbelmann, Marina; Holsboer, Florian; Landgraf, Rainer

2008-07-01

Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a 'stress reactivity test' (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the 'high reactivity' (HR) and the 'low reactivity' (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an 'intermediate reactivity' (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety

Histopathological and Ultrastructural Studies of Liver Tissue from TCDD-Exposed Beach Mice (Peromyscus polionotus).

DTIC Science & Technology

1980-03-01

TQuantitative ultrastructural studies were conducted on liver tissue f ran beach Lj mice, Per~ ascus polionotus, exposed to the toxin 2,3, 7f8...weights per se was not attempted since the ages of the beach mice were not known and the animals could only be classified by sex and treatment. The

Studies of teratomas in mice: possibilities for the future production of animal models.

PubMed Central

Lehman, J. M.

1980-01-01

The murine teratoma-teratocarcinoma has become an interesting model for the study of neoplastic transformation, developmental biology, and possibly a useful system for genetic studies. These tumors arise spontaneously in 129 strain mice and can be induced in other strains by transplanting early embryos or portions of embryos into extrauterine sites. The majority of these tumors are benign, but some are capable of transplantation due to the presence of the stem cell, embryonal carcinoma, which is a multipotential cell able to proliferate and also differentiate into tissues and cell types representative of all the embryonic germ layers. It has been elegantly shown by transplantation of embryonal carcinoma cells into blastocysts which are then placed into a pseudopregnant mouse that a normal mouse is obtained composed of cells from the host blastocyst and also cells from the malignant embryonal carcinoma. Therefore, under this set of circumstances, embryonal carcinoma cells are induced to functionally differentiate into multiple cell and tissue types which are benign and able to contribute to the development of a mouse. The adaptation of the embryonal carcinoma cell to tissue culture has allowed the manipulation of these cells with subsequent selection of mutant cells which can be further transplanted into blastocysts to obtain a mouse which contains these mutant cells. If the mutant cells have populated the germ line, it may be possible to obtain a stock of mice with the lesion present in all cells. This system may be exploitable for studies in neoplasia, developmental biology, and with proper selection procedures, allow the development of new genetic strains of mice. PMID:7457573

NASA Animal Enclosure Module Mouse Odor Containment Study for STS-107 September 15, 1999;SJSU Odor Panel Data

NASA Technical Reports Server (NTRS)

Holley, Daniel C.; Mele, Gary D.; Poffenroth, Mary; Young, Cliff

2000-01-01

Experiment #153 by Scott Brady is manifested for shuttle flight STS-107. This evaluation of space flight induced stress and its effects on neuronal plasticity will use 18 six month old C57Bl/6 male mice. A 21 day evaluation study was proposed to determine the length of time groups of 6, 9, or 12 mice could be housed in the Animal Enclosure Module (AEM) without odor breakthrough. This study was performed at NASA-Ames Research Center beginning on September 15, 1999. NASA personnel, were responsible for animal care, maintenance, facilities, hardware, etc. San Jose State personnel performed the odor panel evaluations and data reduction. We used similar procedures and methods for earlier tests evaluating female mice.

Demonstration of Nondeclarative Sequence Learning in Mice: Development of an Animal Analog of the Human Serial Reaction Time Task

ERIC Educational Resources Information Center

Christie, Michael A.; Hersch, Steven M.

2004-01-01

In this paper, we demonstrate nondeclarative sequence learning in mice using an animal analog of the human serial reaction time task (SRT) that uses a within-group comparison of behavior in response to a repeating sequence versus a random sequence. Ten female B6CBA mice performed eleven 96-trial sessions containing 24 repetitions of a 4-trial…

Syrian Hamster as an Animal Model for the Study of Human Influenza Virus Infection.

PubMed

Iwatsuki-Horimoto, Kiyoko; Nakajima, Noriko; Ichiko, Yurie; Sakai-Tagawa, Yuko; Noda, Takeshi; Hasegawa, Hideki; Kawaoka, Yoshihiro

2018-02-15

Ferrets and mice are frequently used as animal models for influenza research. However, ferrets are demanding in terms of housing space and handling, whereas mice are not naturally susceptible to infection with human influenza A or B viruses. Therefore, prior adaptation of human viruses is required for their use in mice. In addition, there are no mouse-adapted variants of the recent H3N2 viruses, because these viruses do not replicate well in mice. In this study, we investigated the susceptibility of Syrian hamsters to influenza viruses with a view to using the hamster model as an alternative to the mouse model. We found that hamsters are sensitive to influenza viruses, including the recent H3N2 viruses, without adaptation. Although the hamsters did not show weight loss or clinical signs of H3N2 virus infection, we observed pathogenic effects in the respiratory tracts of the infected animals. All of the H3N2 viruses tested replicated in the respiratory organs of the hamsters, and some of them were detected in the nasal washes of infected animals. Moreover, a 2009 pandemic (pdm09) virus and a seasonal H1N1 virus, as well as one of the two H3N2 viruses, but not a type B virus, were transmissible by the airborne route in these hamsters. Hamsters thus have the potential to be a small-animal model for the study of influenza virus infection, including studies of the pathogenicity of H3N2 viruses and other strains, as well as for use in H1N1 virus transmission studies. IMPORTANCE We found that Syrian hamsters are susceptible to human influenza viruses, including the recent H3N2 viruses, without adaptation. We also found that a pdm09 virus and a seasonal H1N1 virus, as well as one of the H3N2 viruses, but not a type B virus tested, are transmitted by the airborne route in these hamsters. Syrian hamsters thus have the potential to be used as a small-animal model for the study of human influenza viruses. Copyright © 2018 American Society for Microbiology.

Propagation of Human Hepatocytes in uPA/SCID Mice: Producing Chimeric Mice with Humanized Liver.

PubMed

Ohshita, Hiroki; Tateno, Chise

2017-01-01

Primary or cryopreserved human hepatocytes (h-heps) have been used as the gold standard for in vitro metabolism and hepatotoxicity studies; however, the supply of h-heps is limited and they cannot grow in vitro. We achieved approximately 1000-fold propagation of h-heps in the liver of albumin promoter/enhancer-driven urokinase-type plasminogen activator transgenic/severe combined immunodeficiency disease (uPA/SCID) mice with genetically induced liver disease and immunodeficiency. When h-heps are transplanted into the uPA/SCID mouse liver via the spleen, the h-heps engraft in the mouse liver, resulting in its repopulation with h-heps. We have named this model "chimeric mouse with humanized liver, PXB-mouse ® ." Fresh h-heps can be isolated from the chimeric mice (PXB-cells ® ) and have been used for in vitro studies.The efficacy and safety of chemical entities for use in humans are estimated using experimental animals such as rats and mice. The drug development of many chemical entities has been halted because of metabolic differences between humans and animals during clinical studies. Therefore, chimeric mice with humanized liver have been used to predict human-type metabolism and safety conditions for h-heps. In addition, until recently there were no suitable hepatitis B or C virus (HBV or HCV) susceptible animal models aside from chimpanzees. Chimeric mice are the sole persistent infectious small animal model for HBV and HCV and they have been used to investigate the efficacy of new anti-HBV or HCV agents.In this chapter, we describe a method for producing chimeric mice with humanized liver using uPA/SCID mice.

Bone Marrow Transplantation in Mice as a Tool to Generate Genetically Modified Animals

NASA Astrophysics Data System (ADS)

Rőszer, Tamás; Pintye, Éva; Benkő, Ilona

2008-12-01

Transgenic mice can be used either as models of known inherited human diseases or can be applied to perform phenotypic tests of genes with unknown function. In some special applications of gene modification we have to create a tissue specific mutation of a given gene. In some cases however the gene modification can be lethal in the intrauterine life, therefore we should engraft the mutated cells in the postnatal life period. After total body irradiation transplantation of bone marrow cells can be a solution to introduce mutant hematopoietic stem cells into a mature animal. Bone marrow transplantation is a useful and novel tool to study the role of hematopoietic cells in the pathogenesis of inflammation, autoimmune syndromes and many metabolic alterations coupled recently to leukocyte functions.

Evidence of lung cancer risk from animal studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cross, F.T.

Human epidemiological data provide the most important basis for assessing risks of radon exposures. However, additional insight into the nature of exposure-response relationships is provided by animal experimentation and dosimetric determinations. Animal studies have now been conducted for more than 50 years to examine the levels of pollutants in underground mines that were responsible for the respiratory effects observed among miners. This work has emphasized respiratory cancer and the interaction of radon with other agents, such as ore dust, diesel-engine-exhaust fumes and cigarette smoke. The more recent data on radon-daughter inhalation exposures were provided by two American research centers, Themore » University of Rochester (UR) and the Pacific Northwest Laboratory (PNL), and by the Compagnie Generale des Matieres Nucleaires (COGEMA) laboratory in France. Approximately 2000 mice, 100 rats and 80 dogs were employed in the completed UR studies, begun in the mid 1950s; 800 hamsters, 5000 rats and 100 dogs in the ongoing PNL studies, begun in the late 1960s; and 10,000 rats in the ongoing COGEMA studies, also begun in the late 1960s. More complete updated biological effects, data resulting from chronic radon-daughter inhalation exposures of mice, hamsters, rats and beagle dogs were examined. Emphasis on the carcinogenic effects of radon-decay product exposure, including the influences of radon-daughter exposure rate, unattached fraction and disequilibrium, and co-exposures to other pollutants. Plausible values for the radon (radon-daughter) lifetime lung-cancer risk coefficients are also provided. 13 refs., 1 fig., 1 tab.« less

Responses of Male C57BL/6N Mice to Observing the Euthanasia of Other Mice.

PubMed

Boivin, Gregory P; Bottomley, Michael A; Grobe, Nadja

2016-01-01

The AVMA Panel on Euthanasia recommends that sensitive animals should not be present during the euthanasia of others, especially of their own species, but does not provide guidelines on how to identify a sensitive species. To determine if mice are a sensitive species we reviewed literature on empathy in mice, and measured the cardiovascular and activity response of mice observing euthanasia of conspecifics. We studied male 16-wk-old C57BL/6N mice and found no increase in cardiovascular parameters or activity in the response of the mice to observing CO2 euthanasia. Mice observing decapitation had an increase in all values, but this was paralleled by a similar increase during mock decapitations in which no animals were handled or euthanized. We conclude that CO2 euthanasia of mice does not have an impact on other mice in the room, and that euthanasia by decapitation likely only has an effect due to the noise of the guillotine. We support the conceptual idea that mice are both a sensitive species and display empathy, but under the controlled circumstances of the euthanasia procedures used in this study there was no signaling of stress to witnessing inhabitants in the room.

WOUND HEALING ACTIVITY OF EXTRACT FROM THYMUS DAENENSIS IN BURN WOUND MODEL: AN EXPERIMENTAL ANIMAL STUDY.

PubMed

Babaeizadeh, Simin; Heydarnejhad, Saeed; Pirbalouti, Abdollah Ghasemi; Khamesipoor, Faham; Moghtadaei-Khorasgani, Elham; Heydari-Soureshjani, Parisa

2016-11-01

Bum wound is one of the most common complications and remains a major public health issue affecting all ages groups in both developed and developing countries. This study was aimed to evaluate the extract from Thymus daenensis and silver sulfadiazine on healing bum wounds in mice. In this experimental study, the ethanol extract from the aerial parts of T. daenensis (Lamiaceae) was used. Second-degree bum wounds were induced in three groups of eight Balb/C mice each. Group-I: the animals were treated with simple cream (control), Group-II: the animals were treated with simple cream containing the herb extract, and Group-III: the animals received the standard drug (silver sulfadiazine). The experimental groups were evaluated based on wound area, epithelialization time and histopathological characteristics. There were significant differences in surface area and the period of bum wound healing between the groups, particularly among Group-II when the animals received the extract of T. daenensis in comparison with control. At the 18" day, there was no significant improvement in healing percentage of the herb treated (94.6%) in comparison to the animals receiving the standard drug (95.8%). The best results of histopathological investigation were obtained with the extract of T. daenensis, when compared to the other group as well as to the control and standard drug. The herbal cream experimentally and histopathologically revealed a bum wound healing activity probably due to the antioxidant and anti-inflammatory activity of its phytochemical contents, especially phenolic compounds. Therefore, T. daenensis accelerated wound healing in mice and thus supports its traditional use.

Study of Camelpox Virus Pathogenesis in Athymic Nude Mice

PubMed Central

Duraffour, Sophie; Matthys, Patrick; van den Oord, Joost J.; De Schutter, Tim; Mitera, Tania; Snoeck, Robert; Andrei, Graciela

2011-01-01

Camelpox virus (CMLV) is the closest known orthopoxvirus genetically related to variola virus. So far, CMLV was restricted to camelids but, recently, three human cases of camelpox have been described in India, highlighting the need to pursue research on its pathogenesis, which has been hampered by the lack of small animal models. Here, we confirm that NMRI immunocompetent mice are resistant to intranasal (i.n.) CMLV infection. However, we demonstrate that CMLV induced a severe disease following i.n. challenge of athymic nude mice, which was accompanied with a failure in gaining weight, leading to euthanasia of the animals. On the other hand, intracutaneous (i.c.) infection resulted in disease development without impacting the body weight evolution. CMLV replication in tissues and body fluids was confirmed in the two models. We further analyzed innate immune and B cell responses induced in the spleen and draining lymph nodes after exposure to CMLV. In both models, strong increases in CD11b+F4/80+ macrophages were seen in the spleen, while neutrophils, NK and B cell responses varied between the routes of infection. In the lymph nodes, the magnitude of CD11c+CD8α+ lymphoid and CD11c+CD11b+ myeloid dendritic cell responses increased in i.n. challenged animals. Analysis of cytokine profiles revealed significant increases of interleukin (IL)-6 and IL-18 in the sera of infected animals, while those of other cytokines were similar to uninfected controls. The efficacy of two antivirals (cidofovir or HPMPC, and its 2, 6-diaminopurine analog) was evaluated in both models. HPMPC was the most effective molecule affording 100% protection from morbidity. It appeared that both treatments did not affect immune cell responses or cytokine expression. In conclusion, we demonstrated that immunodeficient mice are permissive for CMLV propagation. These results provide a basis for studying the pathogenesis of CMLV, as well as for evaluating potential antiviral therapies in an

Chronic Giardia muris infection in anti-IgM-treated mice. I. Analysis of immunoglobulin and parasite-specific antibody in normal and immunoglobulin-deficient animals.

PubMed

Snider, D P; Gordon, J; McDermott, M R; Underdown, B J

1985-06-01

To investigate the role of B cells and antibody in the immune response of mice to the murine intestinal parasite Giardia muris, we used mice treated from birth with rabbit anti-IgM antisera (aIgM). Such mice developed in serum and in gut secretions extreme Ig deficiency (IgM, IgA, and IgG) relative to control animals. The aIgM-treated mice showed no anti-G. muris antibody in serum or in gut wash material. Infections of G. muris in these mice were chronic, with a high load of parasite present in the small bowel, as reflected by prolonged cyst excretion (greater than 11 wk) and high trophozoite counts. In contrast, normal, untreated mice or NRS-treated animals developed anti-parasite IgA and IgG antibody in serum, demonstrated IgA antibody against the parasite in gut washings, and expelled the parasite within 9 wk. These effects of aIgM treatment on the murine response to primary infection with G. muris were demonstrated in two strains of mice: BALB/c and (C57BL/6 X C3H/He) F1. It was also observed that the response to G. muris infection in untreated animals was characterized by higher than normal total secretion of IgA into the gut and a concomitant increase in the serum polymeric IgA level. Mice treated with aIgM had a marked decrease of both monomeric and polymeric IgA in serum, and little detectable IgA in the intestinal lumen. These experiments provide the first demonstration that anti-IgM treatment suppresses a specific intestinal antibody response to antigen, and provide evidence that B cells and antibody play a role in the development of an effective response to a primary infection with G. muris in mice.

Light microscopic study of the effect of new antischistosmal drug (myrrh extract) on the liver of mice.

PubMed

Massoud, Ahmed M A; el Ebiary, Faika H; Ibrahim, Suzi H

2005-12-01

The efficacy of purified oleo-resin extract of myrrh derived from Commiphora molmol tree, (known as Mirazid) was studied against an Egyptian strain of Schistosoma mansoni in mice. Seventy adult male mice were used in this study. They were divided into 4 groups: G.I: consisted of control noninfected nontreated mice. G.II: comprised the noninfected treated mice and was subdivided into two subgroups, subgroup II-A: included mice which received Myrrh extract dissolved in cremophore EL and subgroup II-B: included mice which were treated with cremophore EL. G.III: consisted of the infected nontreated animals and G.IV: included infected mice which were treated with myrrh extract. The drug was given 8 weeks post infection in a dose of 500 mg/kg body weight/day for 5 successive days. All animals were sacrificed after 12 weeks from the beginning of the experiment. Liver paraffin sections were prepared and stained with H&E, Masson's Trichrome stain, PAS stain and Wilder's technique. A morphometric study was performed for the mean number and perimeter of the granulomas. Area percentage of the total collagen content around central veins as well as in portal areas was also estimated. The livers of the animals in G.II which received either myrrh extract (subgroup II-A) or cremophore EL (subgroup II-B) showed a more or less normal histological profile when compared to G.I (noninfected-nontreated group). G.IV (Infected treated G.) showed complete preservation of the hepatic architecture. Most of the hepatocytes appeared almost normal. The reticular network in the central part of the granulomas as well as in the portal tracts appeared rarefied. The hepatic reticular network was preserved. A significant decrease in the number and size of granulomas with significant reduction in the collagen content deposition in portal tracts and around central veins was detected when compared to G.III (infected nontreated mice). The data of this study proved the efficacy of myrrh as a promising

Preflight studies on tolerance of pocket mice to oxygen and heat. III - Effects on eyes

NASA Technical Reports Server (NTRS)

Philpott, D. E.; Corbett, R. L.; Black, S.; Takahashi, A.; Leaffer, D.

1975-01-01

A study was made of the eyes of eight pocket mice exposed to oxygen at partial pressures of 8, 10, or 12 psi over a period of 7 d. At the termination of the exposure, the animals were decompressed to sea-level O2, either immediately or over a period of 30, 60, or 90 min. No pathological changes were found in any of the eyes, except in the retina of one of the animals exposed to 12 psi O2. Here, only a single rod photoreceptor was found damaged, an observation not regarded as significant. Hence, an oxygen partial pressure as high as 12 psi in the canister in which pocket mice were expected to fly on Apollo XVII would probably have no deleterious effect on the eyes of the animals.

Inhalation reproductive toxicology studies: Sperm morphology study of n-hexane in B6C3F1 mice: Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mast, T.J.; Hackett, P.L.; Decker, J.R.

The straight-chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent routinely used in industrial environments. Although myelinated nerve tissue is the primary target organ of hexane, the testes have also been identified as being sensitive to hexacarbon exposure. The objective of this study was to evaluate the epididymal sperm morphology of male B6D3F1 mice 5 weeks after exposure to 0, 200, 1000, or 5000 ppM n-hexane, 20 h/day for 5 consecutive days. Two concurrent positive control groups of animals were injected intraperitoneally with either 200 or 250 mg/kg ethyl methanesulfonate, a known mutagen, once each day for 5 consecutive days. Themore » mice were weighed just prior to the first day of exposure and at weekly intervals until sacrifice. During the fifth post-exposure week the animals were killed and examined for gross lesions of the reproductive tract and suspensions of the epididymal sperm were prepared for morphological evaluations. The appearance and behavior of the mice were unremarkable throughout the experiment and there were no deaths. No evidence of lesions in any organ was noted at sacrifice. Mean body weights of male mice exposed to n-hexane were not significantly different from those for the 0-ppM animals at any time during the study. Analyses of the sperm morphology data obtained 5 weeks post-exposure (the only time point examined) indicated that exposure of male mice to relatively high concentrations of n-hexane vapor for 5 days produced no significant effects on the morphology of sperm relative to that of the 0-ppM control group. 24 refs., 2 figs., 7 tabs.« less

Flaws in animal studies exploring statins and impact on meta-analysis.

PubMed

Moja, Lorenzo; Pecoraro, Valentina; Ciccolallo, Laura; Dall'Olmo, Luigi; Virgili, Gianni; Garattini, Silvio

2014-06-01

Animal experiments should be appropriately designed, correctly analysed and transparently reported to increase their scientific validity and maximise the knowledge gained from each experiment. This systematic review of animal experiments investigating statins evaluates their quality of reporting and methodological aspects as well as their implications for the conduction of meta-analyses. We searched medline and embase for studies reporting research on statins in mice, rats and rabbits. We collected detailed information about the characteristics of studies, animals and experimental methods. We retrieved 161 studies. A little over half did not report randomisation (55%) and most did not describe blinding (88%). All studies reported details on the experimental procedure, although many omitted information about animal gender, age or weight. Four percent did not report the number of animals used. None reported the sample size. Fixed- and random-effects models gave different results (ratio of effect size increased by five folds). Heterogeneity was consistently substantial within animal models, for which accounting for covariates had minimal impact. Publication bias is highly suspected across studies. Although statins showed efficacy in animal models, preclinical studies highlighted fundamental problems in the way in which such research is conducted and reported. Results were often difficult to interpret and reproduce. Different meta-analytic approaches were highly inconsistent: a reliable approach to estimate the true parameter was imperceptible. Policies that address these issues are required from investigators, editors and institutions that care about the quality standards and ethics of animal research. © 2014 Stichting European Society for Clinical Investigation Journal Foundation.

Gender differences in cerebral metabolism for color processing in mice: A PET/MRI Study.

PubMed

Njemanze, Philip C; Kranz, Mathias; Amend, Mario; Hauser, Jens; Wehrl, Hans; Brust, Peter

2017-01-01

Color processing is a central component of mammalian vision. Gender-related differences of color processing revealed by non-invasive functional transcranial Doppler ultrasound suggested right hemisphere pattern for blue/yellow chromatic opponency by men, and a left hemisphere pattern by women. The present study measured the accumulation of [18F]fluorodeoxyglucose ([18F]FDG) in mouse brain using small animal positron emission tomography and magnetic resonance imaging (PET/MRI) with statistical parametric mapping (SPM) during light stimulation with blue and yellow filters compared to darkness condition. PET revealed a reverse pattern relative to dark condition compared to previous human studies: Male mice presented with left visual cortex dominance for blue through the right eye, while female mice presented with right visual cortex dominance for blue through the left eye. We applied statistical parametric mapping (SPM) to examine gender differences in activated architectonic areas within the orbital and medial prefrontal cortex and related cortical and sub-cortical areas that lead to the striatum, medial thalamus and other brain areas. The metabolic connectivity of the orbital and medial prefrontal cortex evoked by blue stimulation spread through a wide range of brain structures implicated in viscerosensory and visceromotor systems in the left intra-hemispheric regions in male, but in the right-to-left inter-hemispheric regions in female mice. Color functional ocular dominance plasticity was noted in the right eye in male mice but in the left eye in female mice. This study of color processing in an animal model could be applied in the study of the role of gender differences in brain disease.

Responses of Male C57BL/6N Mice to Observing the Euthanasia of Other Mice

PubMed Central

Boivin, Gregory P; Bottomley, Michael A; Grobe, Nadja

2016-01-01

The AVMA Panel on Euthanasia recommends that sensitive animals should not be present during the euthanasia of others, especially of their own species, but does not provide guidelines on how to identify a sensitive species. To determine if mice are a sensitive species we reviewed literature on empathy in mice, and measured the cardiovascular and activity response of mice observing euthanasia of conspecifics. We studied male 16-wk-old C57BL/6N mice and found no increase in cardiovascular parameters or activity in the response of the mice to observing CO2 euthanasia. Mice observing decapitation had an increase in all values, but this was paralleled by a similar increase during mock decapitations in which no animals were handled or euthanized. We conclude that CO2 euthanasia of mice does not have an impact on other mice in the room, and that euthanasia by decapitation likely only has an effect due to the noise of the guillotine. We support the conceptual idea that mice are both a sensitive species and display empathy, but under the controlled circumstances of the euthanasia procedures used in this study there was no signaling of stress to witnessing inhabitants in the room. PMID:27423146

Oxytocin in the Treatment of Dystocia in Mice

PubMed Central

Narver, Heather L

2012-01-01

Physicians and veterinarians often prescribe oxytocin to treat dystocia. However, oxytocin administration to pregnant women or animals is not without risk. In the venue of laboratory animal medicine, the use of oxytocin may present confounding variables to research. Although oxytocin has been studied extensively, many of its physiologic effects and interactions with other hormones remain unclear. Investigator concerns about adverse and confounding effects of oxytocin in their research mice prompted the current review of oxytocin and its use to treat murine dystocia. Well-controlled studies of oxytocin in dystocic mice have not been conducted. However, in humans and other animals, inconsistent and adverse effects are well-documented. Limited knowledge of the complex physiologic and molecular mechanisms of action of oxytocin and scant support for the efficacy of oxytocin in dystocic mice fail to meet the standards of evidence-based veterinary medical practice. The administration of oxytocin is contraindicated in many cases of dystocia in research mice, and its use in dystocic mice may be unfounded. A brief review of oxytocin and the physiologic mechanisms of parturition are provided to support this conclusion. Alternative treatments for murine dystocia are discussed, and a holistic approach is advocated to better serve animal welfare and to safeguard the integrity of valuable research. Laboratory animal veterinarians overseeing the development of guidelines or standard operating procedures for technician or investigator treatment of dystocic mice should understand the effects of oxytocin administration in light of relevant research. PMID:22330862

Euthanasia of neonatal mice with carbon dioxide

USGS Publications Warehouse

Pritchett, K.; Corrow, D.; Stockwell, J.; Smith, A.

2005-01-01

Exposure to carbon dioxide (CO2) is the most prevalent method used to euthanize rodents in biomedical research. The purpose of this study was to determine the time of CO2 exposure required to euthanize neonatal mice (0 to 10 days old). Multiple groups of mice were exposed to 100% CO 2 for time periods between 5 and 60 min. Mice were placed in room air for 10 or 20 min after CO2 exposure, to allow for the chance of recovery. If mice recovered at one time point, a longer exposure was examined. Inbred and outbred mice were compared. Results of the study indicated that time to death varied with the age of the animals and could be as long as 50 min on the day of birth and differed between inbred and outbred mice. Institutions euthanizing neonatal mice with CO2 may wish to adjust their CO 2 exposure time periods according the age of the mice and their genetic background. Copyright 2005 by the American Association for Laboratory Animal Science.

Outstanding animal studies in allergy II. From atopic barrier and microbiome to allergen-specific immunotherapy.

PubMed

Jensen-Jarolim, Erika; Pali-Schöll, Isabella; Roth-Walter, Franziska

2017-06-01

Animal studies published within the past 18 months were assessed, focusing on innate and specific immunomodulation, providing knowledge of high translational relevance for human atopic and allergic diseases. Allergic companion animals represent alternative models, but most studies were done in mice. Atopic dermatitis mouse models were refined by the utilization of cytokines like IL-23 and relevant skin allergens or enzymes. A novel IL-6 reporter mouse allows biomonitoring of inflammation. Both skin pH and the (transferable) microflora have a pivotal role in modulating the skin barrier. The microflora of the gastrointestinal mucosa maintains tolerance to dietary compounds and can be disturbed by antiacid drugs. A key mouse study evidenced that dust from Amish households, but not from Hutterites protected mice against asthma. In studies on subcutaneous and sublingual allergen-specific immunotherapy, much focus was given on delivery and adjuvants, using poly-lacto-co-glycolic particles, CpGs, probiotics or Vitamin D3. The epicutaneous and intralymphatic routes showed promising results in mice and horses in terms of prophylactic and therapeutic allergy treatment. In atopic dermatitis, food allergies and asthma, environmental factors, together with the resident microflora and barrier status, decide on sensitization versus tolerance. Also allergen-specific immunotherapy operates with immunomodulatory principles.

Outstanding animal studies in allergy II. From atopic barrier and microbiome to allergen-specific immunotherapy

PubMed Central

Jensen-Jarolim, Erika; Pali-Schöll, Isabella; Roth-Walter, Franziska

2017-01-01

Purpose of review Animal studies published within the past 18 months were assessed, focusing on innate and specific immunomodulation, providing knowledge of high translational relevance for human atopic and allergic diseases. Recent findings Allergic companion animals represent alternative models, but most studies were done in mice. Atopic dermatitis mouse models were refined by the utilization of cytokines like IL-23 and relevant skin allergens or enzymes. A novel IL-6 reporter mouse allows biomonitoring of inflammation. Both skin pH and the (transferable) microflora have a pivotal role in modulating the skin barrier. The microflora of the gastrointestinal mucosa maintains tolerance to dietary compounds and can be disturbed by antiacid drugs. A key mouse study evidenced that dust from Amish households, but not from Hutterites protected mice against asthma. In studies on subcutaneous and sublingual allergen-specific immunotherapy, much focus was given on delivery and adjuvants, using poly-lacto-co-glycolic particles, CpGs, probiotics or Vitamin D3. The epicutaneous and intralymphatic routes showed promising results in mice and horses in terms of prophylactic and therapeutic allergy treatment. Summary In atopic dermatitis, food allergies and asthma, environmental factors, together with the resident microflora and barrier status, decide on sensitization versus tolerance. Also allergen-specific immunotherapy operates with immunomodulatory principles. PMID:28375932

Treatment for Traumatic Brain Injury in Mice Using Transcranial Magnetic Stimulation: A Preliminary Study

NASA Astrophysics Data System (ADS)

Carr, Alexandria; Zenitsky, Gary; Crowther, Lawrence; Hadimani, Ravi; Anantharam, Vellareddy; Kanthasamy, Anumantha; Jiles, David

2014-03-01

Transcranial magnetic stimulation (TMS) is a non-invasive surgery-free tool used to stimulate the brain by time-varying magnetic fields. TMS is currently being investigated as a treatment for neurological disorders such as depression, Parkinson's disease and TBI. Before moving to human TMS/TBI trials, animal testing should be pursued to determine suitability and adverse effects. As an initial study, four healthy mice were treated with TMS at different power levels to determine short-term behavioral effects and set a control group baseline. The mouse's behavior was studied using the Rotorod test, which measures the animal's latency to fall off a rotating rod, and the Versamax test, which measures horizontal and vertical movement, and total distance traveled. The Rotorod test has shown for TMS power levels >=90% the mice begin to fall directly post-treatment. Similarly, the Versamax test has shown for power levels >=80% the mice are less mobile directly post-treatment. Versamax mobility was found to return to normal the day following treatment. These mice were housed in the facility for 4 months and the behavioral tests were repeated. Versamax results showed there was no significant variation in mobility indicating there are no long-term side effects of TMS treatment on the mice. This work was supported by the Barbara and James Palmer Endowment and the Carver Charitable Trust at the Department of Electrical and Computer Engineering, Iowa State University.

Behavior of captive white-footed mice.

PubMed

Kavanau, J L

1967-03-31

Detailed studies of the behavior of captive white-footed mice have cast a number of old problems in new perspectives. Many responses of small captive mammals cannot be interpreted at face value because of severe distortions of behavior that are caused by depriving the wild animal of natural outlets for activity. Confined animals are likely to seize upon and repeatedly exercise virtually any opportunities to modify (and alter their relationships with) their surroundings. In addition they have a strong tendency to counteract nonvolitional and "unexpected" deviations from the status quo. As a result, their responses do not bear an immutable relationship to the nature of the stimulus or other variable being modified; stimuli and activities that are rewarding in certain circumstances are avoided in others. These aspects of behavior have been illustrated by studies of nest occupancy, running in motordriven wheels, and control of intensity of illumination. The results of the control-of-illumination studies suggest the complex interplay of tendencies to modify features of the environment, to avoid conditions imposed compulsorily, and to select preferred levels of illumination. The importance of split-second timing, coordination, and quick reflex actions in the running of activity wheels is indicated by the fact that experienced white-footed mice prefer running in square "wheels" and wheels with hurdles to running in plain round wheels. The relatively conservative behavior of these mice in selecting between multiple sources of food and water and different types of activity wheels suggests the need for careful experimental design in free-choice studies with inexperienced animals. The tendency of trained animals to give some so-called "incorrect" responses even after long experience can be interpreted most reasonably in terms of the adaptive value of a certain degree of variability of behavior in the wild. White-footed mice readily master complex regimes in which several

[Animal experimentation, animal welfare and scientific research].

PubMed

Tal, H

2013-10-01

Hundreds of thousands of laboratory animals are being used every year for scientific experiments held in Israel, mostly mice, rats, rabbits, guinea pigs, and a few sheep, cattle, pigs, cats, dogs, and even a few dozen monkeys. In addition to the animals sacrificed to promote scientific research, millions of animals slain every year for other purposes such as meat and fine leather fashion industries. While opening a front against all is an impossible and perhaps an unjustified task, the state of Israel enacted the Animal Welfare (Animal Experimentation) Law (1994). The law aims to regulate scientific animal experiments and to find the appropriate balance between the need to continue to perform animal experiments for the advancement of research and medicine, and at the same time to avoid unnecessary trials and minimize animal suffering. Among other issues the law deals with the phylogenetic scale according to which experimental animals should be selected, experiments for teaching and practicing, and experiments for the cosmetic industry. This article discusses bioethics considerations in animal experiments as well as the criticism on the scientific validity of such experiments. It further deals with the vitality of animal studies and the moral and legal obligation to prevent suffering from laboratory animals.

Alterations of amino acids and monoamine metabolism in male Fmr1 knockout mice: a putative animal model of the human fragile X mental retardation syndrome.

PubMed

Gruss, M; Braun, K

2001-01-01

The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) gene leading to the absence of the encoded fragile X mental retardation protein 1 (FMRP). We describe morphological and behavioral abnormalities for both affected humans and Fmr1 knockout mice, a putative animal model for the human Fragile X syndrome. The aim of the present study was to identify possible neurochemical abnormalities in Fmr1 knockout mice, with particular focus on neurotransmission. Significant region-specific differences of basal neurotransmitter and metabolite levels were found between wildtype and Fmr1 knockout animals, predominantly in juveniles (post-natal days 28 to 31). Adults (postnatal days 209 to 221) showed only few abnormalities as compared with the wildtype. In juvenile knockout mice, aspartate and taurine were especially increased in cortical regions, striatum, hippocampus, cerebellum, and brainstem. In addition, juveniles showed an altered balance between excitatory and inhibitory amino acids in the caudal cortex, hippocampus, and brainstem. We detected very few differences in monoamine turnover in both age stages. The results presented here provide the first evidence that lack of FMRP expression in FMRP knockout mice is accompanied by age-dependent, region-specific alterations in neurotransmission.

Diabetic neuropathy: electrophysiological and morphological study of peripheral nerve degeneration and regeneration in transgenic mice that express IFNbeta in beta cells.

PubMed

Serafín, Anna; Molín, Jessica; Márquez, Merce; Blasco, Ester; Vidal, Enric; Foradada, Laia; Añor, Sonia; Rabanal, Rosa M; Fondevila, Dolors; Bosch, Fàtima; Pumarola, Martí

2010-05-01

Diabetic neuropathy is one of the most frequent complications in diabetes but there are no treatments beyond glucose control, due in part to the lack of an appropriate animal model to assess an effective therapy. This study was undertaken to characterize the degenerative and regenerative responses of peripheral nerves after induced sciatic nerve damage in transgenic rat insulin I promoter / human interferon beta (RIP/IFNbeta) mice made diabetic with a low dose of streptozotocin (STZ) as an animal model of diabetic complications. In vivo, histological and immunohistological studies of cutaneous and sciatic nerves were performed after left sciatic crush. Functional tests, cutaneous innervation, and sciatic nerve evaluation showed pronounced neurological reduction in all groups 2 weeks after crush. All animals showed a gradual recovery but this was markedly slower in diabetic animals in comparison with normoglycemic animals. The delay in regeneration in diabetic RIP/IFNbeta mice resulted in an increase in active Schwann cells and regenerating neurites 8 weeks after surgery. These findings indicate that diabetic-RIP/IFNbeta animals mimic human diabetic neuropathy. Moreover, when these animals are submitted to nerve crush they have substantial deficits in nerve regrowth, similar to that observed in diabetic patients. When wildtype animals were treated with the same dose of STZ, no differences were observed with respect to nontreated animals, indicating that low doses of STZ and the transgene are not implicated in development of the degenerative and regenerative events observed in our study. All these findings indicate that RIP/IFNbeta transgenic mice are a good model for diabetic neuropathy.

Multiple Antibiotic Resistance Gene Transfer from Animal to Human Enterococci in the Digestive Tract of Gnotobiotic Mice

PubMed Central

Moubareck, C.; Bourgeois, N.; Courvalin, P.; Doucet-Populaire, F.

2003-01-01

It has been proposed that food animals represent the source of glycopeptide resistance genes present in enterococci from humans. We demonstrated the transfer of vanA and of other resistance genes from porcine to human Enterococcus faecium at high frequency in the digestive tract of gnotobiotic mice. Tylosin in the drinking water favored colonization by transconjugants. PMID:12937011

Animal and human studies with the mitochondria-targeted antioxidant MitoQ.

PubMed

Smith, Robin A J; Murphy, Michael P

2010-07-01

As mitochondrial oxidative damage contributes to a wide range of human diseases, antioxidants designed to be accumulated by mitochondria in vivo have been developed. The most extensively studied of these mitochondria-targeted antioxidants is MitoQ, which contains the antioxidant quinone moiety covalently attached to a lipophilic triphenylphosphonium cation. MitoQ has now been used in a range of in vivo studies in rats and mice and in two phase II human trials. Here, we review what has been learned from these animal and human studies with MitoQ.

The guinea pig as an animal model for developmental and reproductive toxicology studies.

PubMed

Rocca, Meredith S; Wehner, Nancy G

2009-04-01

Regulatory guidelines for developmental and reproductive toxicology (DART) studies require selection of "relevant" animal models as determined by kinetic, pharmacological, and toxicological data. Traditionally, rats, mice, and rabbits are the preferred animal models for these studies. However, for test articles that are pharmacologically inactive in the traditional animal models, the guinea pig may be a viable option. This choice should not be made lightly, as guinea pigs have many disadvantages compared to the traditional species, including limited historical control data, variability in pregnancy rates, small and variable litter size, long gestation, relative maturity at birth, and difficulty in dosing and breeding. This report describes methods for using guinea pigs in DART studies and provides results of positive and negative controls. Standard study designs and animal husbandry methods were modified to allow mating on the postpartum estrus in fertility studies and were used for producing cohorts of pregnant females for developmental studies. A positive control study with the pregnancy-disrupting agent mifepristone resulted in the anticipated failure of embryo implantation and supported the use of the guinea pig model. Control data for reproductive endpoints collected from 5 studies are presented. In cases where the traditional animal models are not relevant, the guinea pig can be used successfully for DART studies. (c) 2009 Wiley-Liss, Inc.

The suitability of 129SvEv mice for studying depressive-like behaviour: both males and females develop learned helplessness.

PubMed

Chourbaji, Sabine; Pfeiffer, Natascha; Dormann, Christof; Brandwein, Christiane; Fradley, Rosa; Sheardown, Malcolm; Gass, P

2010-07-29

Behavioural studies using transgenic techniques in mice usually require extensive backcrossing to a defined background strain, e.g. to C57BL/6. In this study we investigated whether backcrossing can be replaced by using the 129SvEv strain from which the embryonic stem cells are generally obtained for gene targeting strategies to analyze e.g. depression-like behaviour. For that purpose we subjected male and female 129SvEv mice to two frequently used depression tests and compared them with commonly used C57BL/6 mice. 129SvEv and C57BL/6 mice exhibited differing profiles with regard to locomotion and pain sensitivity. However, in the learned helplessness paradigm, a procedure, which represents a valid method to detect depressive-like behaviour, 129SvEv animals develop a similar level of helplessness as C57BL/6 mice. One great advantage of the 129SvEv animals though, is the fact that in this strain even females develop helplessness, which could not be produced in C57BL/6 mice. In the tail suspension test, both genders of 129SvEv exhibited more despair behaviour than C57BL/6 animals. We therefore suggest that this strain may be utilized in the establishment of new test procedures for affective diseases, since costly and time-consuming backcrossing can be prevented, depressive-like behaviour may be analyzed effectively, and gender-specific topics could be addressed in an adequate way. Copyright 2010 Elsevier B.V. All rights reserved.

Comparative study of murid gammaherpesvirus 4 infection in mice and in a natural host, bank voles.

PubMed

François, Sylvie; Vidick, Sarah; Sarlet, Michaël; Michaux, Johan; Koteja, Pawel; Desmecht, Daniel; Stevenson, Philip G; Vanderplasschen, Alain; Gillet, Laurent

2010-10-01

Gammaherpesviruses are archetypal pathogenic persistent viruses. The known human gammaherpesviruses (Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus) are host-specific and therefore lack a convenient in vivo infection model. This makes related animal gammaherpesviruses an important source of information. Infection by murid herpesvirus 4 (MuHV-4), a virus originally isolated from bank voles (Myodes glareolus), was studied here. MuHV-4 infection of inbred laboratory mouse strains (Mus musculus) is commonly used as a general model of gammaherpesvirus pathogenesis. However, MuHV-4 has not been isolated from house mice, and no systematic comparison has been made between experimental MuHV-4 infections of mice and bank voles. This study therefore characterized MuHV-4 (strain MHV-68) infection of bank voles through global luciferase imaging and classical virological methods. As in mice, intranasal virus inoculation led to productive replication in bank vole lungs, accompanied by massive cellular infiltrates. However, the extent of lytic virus replication was approximately 1000-fold lower in bank voles than in mice. Peak latency titres in lymphoid tissue were also lower, although latency was still established. Finally, virus transmission was tested between animals maintained in captivity. However, as observed in mice, MuHV-4 was not transmitted between voles under these conditions. In conclusion, this study revealed that, despite quantitative differences, replication and the latency sites of MuHV-4 are comparable in bank voles and mice. Therefore, it appears that, so far, Mus musculus represents a suitable host for studying gammaherpesvirus pathogenesis with MuHV-4. Establishing transmission conditions in captivity will be a vital step for further research in this field.

Animal models of human immunodeficiency virus infection. Public Health Service Animal Models Committee.

PubMed

Spertzel, R O

1989-12-01

The search for a model of HIV infection continues. While much of the initial work focussed on animal models of AIDS, more recent efforts have sought animal models of HIV infection in which one or more signs of AIDS may be reproduced. Most initial small animal modelling efforts were negative and many such efforts remain unpublished. In 1988, the Public Health Service (PHS) AIDS Animal Model Committee conducted a survey among PHS agencies to identify published and unpublished data on animal models of HIV. To date, the chimpanzee is the only animal to be reliably infected with HIV albeit without development of signs and symptoms normally associated with human AIDS. One recent study has shown the gibbon to be similarly susceptible to infection with HIV. Mice carrying a chimera of elements of the human immune system have been shown to support the growth of HIV and F1 progeny of transgenic mice containing intact copies of HIV proviral DNA, have developed a disease that resembles some aspects of human AIDS. Rabbits, baboons and rhesus monkeys have also been shown to be infected under certain conditions and/or with selected strains of HIV but again without the development of AIDS symptomatology. This report briefly summarizes published and available unpublished data on these efforts to develop an animal model of HIV infection.

EXPERIMENTAL ANIMAL MAINTENANCE

DOEpatents

Finkel, M.P.

1962-01-22

A method of housing experimental animals such as mice in individual tube- like plastic enclosures is described. Contrary to experience, when this was tried with metal the mice did not become panicky. Group housing, with its attendant difficulties, may thus be dispensed with. (AEC)

Consistency and Reproducibility of Bioaerosol Delivery for Infectivity Studies on Mice

DTIC Science & Technology

2010-03-01

respiration, the most common being the common laboratory rat (strains of Rattus norvegicus) and mouse ( Mus musculus ). Animal respiratory systems are...validation U U U UU 92 Joseph D. Wander Reset CONSISTENCY AND REPRODUCIBILITY OF BIOAEROSOL DELIVERY FOR INFECTIVITY STUDIES ON MICE...design and construction phase of the project. The data from this thesis appear as part of the US Air Force Research Laboratory technical report AFRL

Using dried blood spot sampling to improve data quality and reduce animal use in mouse pharmacokinetic studies.

PubMed

Wickremsinhe, Enaksha R; Perkins, Everett J

2015-03-01

Traditional pharmacokinetic analysis in nonclinical studies is based on the concentration of a test compound in plasma and requires approximately 100 to 200 μL blood collected per time point. However, the total blood volume of mice limits the number of samples that can be collected from an individual animal-often to a single collection per mouse-thus necessitating dosing multiple mice to generate a pharmacokinetic profile in a sparse-sampling design. Compared with traditional methods, dried blood spot (DBS) analysis requires smaller volumes of blood (15 to 20 μL), thus supporting serial blood sampling and the generation of a complete pharmacokinetic profile from a single mouse. Here we compare plasma-derived data with DBS-derived data, explain how to adopt DBS sampling to support discovery mouse studies, and describe how to generate pharmacokinetic and pharmacodynamic data from a single mouse. Executing novel study designs that use DBS enhances the ability to identify and streamline better drug candidates during drug discovery. Implementing DBS sampling can reduce the number of mice needed in a drug discovery program. In addition, the simplicity of DBS sampling and the smaller numbers of mice needed translate to decreased study costs. Overall, DBS sampling is consistent with 3Rs principles by achieving reductions in the number of animals used, decreased restraint-associated stress, improved data quality, direct comparison of interanimal variability, and the generation of multiple endpoints from a single study.

Particulate matter in animal rooms housing mice in microisolation caging.

PubMed

Langham, Gregory L; Hoyt, Robert F; Johnson, Thomas E

2006-11-01

Reactions to allergens created by laboratory animals are among the most frequently encountered occupational illnesses associated with research animals. Personnel are exposed to these allergens through airborne particulate matter. Although the use of microisolation caging systems can reduce particulate matter concentrations in rooms housing mice, the operating parameters of ventilated caging systems vary extensively. We compared room air in mouse rooms containing 5 different types of caging: 1) individually ventilated caging under positive pressure with filtered intake air and exhaust air returned to the room (VCR+), 2) individually ventilated caging under negative pressure with exhaust air returned to the room (VCR-), 3) individually ventilated caging under positive pressure with exhaust air returned to the heating, ventilation, and air-conditioning (HVAC) system, 4) individually ventilated caging under negative pressure with exhaust air returned to the HVAC system, and 5) static microisolation cages. We found that rooms under VCR conditions had fewer large particles than did those under other conditions, but the numbers of 0.3 microm particles did not differ significantly among systems. Static, positive or negative pressure applied to caging units as well as route of air exhaust were found to have little influence on the total number of particles in the atmosphere. Therefore, considering the heat load, odor, and overall particulate concentration in the room, placing individually ventilated caging under negative pressure with exhaust air returned to the HVAC system appears to be the optimal overall choice when using microisolation housing for rodents.

Obsessive-compulsive disorder: Insights from animal models☆

PubMed Central

Szechtman, Henry; Ahmari, Susanne E.; Beninger, Richard J.; Eilam, David; Harvey, Brian H.; Edemann-Callesen, Henriette; Winter, Christine

2017-01-01

Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests. PMID:27168347

Coping with parvovirus infections in mice: health surveillance and control.

PubMed

Janus, Lydia M; Bleich, Andre

2012-01-01

Parvoviruses of mice, minute virus of mice (MVM) and mouse parvovirus (MPV), are challenging pathogens to eradicate from laboratory animal facilities. Due to the impediment on rodent-based research, recent studies have focused on the assessment of re-derivation techniques and parvoviral potential to induce persistent infections. Summarizing recent data, this review gives an overview on studies associated with parvoviral impact on research, diagnostic methods, parvoviral persistence and re-derivation techniques, demonstrating the complex nature of parvovirus infection in mice and unfolding the challenge of controlling parvovirus infections in laboratory animal facilities.

Animal imaging studies of potential brain damage

NASA Astrophysics Data System (ADS)

Gatley, S. J.; Vazquez, M. E.; Rice, O.

To date, animal studies have not been able to predict the likelihood of problems in human neurological health due to HZE particle exposure during space missions outside the Earth's magnetosphere. In ongoing studies in mice, we have demonstrated that cocaine stimulated locomotor activity is reduced by a moderate dose (120 cGy) of 1 GeV 56Fe particles. We postulate that imaging experiments in animals may provide more sensitive and earlier indicators of damage due to HZE particles than behavioral tests. Since the small size of the mouse brain is not well suited to the spatial resolution offered by microPET, we are now repeating some of our studies in a rat model. We anticipate that this will enable us to identify imaging correlates of behavioral endpoints. A specific hypothesis of our studies is that changes in the metabolic rate for glucose in striatum of animals will be correlated with alterations in locomotor activity. We will also evaluate whether the neuroprotective drug L-deprenyl reduces the effect of radiation on locomotor activity. In addition, we will conduct microPET studies of brain monoamine oxidase A and monoamine oxidase B in rats before and at various times after irradiation with HZE particles. The hypothesis is that monoamine oxidase A, which is located in nerve terminals, will be unchanged or decreased after irradiation, while monoamine oxidase B, which is located in glial cells, will be increased after irradiation. Neurochemical effects that could be measured using PET could in principle be applied in astronauts, in terms of detecting and monitoring subtle neurological damage that might have occurred during long space missions. More speculative uses of PET are in screening candidates for prolonged space missions (for example, for adequate reserve in critical brain circuits) and in optimizing medications to treat impairments after missions.

Mice prefer draught-free housing.

PubMed

Krohn, T C; Hansen, A K

2010-10-01

An increasing number of rodents are housed in individually ventilated cage (IVC) systems, as these seem to be very effective for the protection of animals against infections, as well as protecting the staff against allergens. For the IVC systems to be properly ventilated, a huge amount of air has to be blown into the cage, which may cause a draught at animal level inside the cage. The aim of the present study was to evaluate the preferences of mice for differing levels of air speeds and air changes inside the cage. It has been concluded that mice do react to draughts, whereas they do not seem to be affected by a high number of air changes delivered without draught, which underlines the importance of applying draught-free IVC systems for mice.

A Model for Precise and Uniform Pelvic- and Limb-Sparing Abdominal Irradiation to Study the Radiation-Induced Gastrointestinal Syndrome in Mice Using Small Animal Irradiation Systems.

PubMed

Brodin, N Patrik; Velcich, Anna; Guha, Chandan; Tomé, Wolfgang A

2017-01-01

Currently, no readily available mitigators exist for acute abdominal radiation injury. Here, we present an animal model for precise and homogenous limb-sparing abdominal irradiation (LSAIR) to study the radiation-induced gastrointestinal syndrome (RIGS). The LSAIR technique was developed using the small animal radiation research platform (SARRP) with image guidance capabilities. We delivered LSAIR at doses between 14 and 18 Gy on 8- to 10-week-old male C57BL/6 mice. Histological analysis was performed to confirm that the observed mortality was due to acute abdominal radiation injury. A steep dose-response relationship was found for survival, with no deaths seen at doses below 16 Gy and 100% mortality at above 17 Gy. All deaths occurred between 6 and 10 days after irradiation, consistent with the onset of RIGS. This was further confirmed by histological analysis showing clear differences in the number of regenerative intestinal crypts between animals receiving sublethal (14 Gy) and 100% lethal (18 Gy) radiation. The developed LSAIR technique provides uniform dose delivery with a clear dose response, consistent with acute abdominal radiation injury on histological examination. This model can provide a useful tool for researchers investigating the development of mitigators for accidental or clinical high-dose abdominal irradiation.

Developmental Exposure of Mice to TCDD Elicits a Similar Uterine Phenotype in Adult Animals as Observed in Women with Endometriosis

PubMed Central

Nayyar, Tultul; Bruner-Tran, Kaylon L.; Piestrzeniewicz-Ulanska, Dagmara; Osteen, Kevin G.

2007-01-01

Whether environmental toxicants impact an individual woman’s risk for developing endometriosis remains uncertain. Although the growth of endometrial glands and stroma at extra-uterine sites is associated with retrograde menstruation, our studies suggest that reduced responsiveness to progesterone may increase the invasive capacity of endometrial tissue in women with endometriosis. Interestingly, our recent studies using isolated human endometrial cells in short-term culture suggest that experimental exposure to the environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the expression of progesterone receptor isotypes. Compared to adult exposure, toxicant exposure during development can exert a significantly greater biological impact, potentially affecting the incidence of endometriosis in adults. To address this possibility, we exposed mice to TCDD at critical developmental time points and subsequently examined uterine progesterone receptor expression and steroid responsive transforming growth factor-β2 expression in adult animals. We find that the uterine phenotype of toxicant-exposed mice is markedly similarly to the endometrial phenotype of women with endometriosis. PMID:17056225

9 CFR 355.16 - Control of flies, rats, mice, etc.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Control of flies, rats, mice, etc. 355.16 Section 355.16 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF....16 Control of flies, rats, mice, etc. Flies, rats, mice, and other vermin shall be excluded from...

9 CFR 355.16 - Control of flies, rats, mice, etc.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Control of flies, rats, mice, etc. 355.16 Section 355.16 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF....16 Control of flies, rats, mice, etc. Flies, rats, mice, and other vermin shall be excluded from...

9 CFR 355.16 - Control of flies, rats, mice, etc.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Control of flies, rats, mice, etc. 355.16 Section 355.16 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF....16 Control of flies, rats, mice, etc. Flies, rats, mice, and other vermin shall be excluded from...

9 CFR 355.16 - Control of flies, rats, mice, etc.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Control of flies, rats, mice, etc. 355.16 Section 355.16 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF....16 Control of flies, rats, mice, etc. Flies, rats, mice, and other vermin shall be excluded from...

9 CFR 355.16 - Control of flies, rats, mice, etc.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Control of flies, rats, mice, etc. 355.16 Section 355.16 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF....16 Control of flies, rats, mice, etc. Flies, rats, mice, and other vermin shall be excluded from...

Early myocardial dysfunction in streptozotocin-induced diabetic mice: a study using in vivo magnetic resonance imaging (MRI)

PubMed Central

Yu, Xichun; Tesiram, Yasvir A; Towner, Rheal A; Abbott, Andrew; Patterson, Eugene; Huang, Shijun; Garrett, Marion W; Chandrasekaran, Suresh; Matsuzaki, Satoshi; Szweda, Luke I; Gordon, Brian E; Kem, David C

2007-01-01

Background Diabetes is associated with a cardiomyopathy that is independent of coronary artery disease or hypertension. In the present study we used in vivo magnetic resonance imaging (MRI) and echocardiographic techniques to examine and characterize early changes in myocardial function in a mouse model of type 1 diabetes. Methods Diabetes was induced in 8-week old C57BL/6 mice with two intraperitoneal injections of streptozotocin. The blood glucose levels were maintained at 19–25 mmol/l using intermittent low dosages of long acting insulin glargine. MRI and echocardiography were performed at 4 weeks of diabetes (age of 12 weeks) in diabetic mice and age-matched controls. Results After 4 weeks of hyperglycemia one marker of mitochondrial function, NADH oxidase activity, was decreased to 50% of control animals. MRI studies of diabetic mice at 4 weeks demonstrated significant deficits in myocardial morphology and functionality including: a decreased left ventricular (LV) wall thickness, an increased LV end-systolic diameter and volume, a diminished LV ejection fraction and cardiac output, a decreased LV circumferential shortening, and decreased LV peak ejection and filling rates. M-mode echocardiographic and Doppler flow studies of diabetic mice at 4 weeks showed a decreased wall thickening and increased E/A ratio, supporting both systolic and diastolic dysfunction. Conclusion Our study demonstrates that MRI interrogation can identify the onset of diabetic cardiomyopathy in mice with its impaired functional capacity and altered morphology. The MRI technique will lend itself to repetitive study of early changes in cardiac function in small animal models of diabetic cardiomyopathy. PMID:17309798

An Animal Model of Trichloroethylene-Induced Skin Sensitization in BALB/c Mice.

PubMed

Wang, Hui; Zhang, Jia-xiang; Li, Shu-long; Wang, Feng; Zha, Wan-sheng; Shen, Tong; Wu, Changhao; Zhu, Qi-xing

2015-01-01

Trichloroethylene (TCE) is a major occupational hazard and environmental contaminant that can cause multisystem disorders in the form of occupational medicamentosa-like dermatitis. Development of dermatitis involves several proinflammatory cytokines, but their role in TCE-mediated dermatitis has not been examined in a well-defined experimental model. In addition, few animal models of TCE sensitization are available, and the current guinea pig model has apparent limitations. This study aimed to establish a model of TCE-induced skin sensitization in BALB/c mice and to examine the role of several key inflammatory cytokines on TCE sensitization. The sensitization rate of dorsal painted group was 38.3%. Skin edema and erythema occurred in TCE-sensitized groups, as seen in 2,4-dinitrochlorobenzene (DNCB) positive control. Trichloroethylene sensitization-positive (dermatitis [+]) group exhibited increased thickness of epidermis, inflammatory cell infiltration, swelling, and necrosis in dermis and around hair follicle, but ear painted group did not show these histological changes. The concentrations of serum proinflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2 were significantly increased in 24, 48, and 72 hours dermatitis [+] groups treated with TCE and peaked at 72 hours. Deposition of TNF-α, IFN-γ, and IL-2 into the skin tissue was also revealed by immunohistochemistry. We have established a new animal model of skin sensitization induced by repeated TCE stimulations, and we provide the first evidence that key proinflammatory cytokines including TNF-α, IFN-γ, and IL-2 play an important role in the process of TCE sensitization. © The Author(s) 2015.

Robotically assisted small animal MRI-guided mouse biopsy

NASA Astrophysics Data System (ADS)

Wilson, Emmanuel; Chiodo, Chris; Wong, Kenneth H.; Fricke, Stanley; Jung, Mira; Cleary, Kevin

2010-02-01

Small mammals, namely mice and rats, play an important role in biomedical research. Imaging, in conjunction with accurate therapeutic agent delivery, has tremendous value in small animal research since it enables serial, non-destructive testing of animals and facilitates the study of biomarkers of disease progression. The small size of organs in mice lends some difficulty to accurate biopsies and therapeutic agent delivery. Image guidance with the use of robotic devices should enable more accurate and repeatable targeting for biopsies and delivery of therapeutic agents, as well as the ability to acquire tissue from a pre-specified location based on image anatomy. This paper presents our work in integrating a robotic needle guide device, specialized stereotaxic mouse holder, and magnetic resonance imaging, with a long-term goal of performing accurate and repeatable targeting in anesthetized mice studies.

Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain.

PubMed

Giorgini, Flaviano; Huang, Shao-Yi; Sathyasaikumar, Korrapati V; Notarangelo, Francesca M; Thomas, Marian A R; Tararina, Margarita; Wu, Hui-Qiu; Schwarcz, Robert; Muchowski, Paul J

2013-12-20

Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo(-/-) mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo(-/-) mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo(-/-) mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD(+), did not differ between Kmo(-/-) and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo(-/-) mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo(-/-) mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease.

Virulence, pathology, and pathogenesis of Pteropine orthoreovirus (PRV) in BALB/c mice: Development of an animal infection model for PRV.

PubMed

Egawa, Kazutaka; Shimojima, Masayuki; Taniguchi, Satoshi; Nagata, Noriyo; Tani, Hideki; Yoshikawa, Tomoki; Kurosu, Takeshi; Watanabe, Shumpei; Fukushi, Shuetsu; Saijo, Masayuki

2017-12-01

Cases of acute respiratory tract infection caused by Pteropine orthoreovirus (PRV) of the genus Orthoreovirus (family: Reoviridae) have been reported in Southeast Asia, where it was isolated from humans and bats. It is possible that PRV-associated respiratory infections might be prevalent in Southeast Asia. The clinical course of PRV is not fully elucidated. The virulence, pathology, and pathogenesis of two PRV strains, a human-borne PRV strain (isolated from a patient, who returned to Japan from Bali, Indonesia in 2007) and a bat-borne PRV (isolated from a bat [Eonycteris spelaea] in the Philippines in 2013) were investigated in BALB/c mice using virological, pathological, and immunological study methods. The intranasal inoculation of BALB/c mice with human-borne PRV caused respiratory infection. In addition, all mice with immunity induced by pre-inoculation with a non-lethal dose of PRV were completely protected against lethal PRV infection. Mice treated with antiserum with neutralizing antibody activity after inoculation with a lethal dose of PRV showed a reduced fatality rate. In this mouse model, bat-borne PRV caused respiratory infection similar to human-borne PRV. PRV caused lethal respiratory disease in an animal model of PRV infection, in which BALB/c mice were used. The BALB/c mouse model might help to accelerate research on the virulence of PRV and be useful for evaluating the efficacy of therapeutic agents and vaccines for the treatment and prevention of PRV infection. PRV was shown for the first time to be a causative virus of respiratory disease on the basis of Koch's postulations by the additional demonstration that PRV caused respiratory disease in mice through their intranasal inoculation with PRV.

Trends in animal use at US research facilities.

PubMed

Goodman, Justin; Chandna, Alka; Roe, Katherine

2015-07-01

Minimising the use of animals in experiments is universally recognised by scientists, governments and advocates as an ethical cornerstone of research. Yet, despite growing public opposition to animal experimentation, mounting evidence that animal studies often do not translate to humans, and the development of new research technologies, a number of countries have reported increased animal use in recent years. In the USA--one of the world's largest users of animals in experiments--a lack of published data on the species most commonly used in laboratories (eg, mice, rats and fish) has prevented such assessments. The current study aimed to fill this gap by analysing the use of all vertebrate animals by the top institutional recipients of National Institutes of Health research funds over a 15-year period. These data show a statistically significant 72.7% increase in the use of animals at these US facilities during this time period-driven primarily by increases in the use of mice. Our results highlight a need for greater efforts to reduce animal use. We discuss technical, institutional, sociological and psychological explanations for this trend. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Health surveillance of specific pathogen-free and conventionally-housed mice and rats in Korea.

PubMed

Seok, Seunghyeok; Park, Jonghwan; Cho, Suna; Baek, Minwon; Lee, Huiyoung; Kim, Dongjae; Yang, Kihwa; Jang, Dongdeuk; Han, Beomseok; Nam, Kitaek; Park, Jaehak

2005-01-01

The present study contains information about proper microbiological monitoring of laboratory animals' health and the standardization of microbiological monitoring methods in Korea. Microbiological quality control for laboratory animals, composed of biosecurity and health surveillance, is essential to guard against research complications and public health dangers that have been associated with adventitious infections. In this study, one hundred and twenty-two mice and ninety rats from laboratory animal breeding companies and one animal facility of the national universities in Korea were monitored in 2000-2003. Histopathologically, thickening of the alveolar walls and lymphocytic infiltration around the bronchioles were observed in mice and rats from microbiologically contaminated facilities. Cryptosporidial oocysts were observed in the gastric pits of only conventionally-housed mice and rats. Helicobacter spp. infection was also detected in 1 of 24 feces DNA samples in mice and 9 of 40 feces DNA samples in rats by PCR in 2003, but they were not Helicobacter hepaticus. This paper describes bacteriological, parasitological, and virological examinations of the animals.

Endogenous IL-1 in Cognitive Function and Anxiety: A Study in IL-1RI−/− Mice

PubMed Central

Murray, Carol L.; Obiang, Pauline; Bannerman, David; Cunningham, Colm

2013-01-01

Interleukin-1 (IL-1) is a key pro-inflammatory cytokine, produced predominantly by peripheral immune cells but also by glia and some neuronal populations within the brain. Its signalling is mediated via the binding of IL-1α or IL-1β to the interleukin-1 type one receptor (IL-1RI). IL-1 plays a key role in inflammation-induced sickness behaviour, resulting in depressed locomotor activity, decreased exploration, reduced food and water intake and acute cognitive deficits. Conversely, IL-1 has also been suggested to facilitate hippocampal-dependent learning and memory: IL-1RI−/− mice have been reported to show deficits on tasks of visuospatial learning and memory. We sought to investigate whether there is a generalised hippocampal deficit in IL-1RI−/− animals. Therefore, in the current study we compared wildtype (WT) mice to IL-1RI−/− mice using a variety of hippocampal-dependent learning and memory tasks, as well as tests of anxiety and locomotor activity. We found no difference in performance of the IL-1RI−/− mice compared to WT mice in a T-maze working memory task. In addition, the IL-1RI−/− mice showed normal learning in various spatial reference memory tasks including the Y-maze and Morris mater maze, although there was a subtle deficit in choice behaviour in a spatial discrimination, beacon watermaze task. IL-1RI−/− mice also showed normal memory for visuospatial context in the contextual fear conditioning paradigm. In the open field, IL-1RI−/− mice showed a significant increase in distance travelled and rearing behaviour compared to the WT mice and in the elevated plus-maze spent more time in the open arms than did the WT animals. The data suggest that, contrary to prior studies, IL-1RI−/− mice are not robustly impaired on hippocampal-dependent memory and learning but do display open field hyperactivity and decreased anxiety compared to WT mice. The results argue for a careful evaluation of the roles of endogenous IL-1 in

Experimental root canal infections in conventional and germ-free mice.

PubMed

Sobrinho, A P; Barros, M H; Nicoli, J R; Carvalho, M A; Farias, L M; Bambirra, E A; Bahia, M G; Vieira, E C

1998-06-01

A small animal model was evaluated to study the interrelationships between microorganisms after their implantation in root canals (inferior central incisors) using germ-free (GF) and conventional (CV) mice. The selected microorganisms were: Porphyromonas endodontalis (ATCC 35406), Eubacterium lentum (ATCC 25559), Peptostreptococcus anaerobius (ATCC 27337), Fusobacterium nucleatum (ATCC 10953), Escherichia coli (ATCC 25922), and Enterococcus faecalis (ATCC 4083). Only P. anaerobius, E. coli, and E. faecalis, respectively, were able to colonize when inoculated alone into the root canal of both CV and GF mice. E. lentum, when inoculated alone colonized only in CV animals. P. endodontalis and F. nucleatum were unable to colonize in CV and GF animals after single inoculation. It is concluded that the experimental animal model presented herein is valuable for ecological studies of root canal infections and that only some strict anaerobic bacteria are able to colonize mice root canals when inoculated by themselves alone in pure culture.

Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life Span of Wild-Type Mice: A PET Study.

PubMed

Brendel, Matthias; Focke, Carola; Blume, Tanja; Peters, Finn; Deussing, Maximilian; Probst, Federico; Jaworska, Anna; Overhoff, Felix; Albert, Nathalie; Lindner, Simon; von Ungern-Sternberg, Barbara; Bartenstein, Peter; Haass, Christian; Kleinberger, Gernot; Herms, Jochen; Rominger, Axel

2017-12-01

Contrary to findings in the human brain, 18 F-FDG PET shows cerebral hypermetabolism of aged wild-type (WT) mice relative to younger animals, supposedly due to microglial activation. Therefore, we used dual-tracer small-animal PET to examine directly the link between neuroinflammation and hypermetabolism in aged mice. Methods: WT mice (5-20 mo) were investigated in a cross-sectional design using 18 F-FDG ( n = 43) and translocator protein (TSPO) ( 18 F-GE180; n = 58) small-animal PET, with volume-of-interest and voxelwise analyses. Biochemical analysis of plasma cytokine levels and immunohistochemical confirmation of microglial activity were also performed. Results: Age-dependent cortical hypermetabolism in WT mice relative to young animals aged 5 mo peaked at 14.5 mo (+16%, P < 0.001) and declined to baseline at 20 mo. Similarly, cortical TSPO binding increased to a maximum at 14.5 mo (+15%, P < 0.001) and remained high to 20 mo, resulting in an overall correlation between 18 F-FDG uptake and TSPO binding (R = 0.69, P < 0.005). Biochemical and immunohistochemical analyses confirmed the TSPO small-animal PET findings. Conclusion: Age-dependent neuroinflammation is associated with the controversial observation of cerebral hypermetabolism in aging WT mice. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Animal models of sepsis.

PubMed

Fink, Mitchell P

2014-01-01

Sepsis remains a common, serious, and heterogeneous clinical entity that is difficult to define adequately. Despite its importance as a public health problem, efforts to develop and gain regulatory approval for a specific therapeutic agent for the adjuvant treatment of sepsis have been remarkably unsuccessful. One step in the critical pathway for the development of a new agent for adjuvant treatment of sepsis is evaluation in an appropriate animal model of the human condition. Unfortunately, the animal models that have been used for this purpose have often yielded misleading findings. It is likely that there are multiple reasons for the discrepancies between the results obtained in tests of pharmacological agents in animal models of sepsis and the outcomes of human clinical trials. One of important reason may be that the changes in gene expression, which are triggered by trauma or infection, are different in mice, a commonly used species for preclinical testing, and humans. Additionally, many species, including mice and baboons, are remarkably resistant to the toxic effects of bacterial lipopolysaccharide, whereas humans are exquisitely sensitive. New approaches toward the use of animals for sepsis research are being investigated. But, at present, results from preclinical studies of new therapeutic agents for sepsis must be viewed with a degree of skepticism.

Influence of indigenous microbiota on experimental toxoplasmosis in conventional and germ-free mice.

PubMed

Nascimento, Bruna B; Cartelle, Christiane T; Noviello, Maria de L; Pinheiro, Breno V; de Almeida Vitor, Ricardo W; Souza, Danielle da G; de Vasconcelos Generoso, Simone; Cardoso, Valbert N; Martins, Flaviano Dos S; Nicoli, Jacques R; Arantes, Rosa M E

2017-08-01

Toxoplasmosis represents one of the most common zoonoses worldwide. Its agent, Toxoplasma gondii, causes a severe innate pro-inflammatory response. The indigenous intestinal microbiota promotes host animal homoeostasis and may protect the host against pathogens. Germ-free (GF) animals provide an important tool for the study of interactions between host and microbiota. In this study, we assessed the role of indigenous microorganisms in disease development utilizing a murine toxoplasmosis model, which includes conventional (CV) and GF NIH Swiss mice. CV and GF mice orally inoculated with T. gondii had similar survival curves. However, disease developed differently in the two animal groups. In CV mice, intestinal permeability increased and levels of intestinal pro-inflammatory cytokines were altered. In GF animals, there were discrete epithelial degenerative changes and mucosal oedema, but the liver and lungs displayed significant lesions. We conclude that, despite similar survival curves, CV animals succumb to an exaggerated inflammatory response, whereas GF mice fail to produce an adequate systemic response. © 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.

Virtual reality for freely moving animals.

PubMed

Stowers, John R; Hofbauer, Maximilian; Bastien, Renaud; Griessner, Johannes; Higgins, Peter; Farooqui, Sarfarazhussain; Fischer, Ruth M; Nowikovsky, Karin; Haubensak, Wulf; Couzin, Iain D; Tessmar-Raible, Kristin; Straw, Andrew D

2017-10-01

Standard animal behavior paradigms incompletely mimic nature and thus limit our understanding of behavior and brain function. Virtual reality (VR) can help, but it poses challenges. Typical VR systems require movement restrictions but disrupt sensorimotor experience, causing neuronal and behavioral alterations. We report the development of FreemoVR, a VR system for freely moving animals. We validate immersive VR for mice, flies, and zebrafish. FreemoVR allows instant, disruption-free environmental reconfigurations and interactions between real organisms and computer-controlled agents. Using the FreemoVR platform, we established a height-aversion assay in mice and studied visuomotor effects in Drosophila and zebrafish. Furthermore, by photorealistically mimicking zebrafish we discovered that effective social influence depends on a prospective leader balancing its internally preferred directional choice with social interaction. FreemoVR technology facilitates detailed investigations into neural function and behavior through the precise manipulation of sensorimotor feedback loops in unrestrained animals.

Animal welfare and use of silkworm as a model animal.

PubMed

Sekimizu, N; Paudel, A; Hamamoto, H

2012-08-01

Sacrificing model animals is required for developing effective drugs before being used in human beings. In Japan today, at least 4,210,000 mice and other mammals are sacrificed to a total of 6,140,000 per year for the purpose of medical studies. All the animals treated in Japan, including test animals, are managed under control of "Act on Welfare and Management of Animals". Under the principle of this Act, no person shall kill, injure, or inflict cruelty on animals without due cause. "Animal" addressed in the Act can be defined as a "vertebrate animal". If we can make use of invertebrate animals in testing instead of vertebrate ones, that would be a remarkable solution for the issue of animal welfare. Furthermore, there are numerous advantages of using invertebrate animal models: less space and small equipment are enough for taking care of a large number of animals and thus are cost-effective, they can be easily handled, and many biological processes and genes are conserved between mammals and invertebrates. Today, many invertebrates have been used as animal models, but silkworms have many beneficial traits compared to mammals as well as other insects. In a Genome Pharmaceutical Institute's study, we were able to achieve a lot making use of silkworms as model animals. We would like to suggest that pharmaceutical companies and institutes consider the use of the silkworm as a model animal which is efficacious both for financial value by cost cutting and ethical aspects in animals' welfare.

Hypoxia facilitates neurogenic dural plasma protein extravasation in mice: a novel animal model for migraine pathophysiology

PubMed Central

Hunfeld, Anika; Segelcke, Daniel; Bäcker, Ingo; Mecheri, Badreddine; Hemmer, Kathrin; Dlugosch, Elisabeth; Andriske, Michael; Paris, Frank; Zhu, Xinran; Lübbert, Hermann

2015-01-01

Migraine animal models generally mimic the onset of attacks and acute treatment processes. A guinea pig model used the application of meta-chlorophenylpiperazine (mCPP) to trigger immediate dural plasma protein extravasation (PPE) mediated by 5-HT2B receptors. This model has predictive value for antimigraine drugs but cannot explain the delayed onset of efficacy of 5-HT2B receptor antagonists when clinically used for migraine prophylaxis. We found that mCPP failed to induce dural PPE in mice. Considering the role 5-HT2B receptors play in hypoxia-induced pulmonary vessel muscularization, we were encouraged to keep mice under hypoxic conditions and tested whether this treatment will render them susceptible to mCPP-induced dural PPE. Following four-week of hypoxia, PPE, associated with increased transendothelial transport, was induced by mCPP. The effect was blocked by sumatriptan. Chronic application of 5-HT2B receptor or nitric oxide synthase blockers during hypoxia prevented the development of susceptibility. Here we present a migraine model that distinguishes between a migraine-like state (hypoxic mice) and normal, normoxic mice and mimics processes that are related to chronic activation of 5-HT2B receptors under hypoxia. It seems striking, that chronic endogenous activation of 5-HT2B receptors is crucial for the sensitization since 5-HT2B receptor antagonists have strong, albeit delayed migraine prophylactic efficacy. PMID:26644235

Gene Expression Changes in the Olfactory Bulb of Mice Induced by Exposure to Diesel Exhaust Are Dependent on Animal Rearing Environment

PubMed Central

Yokota, Satoshi; Hori, Hiroshi; Umezawa, Masakazu; Kubota, Natsuko; Niki, Rikio; Yanagita, Shinya; Takeda, Ken

2013-01-01

There is an emerging concern that particulate air pollution increases the risk of cranial nerve disease onset. Small nanoparticles, mainly derived from diesel exhaust particles reach the olfactory bulb by their nasal depositions. It has been reported that diesel exhaust inhalation causes inflammation of the olfactory bulb and other brain regions. However, these toxicological studies have not evaluated animal rearing environment. We hypothesized that rearing environment can change mice phenotypes and thus might alter toxicological study results. In this study, we exposed mice to diesel exhaust inhalation at 90 µg/m3, 8 hours/day, for 28 consecutive days after rearing in a standard cage or environmental enrichment conditions. Microarray analysis found that expression levels of 112 genes were changed by diesel exhaust inhalation. Functional analysis using Gene Ontology revealed that the dysregulated genes were involved in inflammation and immune response. This result was supported by pathway analysis. Quantitative RT-PCR analysis confirmed 10 genes. Interestingly, background gene expression of the olfactory bulb of mice reared in a standard cage environment was changed by diesel exhaust inhalation, whereas there was no significant effect of diesel exhaust exposure on gene expression levels of mice reared with environmental enrichment. The results indicate for the first time that the effect of diesel exhaust exposure on gene expression of the olfactory bulb was influenced by rearing environment. Rearing environment, such as environmental enrichment, may be an important contributive factor to causation in evaluating still undefined toxic environmental substances such as diesel exhaust. PMID:23940539

Health Benefits of Animal Research: The Mouse in Biomedical Research.

ERIC Educational Resources Information Center

Jonas, Albert M.

1984-01-01

Traces the history of using mice for medical research and discusses the benefits of using these animals for studies in bacteriology, virology, genetics (considering X-linked genetic homologies between mice and humans), molecular biology, immunology, hematology, immune response disorders, oncology, radiobiology, pharmacology, behavior genetics,…

Immunology and Homeopathy. 3. Experimental Studies on Animal Models

PubMed Central

Bellavite, Paolo; Ortolani, Riccardo; Conforti, Anita

2006-01-01

A search of the literature and the experiments carried out by the authors of this review show that there are a number of animal models where the effect of homeopathic dilutions or the principles of homeopathic medicine have been tested. The results relate to the immunostimulation by ultralow doses of antigens, the immunological models of the ‘simile’, the regulation of acute or chronic inflammatory processes and the use of homeopathic medicines in farming. The models utilized by different research groups are extremely etherogeneous and differ as the test medicines, the dilutions and the outcomes are concerned. Some experimental lines, particularly those utilizing mice models of immunomodulation and anti-inflammatory effects of homeopathic complex formulations, give support to a real effect of homeopathic high dilutions in animals, but often these data are of preliminary nature and have not been independently replicated. The evidence emerging from animal models is supporting the traditional ‘simile’ rule, according to which ultralow doses of compounds, that in high doses are pathogenic, may have paradoxically a protective or curative effect. Despite a few encouraging observational studies, the effectiveness of the homeopathic prevention or therapy of infections in veterinary medicine is not sufficiently supported by randomized and controlled trials. PMID:16786046

Biochemical effects of commercial feedstuffs on the fry of climbing perch (Anabas testudineus) and its impact on Swiss albino mice as an animal model.

PubMed

Munshi, Mita; Tumu, Khairun Nafiz; Hasan, Md Nazmul; Amin, Md Ziaul

2018-01-01

This study assesses the biochemical effects of commercially available fish feedstuffs on the fry of climbing perch ( Anabas testudineus ). Subsequently, its impact on experimental animal, Swiss albino mice, is also examined. In order to access the impact of commercial fish feed and feed consumption fish on the experimental animal, the proximate, biochemical and histopathological analyses were done using standard methods. The proximate composition as well as the concentrations of Pb, Ni, Mn, As, Zn, and Cd in the fish feed, different parts of the A. testudineus fish and different parts of the A. testudineus fish-treated experimental mice liver, were all determined using Energy Dispersive X-ray Fluorescence (EDXRF) Spectrometry. The highest levels of Cr, Pb and As were observed in the liver of Swiss albino mice treated with FFT2 and FFBB2 and their concentrations were 0.156, 0.491, 0.172 μg/g and 0.166, 0.771, 0.157 μg/g respectively. No significant changes of protein, fat, crude fiber, moisture and ash contents were observed after proximate composition analysis of fish feeds, A. testudineus and A. testudineus treated experimental mice. Significant amounts of heavy metals (Cr, Mn, Zn Cu, Ni) were found in fish feed, different parts of A. testudineus fish and in the experimental mice. However, remarkably high amounts were observed in the A. testudineus fish's head and bone with body parts. Biochemical analysis of blood samples of A. testudineus fish treated experimental mice indicated that the cholesterol, TG, LDL and glucose levels were significantly higher. Yet no significant alteration in the HDL level was observed when compared to the control. In histopathological analysis, a remarkable degeneration was observed in the liver and kidney of A. testudineus treated mice. It can therefore be concluded that although A. testudineus has nutritional benefits the quality of this fish may be compromised as a consequence of contamination through various anthropogenic

Exendin-4 improves resistance to Listeria monocytogenes infection in diabetic db/db mice

PubMed Central

Liu, Hsien Yueh; Chung, Chih-Yao; Yang, Wen-Chin; Liang, Chih-Lung; Wang, Chi-Young; Chang, Chih-Yu

2012-01-01

The incidence of diabetes mellitus is increasing among companion animals. This disease has similar characteristics in both humans and animals. Diabetes is frequently identified as an independent risk factor for infections associated with increased mortality. In the present study, homozygous diabetic (db/db) mice were infected with Listeria (L.) monocytogenes and then treated with the anti-diabetic drug exendin-4, a glucagon-like peptide 1 analogue. In aged db/db mice, decreased CD11b+ macrophage populations with higher lipid content and lower phagocytic activity were observed. Exendin-4 lowered high lipid levels and enhanced phagocytosis in macrophages from db/db mice infected with L. monocytogenes. Exendin-4 also ameliorated obesity and hyperglycemia, and improved ex vivo bacteria clearance by macrophages in the animals. Liver histology examined during L. monocytogenes infection indicated that abscess formation was much milder in exendin-4-treated db/db mice than in the control animals. Moreover, mechanistic studies demonstrated that expression of ATP binding cassette transporter 1, a sterol transporter, was higher in macrophages isolated from the exendin-4-treated db/db mice. Overall, our results suggest that exendin-4 decreases the risk of infection in diabetic animals by modifying the interaction between intracellular lipids and phagocytic macrophages. PMID:23000581

Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns.

PubMed

Golub, M S; Macintosh, M S; Baumrind, N

1998-01-01

Information on the reproductive and developmental toxicity of inorganic arsenic is available primarily from studies in animals using arsenite and arsenate salts and arsenic trioxide. Inorganic arsenic has been extensively studied as a teratogen in animals. Data from animal studies demonstrate that arsenic can produce developmental toxicity, including malformation, death, and growth retardation, in four species (hamsters, mice, rats, rabbits). A characteristic pattern of malformations is produced, and the developmental toxicity effects are dependent on dose, route, and the day of gestation when exposure occurs. Studies with gavage and diet administration indicate that death and growth retardation are produced by oral arsenic exposure. Arsenic is readily transferred to the fetus and produces developmental toxicity in embryo culture. Animal studies have not identified an effect of arsenic on fertility in males or females. When females were dosed chronically for periods that included pregnancy, the primary effect of arsenic on reproduction was a dose-dependent increase in conceptus mortality and in postnatal growth retardation. Human data are limited to a few studies of populations exposed to arsenic from drinking water or from working at or living near smelters. Associations with spontaneous abortion and stillbirth have been reported in more than one of these studies, but interpretation of these studies is complicated because study populations were exposed to multiple chemicals. Thus, animal studies suggest that environmental arsenic exposures are primarily a risk to the developing fetus. In order to understand the implications for humans, attention must be given to comparative pharmacokinetics and metabolism, likely exposure scenarios, possible mechanisms of action, and the potential role of arsenic as an essential nutrient.

Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice.

PubMed

Niemiec, T; Sikorska, J; Harrison, A; Szmidt, M; Sawosz, E; Wirth-Dzieciolowska, E; Wilczak, J; Pierzynowski, S

2011-02-01

The objective of this study was to evaluate the effect of α-ketoglutarate on redox state parameters and arterial elasticity in elderly mice. Mice in the control group were fed with standard diet, while the experimental animals received the diet supplemented either with calcium (Ca-AKG) or sodium salt of α-ketoglutarate (Na-AKG). The experimental animals were divided into 4 groups with 10 individuals in each: control I (12 months old), control II (2 months old), experimental group I fed with Ca-AKG (12 months old) and experimental group II fed with Na-AKG (12 months old). Mice treated with Ca-AKG as well as the control II animals demonstrated significantly higher level of total antioxidant status (TAS), comparing to the control I animals and those treated with Ca-AKG. Thiobarbituric acid reactive substances (TBARS) level in blood plasma was found significantly lower in young and Ca-AKG treated mice. TBARS liver concentration was significantly different in each examined group. The study also demonstrates the decrease in TBARS level in Ca-AKG treated animals. Treatment with Na-AKG significantly increased glutathione peroxidase activity and decreased the activity of superoxide dismutase. The presented results suggest that Ca-AKG protects the organism against the free radicals related elderly processes. The study presents also the effect of Ca-AKG treatment on arterial elastic characteristics in elderly mice. The beneficial effect of Ca-AKG on ageing organisms was confirmed via redox state stabilization and blood vessel elasticity improvement.

Development of an Advanced Animal Habitat for Spaceflight

NASA Technical Reports Server (NTRS)

Baer, L.; Vasques, M.; Martwick, F.; Hines, M.; Grindeland, R. E.

1994-01-01

It is necessary to fly a group-housed animals for many Life Science spaceflight studies. Currently, group-housed rodents are flown aboard the shuttle in the Animal Enclosure Module (AEM). Although the AEM has been used successfully for a number of flights, it has significant limitations in the number of animals it can accommodate, limited flight duration, passive temperature control and limited in flight data acquisition capability. An Advanced Animal Habitat (AAH) is being developed, which can be flown on the shuttle middeck, both spacelab and spacehab shuttle payload modules, and the space station. The AAH is designed to house 12 rats or 30 mice for up to 30 days. The AAH will have active temperature control, a window mechanism to facilitate video monitoring/recording of the animals, and biotelemetry capabilities. In addition, the design will permit access to the animals for experimental manipulations in space. The AAH can be refitted to experiment-specific requirements as needed. In initial 7-day hardware tests 12 male rats and 10 female mice show no adverse affects with respect to final body and organ weights as compared to vivarium. controls. The Advanced Animal Habitat will provide the science community opportunities to perform a greater variety of studies for longer duration in the microgravity environment than the current Animal Enclosure Module.

Infectious microorganisms in mice (Mus musculus) purchased from commercial pet shops in Germany.

PubMed

Dammann, P; Hilken, G; Hueber, B; Köhl, W; Bappert, M T; Mähler, M

2011-10-01

In this study, we investigated the prevalence of infectious microorganisms (viruses, bacteria, fungi and eukaryotic parasites) in mice from different pet shops in Germany; such animals may compromise the hygienic integrity of laboratory animal vivaria if private pet holders act as unintended vectors of infections carried by them. House mice sold as pets or feed specimens were purchased from different pet shops and tested for a comprehensive panel of unwanted microorganisms. We found a number of microorganisms in these pet shop mice, the most prevalent of which were Helicobacter species (92.9%), mouse parvovirus (89.3%), mouse hepatitis virus (82.7%), Pasteurella pneumotropica (71.4%) and Syphacia species (57.1%). Several microorganisms (e.g. mouse parvovirus, Theiler's murine encephalomyelitis virus, pneumonia virus of mice, Encephalitozoon cuniculi, Clostridium piliforme) had considerably higher prevalences than those reported in similar studies on wild mice from North America, Europe or Australia. Our study shows that direct contact with pet shop mice may constitute a risk for laboratory animal vivaria if hygienic precautions are not taken. However, even relatively simple precautions seem effective enough to hold the risk at bay.

[Study the rudimentary immunoregulatory mechanisms of Ganoderma Spore oil on immunocompromized mice].

PubMed

Yi, Youjin; Hu, Shun; Xiong, Xingyao; Liu, Dongbo; Zhong, Yingli

2012-09-01

To study the rudimentary immunoregulatory mechanisms of Ganoderma spore oil on immunocompromized mice model. Thrity KM mice were randomly selected and assigned into three groups (ten animals per group): the model control group, Ganoderma Lucidum spores oil group and the normal control group. The model control group and Ganoderma Lucidum spores oil group were injected intraperitoneally with cyclophosphamide at 40 mg x kg(-1) d to generate a immunocompromized mice model. The normal control group were administered with 0.9% NaCl solution 0.1 ml/10 g BW as placebo. All agents were given orally once a day, given for consecutive 30 days, Ganoderma Lucidum spores oil group 150 mg/kg, the others given maize 0.1 ml/10 g BW. The serum TNF-alpha , IFN-gamma content of the mice through ELISA kit and the expression levels of IL-2, IL-10, IL-12, IL-4, IFN-gamma, TNF-alpha mRNA in mouse spleen and thymus were examined by RT-PCR to rudimentary study its immunoregulatory mechanisms. Ganoderma spore oil can significantly increased the content of TNF-alpha and IFN-gamma in the serum and the expression levels of IL-2, IL-10, IL-12, IL-4, IFN-gamma, TNF-alpha mRNA in spleen and thymus, with obvious difference from the model control (P < or = 0.05). Ganoderma spore oil can be able to improve the above cytokine ion expression to immunoregulate the immunocompromized mice.

Vestibular Evoked Myogenic Potentials in Normal Mice and Phex Mice With Spontaneous Endolymphatic Hydrops

PubMed Central

Sheykholeslami, Kianoush; Megerian, Cliff A.; Zheng, Qing Y.

2010-01-01

Objective and Background Vestibular evoked myogenic potentials (VEMPs) have been recorded from the neck musculature and the cervical spinal cord in humans and a limited number of laboratory animals in response to loud sound. However, the mouse VEMP has yet to be described. Evaluation of the sacculocollic pathway via VEMPs in mice can set the stage for future evaluations of mutant mice that now play an important role in research regarding human auditory and vestibular dysfunction. Materials and Methods Sound-evoked potentials were recorded from the neck extensor muscles and the cervical spinal cord in normal adult mice and in circling PhexHyp-Duk/y mice with known vestibular abnormalities, including endolymphatic hydrops (ELH). Results Biphasic potentials were recorded from all normal animals. The mean threshold of the VEMP response in normal adult mice was 60 dB normal hearing level with a mean peak latency of 6.25 ± 0.46 and 7.95 ± 0.42 milliseconds for p1 and n1 peaks, respectively. At the maximum sound intensity used (100 dB normal hearing level), 4 of 5 Phex mice did not exhibit VEMP responses, and 1 showed an elevated threshold, but normal response, with regard to peak latency and amplitude. The histologic findings in all of these Phex mice were consistent with distended membranous labyrinth, displaced Reissner membrane, ganglion cell loss, and ELH. Conclusion This is the first report of VEMP recordings in mice and the first report of abnormal VEMPs in a mouse model with ELH. The characteristics of these potentials such as higher response threshold in comparison to auditory brainstem response, myogenic nature of the response, and latency correlation with the cervical recording (accessory nerve nucleus) were similar to those of VEMPs in humans, guinea pigs, cats, and rats, suggesting that the mouse may be used as an animal model in the study of VEMPs. The simplicity and reliability of these recordings make the VEMP a uniquely informative test for assessing

Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: A potential model for study of defective copper regulation in metabolic liver disease.

PubMed

Church, Stephanie J; Begley, Paul; Kureishy, Nina; McHarg, Selina; Bishop, Paul N; Bechtold, David A; Unwin, Richard D; Cooper, Garth J S

2015-05-08

Ob/ob mice provide an animal model for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) in patients with obesity and type-2 diabetes. Low liver copper has been linked to hepatic lipid build-up (steatosis) in animals with systemic copper deficiency caused by low-copper diets. However, hepatic copper status in patients with NAFLD or NASH is uncertain, and a validated animal model useful for the study of hepatic copper regulation in common forms of metabolic liver disease is lacking. Here, we report parallel measurements of essential metal levels in whole-liver tissue and defatted-dried liver tissue from ob/ob and non-obese control mice. Measurements in whole-liver tissue from ob/ob mice at an age when they have developed NAFLD/NASH, provide compelling evidence for factitious lowering of copper and all other essential metals by steatosis, and so cannot be used to study hepatic metal regulation in this model. By marked contrast, metal measurements in defatted-dried liver samples reveal that most essential metals were actually normal and indicate specific lowering of copper in ob/ob mice, consistent with hepatic copper deficiency. Thus ob/ob mice can provide a model useful for the study of copper regulation in NAFLD and NASH, provided levels are measured in defatted-dried liver tissue. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

A histomorphometric study of alveolar bone modelling and remodelling in mice fed a boron-deficient diet.

PubMed

Gorustovich, Alejandro A; Steimetz, Tammy; Nielsen, Forrest H; Guglielmotti, María B

2008-07-01

Emerging evidence indicates that boron (B) plays a role in bone formation and maintenance. Thus, a study was performed to determine whether dietary B-deficiency affects periodontal alveolar bone modelling and remodelling. Weanling Swiss mice (n=30) were divided into three groups: control diet (GI, 3mg B/kg); B-deficient diet (GII, 0.07 mg B/kg); and pair-fed with GII (GIII). The animals were maintained on their respective diets for 9 weeks and then sacrificed. The guidelines of the NIH for the care and use of laboratory animals were observed. The mandibles were resected, fixed, decalcified in 10% EDTA and embedded in paraffin. Buccolingually oriented sections were obtained at the level of the mesial root of the first lower molar and stained with H-E. Histomorphometric studies were performed separately on the buccal and lingual sides of the periodontal alveolar bone. Percentages of osteoblast surfaces (ObSs), eroded surfaces (ESs), and quiescent surfaces (QSs) were determined. No statistically significant differences in food intake and body weight were observed between the groups. When compared with GI and GIII mice, GII mice (B-deficient) had 63% and 48% reductions in ObS and 58% and 73% increases in QS in buccal and lingual plates, respectively. ES were not affected by B nutriture. The results are evidence that dietary boron deprivation in mice alters periodontal alveolar bone modelling and remodelling by inhibiting bone formation.

Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se.

PubMed

Haussmann, Hans-Juergen; Fariss, Marc W

2016-09-01

The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General's 2014 report on the health consequences of nicotine exposure.

Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se

PubMed Central

Haussmann, Hans-Juergen; Fariss, Marc W.

2016-01-01

Abstract The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General’s 2014 report on the health consequences of nicotine exposure. PMID:27278157

Transgenic mice: an irreplaceable tool for the study of mammalian development and biology.

PubMed

Babinet, C

2000-11-01

Stable integration into the mouse genome of exogenous genetic information, i.e., the creation of transgenic mice, has become a privileged way of analyzing gene function in normal development and pathology. Both gene addition and gene replacement may be performed. This has allowed, in particular, the creation of mice in which precise mutations are introduced into a given gene. Furthermore, in recent years, strategies that induce the expression of a mutation in a given type of cell and/or at a given time in development have been developed. Thus, the transgenic methodology affords a unique and irreplaceable tool for the study of mammalian development and biology and for the creation of animal models for human genetic diseases.

Local versus global aortic pulse wave velocity in early atherosclerosis: An animal study in ApoE-/--mice using ultrahigh field MRI

PubMed Central

Gotschy, Alexander; Bauer, Wolfgang R.; Winter, Patrick; Nordbeck, Peter; Rommel, Eberhard; Jakob, Peter M.; Herold, Volker

2017-01-01

Increased aortic stiffness is known to be associated with atherosclerosis and has a predictive value for cardiovascular events. This study aims to investigate the local distribution of early arterial stiffening due to initial atherosclerotic lesions. Therefore, global and local pulse wave velocity (PWV) were measured in ApoE-/- and wild type (WT) mice using ultrahigh field MRI. For quantification of global aortic stiffness, a new multi-point transit-time (TT) method was implemented and validated to determine the global PWV in the murine aorta. Local aortic stiffness was measured by assessing the local PWV in the upper abdominal aorta, using the flow/area (QA) method. Significant differences between age matched ApoE-/- and WT mice were determined for global and local PWV measurements (global PWV: ApoE-/-: 2.7±0.2m/s vs WT: 2.1±0.2m/s, P<0.03; local PWV: ApoE-/-: 2.9±0.2m/s vs WT: 2.2±0.2m/s, P<0.03). Within the WT mouse group, the global PWV correlated well with the local PWV in the upper abdominal aorta (R2 = 0.75, P<0.01), implying a widely uniform arterial elasticity. In ApoE-/- animals, however, no significant correlation between individual local and global PWV was present (R2 = 0.07, P = 0.53), implying a heterogeneous distribution of vascular stiffening in early atherosclerosis. The assessment of global PWV using the new multi-point TT measurement technique was validated against a pressure wire measurement in a vessel phantom and showed excellent agreement. The experimental results demonstrate that vascular stiffening caused by early atherosclerosis is unequally distributed over the length of large vessels. This finding implies that assessing heterogeneity of arterial stiffness by multiple local measurements of PWV might be more sensitive than global PWV to identify early atherosclerotic lesions. PMID:28207773

Local versus global aortic pulse wave velocity in early atherosclerosis: An animal study in ApoE-/--mice using ultrahigh field MRI.

PubMed

Gotschy, Alexander; Bauer, Wolfgang R; Winter, Patrick; Nordbeck, Peter; Rommel, Eberhard; Jakob, Peter M; Herold, Volker

2017-01-01

Increased aortic stiffness is known to be associated with atherosclerosis and has a predictive value for cardiovascular events. This study aims to investigate the local distribution of early arterial stiffening due to initial atherosclerotic lesions. Therefore, global and local pulse wave velocity (PWV) were measured in ApoE-/- and wild type (WT) mice using ultrahigh field MRI. For quantification of global aortic stiffness, a new multi-point transit-time (TT) method was implemented and validated to determine the global PWV in the murine aorta. Local aortic stiffness was measured by assessing the local PWV in the upper abdominal aorta, using the flow/area (QA) method. Significant differences between age matched ApoE-/- and WT mice were determined for global and local PWV measurements (global PWV: ApoE-/-: 2.7±0.2m/s vs WT: 2.1±0.2m/s, P<0.03; local PWV: ApoE-/-: 2.9±0.2m/s vs WT: 2.2±0.2m/s, P<0.03). Within the WT mouse group, the global PWV correlated well with the local PWV in the upper abdominal aorta (R2 = 0.75, P<0.01), implying a widely uniform arterial elasticity. In ApoE-/- animals, however, no significant correlation between individual local and global PWV was present (R2 = 0.07, P = 0.53), implying a heterogeneous distribution of vascular stiffening in early atherosclerosis. The assessment of global PWV using the new multi-point TT measurement technique was validated against a pressure wire measurement in a vessel phantom and showed excellent agreement. The experimental results demonstrate that vascular stiffening caused by early atherosclerosis is unequally distributed over the length of large vessels. This finding implies that assessing heterogeneity of arterial stiffness by multiple local measurements of PWV might be more sensitive than global PWV to identify early atherosclerotic lesions.

C57 mice increase wheel-running behavior following stress: preliminary findings.

PubMed

Sibold, Jeremy S; Hammack, Sayamwong E; Falls, William A

2011-10-01

Exercise has been shown to reduce anxiety in both humans and animals. To date, there are few, if any studies that examine the effect of stress on self-selected exercise using an animal model. This study examined the effect of acute stress on wheel-running distance in mice. Forty 8-week-old, male C57BL/6J mice were randomly assigned to one of three groups: no stress + wheel-running experience, stress + wheel-running experience, or stress with no wheel-running experience. Stressed mice were exposed to foot shock in a brightly lit environment. Following treatment, wheel-running distances were observed for three hours. Stress significantly increased voluntary wheel-running in mice with wheel-running experience as compared to nonstressed controls and stressed mice with no wheel-running experience. These results suggest that mice familiar with wheel-running may self-select this exercise as a modality for the mitigation of accumulated anxiety.

Raloxifen prevents bone loss in castrated male mice.

PubMed

Broulík, P D; Broulíková, K

2007-01-01

Raloxifen is a selective estrogen receptor modulator which prevents bone loss in ovariectomized female mice in a fashion similar to estrogens. Since testosterone-deficient male mice also lose bone mass, we were interested in testing the effects of raloxifen on bones in intact and castrated male mice. Bone density was significantly reduced in castrated animals (1.36+/-0.04 g/ml) as compared to intact animals (1.42+/-0.03 g/ml) (p<0.01). When castrated mice with extraordinarily low concentrations of testosterone and with reduced weight of seminal vesicles were treated with raloxifen, the changes in bone density and bone minerals resulting from castration (1.36+/-0.04 g/ml) were entirely prevented (1.40+/-0.01 g/ml). Cortical bone was lost in orchidectomized mice, and this decrease in cortical thickness of the femur was prevented by raloxifen administration. Raloxifen in a dose used in humans for treatment of osteoporosis decreased the weight of seminal vesicles, an organ which is highly sensitive to the androgenic effect, decreased the concentration of testosterone (12.5+/-2.8 micromol/l) (p<0.01) but not to the same level as in the case of castrated animals (0.6+/-0.3 micromol/l), and did not have any effect on bone density or mineral content in intact mice. The results of the present study may thus be interpreted as supporting the hypothesis that raloxifen is an effective agent against the deleterious effects of castration-induced osteopenia in male mice and also support the hypothesis that estrogens may have physiological skeletal effects in male mice.

Intestinal IgA responses to Giardia muris in mice depleted of helper T lymphocytes and in immunocompetent mice.

PubMed

Heyworth, M F

1989-04-01

Immunocompetent mice infected with Giardia muris generate an intestinal antibody response to this parasite and clear G. muris infection. Previous work has shown that G. muris infection is prolonged in mice that have been depleted of helper (CD4+) T lymphocytes by treatment with a monoclonal antibody (mAb) directed against the murine CD4 antigen. The aim of the present study was to compare the intestinal anti-Giardia antibody response in immunocompetent mice and in mice depleted of helper T (Th) lymphocytes by treatment with anti-CD4 mAb. Immunocompetent mice generated an IgA response to G. muris, as judged by the presence of IgA on Giardia trophozoites harvested from the intestine of these animals more than 10 days after the start of the infection. The anti-Giardia IgA response was impaired in mice depleted of Th lymphocytes, as judged by virtual absence of immunofluorescent staining of trophozoites from these animals for surface-bound IgA. Clearance of G. muris infection was impaired by treatment of mice with anti-CD4 mAb. The results suggest that Th (CD4+) lymphocytes are important for the generation of a local IgA response against G. muris trophozoites in the mouse intestine and that IgA anti-trophozoite antibody may contribute to the clearance of G. muris from the intestine of immunocompetent mice.

Early phenotypical diagnoses in Trembler-J mice model.

PubMed

Rosso, Gonzalo; Cal, Karina; Canclini, Lucía; Damián, Juan Pablo; Ruiz, Paul; Rodríguez, Héctor; Sotelo, José Roberto; Vazquez, Cristina; Kun, Alejandra

2010-06-30

Pmp-22 mutant mice (Trembler-J: B6.D2-Pmp22/J), are used as a model to study Charcot-Marie-Tooth type 1A (CMT1A). The identification of individual genotypes is a routine in the management of the Tr(J) colony. The earliest phenotypic manifestation of the pmp-22 mutation is just about 20th postnatal days, when pups begin to tremble. In this study, a rapid and simple diagnostic method was developed by modifying the Tail Suspension Test (MTST) to determine the difference between the Tr(J) and the wild-type mice phenotype. The animal behavioral phenotypes generated during the test were consistent with the specific genotype of each animal. The MTST allowed us to infer the heterozygous genotype in early postnatal stages, at 11 days after birth. The motor impairment of Tr(J) mice was also analyzed by a Fixed Bar Test (FBT), which revealed the disease evolution according to age. The main advantages of MTST are its objectivity, simplicity, and from the viewpoint of animal welfare, it is a non-invasive technique that combined with his rapidity show its very well applicability for use from an early age in these mice. Copyright 2010 Elsevier B.V. All rights reserved.

Murine norovirus infection in Brazilian animal facilities

PubMed Central

Rodrigues, Daniele Masselli; Moreira, Josélia Cristina de Oliveira; Lancellotti, Marcelo; Gilioli, Rovilson; Corat, Marcus Alexandre Finzi

2016-01-01

Murine norovirus (MNV) is a single-stranded positive-sense RNA virus of the Caliciviridae family. MNV has been reported to infect laboratory mice with the ability to cause lethal infections in strains lacking components of the innate immune response. Currently, MNV is considered the most prevalent infectious agent detected in laboratory mouse facilities. In this study, mice in 22 laboratory animal facilities within Brazil were analyzed for MNV infection. Using primers targeting a conserved region of the viral capsid, MNV was detected by RT-PCR in 137 of 359 mice from all 22 facilities. Nucleotide sequencing and phylogenetic analysis of the capsid region from the viral genome showed identity ranging from 87% to 99% when compared to reported MNV sequences. In addition, RAW264.7 cells inoculated with a mouse fecal suspension displayed cytopathic effect after the fifth passage. This study represents the first report of MNV in mouse colonies in Brazilian laboratory animal facilities, emphasizing the relevance of a health surveillance program in such environments. PMID:28049885

Small-animal research imaging devices.

PubMed

Fine, Eugene J; Herbst, Lawrence; Jelicks, Linda A; Koba, Wade; Theele, Daniel

2014-01-01

The scientific study of living animals may be dated to Aristotle's original dissections, but modern animal studies are perhaps a century in the making, and advanced animal imaging has emerged only during the past few decades. In vivo imaging now occupies a growing role in the scientific research paradigm. Imaging of small animals has been particularly useful to help understand human molecular biology and pathophysiology using rodents, especially using genetically engineered mice (GEM) with spontaneous diseases that closely mimic human diseases. Specific examples of GEM models of veterinary diseases exist, but in general, GEM for veterinary research has lagged behind human research applications. However, the development of spontaneous disease models from GEM may also hold potential for veterinary research. The imaging techniques most widely used in small-animal research are CT, PET, single-photon emission CT, MRI, and optical fluorescent and luminescent imaging. Copyright © 2014 Elsevier Inc. All rights reserved.

Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system.

PubMed

Corpet, Denis E; Pierre, Fabrice

2003-05-01

The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents.

Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice.

PubMed

Saliba, Alexandra; Du, Yunpeng; Liu, Haitao; Patel, Shyam; Roberts, Robin; Berkowitz, Bruce A; Kern, Timothy S

2015-01-01

Daily application of far-red light from the onset of diabetes mitigated diabetes-induced abnormalities in retinas of albino rats. Here, we test the hypothesis that photobiomodulation (PBM) is effective in diabetic, pigmented mice, even when delayed until weeks after onset of diabetes. Direct and indirect effects of PBM on the retina also were studied. Diabetes was induced in C57Bl/6J mice using streptozotocin. Some diabetics were exposed to PBM therapy (4 min/day; 670 nm) daily. In one study, mice were diabetic for 4 weeks before initiation of PBM for an additional 10 weeks. Retinal oxidative stress, inflammation, and retinal function were measured. In some mice, heads were covered with a lead shield during PBM to prevent direct illumination of the eye, or animals were treated with an inhibitor of heme oxygenase-1. In a second study, PBM was initiated immediately after onset of diabetes, and administered daily for 2 months. These mice were examined using manganese-enhanced MRI to assess effects of PBM on transretinal calcium channel function in vivo. PBM intervention improved diabetes-induced changes in superoxide generation, leukostasis, expression of ICAM-1, and visual performance. PBM acted in part remotely from the retina because the beneficial effects were achieved even with the head shielded from the light therapy, and because leukocyte-mediated cytotoxicity of retinal endothelial cells was less in diabetics treated with PBM. SnPP+PBM significantly reduced iNOS expression compared to PBM alone, but significantly exacerbated leukostasis. In study 2, PBM largely mitigated diabetes-induced retinal calcium channel dysfunction in all retinal layers. PBM induces retinal protection against abnormalities induced by diabetes in pigmented animals, and even as an intervention. Beneficial effects on the retina likely are mediated by both direct and indirect mechanisms. PBM is a novel non-pharmacologic treatment strategy to inhibit early changes of diabetic retinopathy.

Estrous Cyclicity of Mice During Simulated Weightlessness

NASA Technical Reports Server (NTRS)

Moyer, Eric; Talyansky, Yuli; Scott, Ryan; Tash, Joseph; Christenson, Lane; Alwood, Joshua; Ronca, April

2017-01-01

Hindlimb unloading (HU) is a rodent model system used to simulate weightlessness experienced in space. However, some effects of this approach on rodent physiology are under-studied, specifically the effects on ovarian estrogen production which drives the estrous cycle. To resolve this deficiency, we conducted a ground-based validation study using the HU model, while monitoring estrous cycles in 16-weeks-old female C57BL6 mice. Animals were exposed to HU for 12 days following a 3 day HU cage acclimation period, and estrous cycling was analyzed in HU animals (n22), normally loaded HU Cage Pair-Fed controls (CPF; n22), and Vivarium controls fed ad libitum (VIV; n10). Pair feeding was used to control for potential nutritional deficits on ovarian function. Vaginal cells were sampled daily in all mice via saline lavage. Cells were dried and stained with crystal violet, and the smears evaluated using established vaginal cytology techniques by two individuals blinded to the animal treatment group. Estrous cyclicity was disrupted in nearly all HU and CPF mice, while those maintained in VIV had an average normal cycle length of 4.8 0.5 days, with all stages in the cycle visibly observed. CPF and HU animals arrested in the diestrous phase, which precedes the pre-ovulatory estrogen surge. Additionally, infection-like symptoms characterized by vaginal discharge and swelling arose in several HU animals, which we suspect was due to an inability of these mice to properly groom themselves, andor due to the change in the gravity vector relative to the vaginal opening, which prevented drainage of the lavage solution. Pair-feeding resulted in similar weight gains of HU and CPF (1.5 vs 3.0, respectively). The current results indicate that pair-feeding controlled weight gain and that the HU cage alone influenced estrous cyclicity. Thus, longer acclimation needs to be tested to determine if and when normal estrous cycling resumes in non-loaded mice in HU cages prior to HU testing. Future

Estrous Cyclicity in Mice During Simulated Weightlessness

NASA Technical Reports Server (NTRS)

Moyer, E. L.; Talyansky, Y.; Scott, R. T.; Tash, J. S.; Christenson, L. K.; Alwood, J. S.; Ronca, A. E.

2017-01-01

Hindlimb unloading (HU) is a rodent model system used to simulate weightlessness experienced in space. However, some effects of this approach on rodent physiology are under-studied, specifically the effects on ovarian estrogen production which drives the estrous cycle. To resolve this deficiency, we conducted a ground-based validation study using the HU model, while monitoring estrous cycles in 16-weeks-old female C57BL6 mice. Animals were exposed to HU for 12 days following a 3 day HU cage acclimation period, and estrous cycling was analyzed in HU animals (n=22), normally loaded HU Cage Pair-Fed controls (CPF; n=22), and Vivarium controls fed ad libitum (VIV; n=10). Pair feeding was used to control for potential nutritional deficits on ovarian function. Vaginal cells were sampled daily in all mice via saline lavage. Cells were dried and stained with crystal violet, and the smears evaluated using established vaginal cytology techniques by two individuals blinded to the animal treatment group. Estrous cyclicity was disrupted in nearly all HU and CPF mice, while those maintained in VIV had an average normal cycle length of 4.8+/- 0.5 days, with all stages in the cycle visibly observed. CPF and HU animals arrested in the diestrous phase, which precedes the pre-ovulatory estrogen surge. Additionally, infection-like symptoms characterized by vaginal discharge and swelling arose in several HU animals, which we suspect was due to an inability of these mice to properly groom themselves, and/or due to the change in the gravity vector relative to the vaginal opening, which prevented drainage of the lavage solution. Pair-feeding resulted in similar weight gains of HU and CPF (1.5% vs 3.0%, respectively). The current results indicate that pair-feeding controlled weight gain and that the HU cage alone influenced estrous cyclicity. Thus, longer acclimation needs to be tested to determine if and when normal estrous cycling resumes in non-loaded mice in HU cages prior to HU

Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: Implications for an animal model of psychiatric comorbidity in autism.

PubMed

Chao, Owen Y; Yunger, Richelle; Yang, Yi-Mei

2018-07-16

Autism spectrum disorders (ASD) are diagnosed based on the behavioral criteria of impaired social interaction, defective communication and repetitive behaviors. Psychiatric comorbidities, such as anxiety and intellectual disability, are commonly present in ASD. The BTBR T+ Itpr3tf/J (BTBR) mice display a range of autistic phenotypes, yet whether this mouse model is appropriate to study psychiatric comorbidity in ASD remains unclear. We addressed this issue by subjecting the BTBR animals to three-chambered apparatus, open field, object attention test and elevated open platform. Compared to C57BL/6J control mice, the BTBR mice displayed hyperactivity in most of the tests. In the three-chamber assessment, they exhibited deficits in sociability. In the open field, more grooming and thigmotaxis and less rearing behaviors were observed. They also showed impaired object-based attention. On the elevated open platform, the BTBR animals stayed more to the edges than in the center of the platform. To further examine the properties of this test, naïve C57BL/6J mice were randomly administrated with saline or an anxiogenic substance, caffeine. The caffeine group demonstrated a similar behavioral pattern as the BTBR mice. When the saline group was re-exposed to the same platform, the time they stayed in the center substantially increased, likely due to reduced anxiety by habituation. These results indicate that the BTBR were more anxious than control mice on the open platform. Taken together, the BTBR strain exhibit emotional and cognitive impairments in addition to autistic behaviors, suggesting that they can be a valid model for ASD with psychiatric comorbidity. Copyright © 2018 Elsevier B.V. All rights reserved.

High animal fat intake enhances prostate cancer progression and reduces glutathione peroxidase 3 expression in early stages of TRAMP mice.

PubMed

Chang, Seo-Na; Han, Juhee; Abdelkader, Tamer Said; Kim, Tae-Hyoun; Lee, Ji Min; Song, Juha; Kim, Kyung-Sul; Park, Jong-Hwan; Park, Jae-Hak

2014-09-01

Prostate cancer is the most frequently diagnosed cancer in Western men, and more men have been diagnosed at younger ages in recent years. A high-fat Western-style diet is a known risk factor for prostate cancer and increases oxidative stress. We evaluated the association between dietary animal fat and expression of antioxidant enzymes, particularly glutathione peroxidase 3 (GPx3), in the early stages of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Six-week-old male nontransgenic and TRAMP mice were placed on high animal fat (45% Kcal fat) or control (10% Kcal fat) diets and sacrificed after 5 or 10 weeks. The histopathological score increased with age and high-fat diet consumption. The histopathological scores in dorsal and lateral lobes increased in the 10-week high-fat diet group (6.2±0.2 and 6.2±0.4, respectively) versus the 10-week control diet group (5.3±0.3 and 5.2±0.2, respectively). GPx3 decreased both at the mRNA and protein levels in mouse prostate. GPx3 mRNA expression decreased (∼36.27% and ∼23.91%, respectively) in the anterior and dorsolateral prostate of TRAMP mice fed a high-fat diet compared to TRAMP mice fed a control diet. Cholesterol treatment increased PC-3 human prostate cancer cell proliferation, decreased GPx3 mRNA and protein levels, and increased H2 O2 levels in culture medium. Moreover, increasing GPx3 mRNA expression by troglitazone in PC-3 cells decreased cell proliferation and lowered H2 O2 levels. Dietary fat enhances prostate cancer progression, possibly by suppressing GPx3 expression and increasing proliferation of prostate intraepithelial neoplasia (PIN) epithelial cells. © 2014 Wiley Periodicals, Inc.

Light and water are not simple conditions: fine tuning of animal housing in male C57BL/6 mice.

PubMed

Langgartner, Dominik; Foertsch, Sandra; Füchsl, Andrea M; Reber, Stefan O

2017-01-01

While animal housing conditions are highly controlled and standardized between different laboratories, there are still many subtle differences that unavoidably influence the host organisms and, consequently, interlaboratory reproducibility. Here, we investigated the physiological and immunological consequences between two light/dark cycle (LDC) lengths (14-h/10-h vs. 12-h/12-h LDC) and two commonly used forms of drinking water (acidified drinking water (AW) versus normal tap water (NW)) in single-housed (SH) mice. Our results indicate that SH mice bred under a 12-h/12-h LDC and NW at the supplier's facility showed increased basal morning plasma corticosterone (CORT) levels even 4 weeks after arrival at our animal facility employing a 14-h/10-h LDC and AW. This effect was even more pronounced two weeks after arrival and had abated after 8 weeks. In agreement, increased plasma adrenocorticotropic hormone (ACTH), adrenal in vitro ACTH sensitivity, as well as relative and absolute adrenal weight normalized during this 8-week exposure to the novel and unfamiliar 14-h/10-h LDC and AW. Employment of a 12-h/12-h LDC in our facility completely abrogated the CORT-elevating effects of the 14-h/10-h LDC, despite these animals drinking AW. When both the water and light conditions were matched to those at the supplier's facility, we observed a further reduction in adrenal weight, increased thymus weight, and decreased pro-inflammatory cytokine secretion of isolated and anti-CD3/28-stimulated mesenteric lymph node cells. In summary, our results indicate that prolonged alteration of both the light phase and drinking water represent severe and long-lasting stressors for laboratory rodents. These findings are of general interest for all scientists obtaining their experimental animals from conventional suppliers.

Calculation of Glucose Dose for Intraperitoneal Glucose Tolerance Tests in Lean and Obese Mice.

PubMed

Jørgensen, Mikkel S; Tornqvist, Kristina S; Hvid, Henning

2017-01-01

Glucose tolerance tests are used frequently in nonclinical research with laboratory animals, for example during characterization of obese phenotypes. Despite published standard operating procedures for glucose tolerance tests in rodents, how glucose doses should be calculated when obese and lean animals are compared is not well documented. Typically the glucose dose is calculated as 2 g/kg body weight, regardless of body composition. With this approach, obese mice receive larger glucose doses than do lean animals, potentially leading to overestimation of glucose intolerance in obese animals. In this study, we performed intraperitoneal glucose tolerance tests in mice with diet-induced obesity and their lean controls, with glucose doses based on either the total body weight or the lean body mass of the animals. To determine glucose tolerance, we determined the blood glucose AUC during the glucose tolerance test. We found that the blood glucose AUC was increased significantly in obese mice compared with lean mice by 75% on average when glucose was dosed according to the lean body mass and by 87% when the glucose dose was calculated according to total body weight. Therefore, mice with diet-induced obesity were approximately equally glucose intolerant between the 2 dose-calculation protocols. However, we recommend calculating the glucose dose according to the lean body mass of the mice, because doing so eliminates the concern regarding overdosing of obese animals.

Animal carcinogenicity studies on radiofrequency fields related to mobile phones and base stations.

PubMed

Dasenbrock, Clemens

2005-09-01

Since a report in 1997 on an increased lymphoma incidence in mice chronically exposed to a mobile phone radiofrequency signal, none of the subsequent long-term studies in rodents have confirmed these results. On the other hand, several of the follow-up co- and carcinogenicity studies are still underway or are presently being initiated. Most of the published long-term studies used 1 exposure level only and suffer from a poor dosimetry which does not consider the animal's growth. Additional points of criticism are a limited, in some cases, questionable histopathology and inadequate group sizes. Overall, if dealing with new chemicals or drugs, these studies would not be acceptable for registration with the responsible authorities. The major critical points are taken into consideration within the European co- and carcinogenicity projects (CEMFEC and PERFORM-A), which are in their final stages and in the US long-term studies in mice and rats which are about to be initiated. Nevertheless, the WHO evaluation for health risk assessment of long-term telephone use and base station exposure will start in late 2005.

Review of certain low-level ionizing radiation studies in mice and guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Congdon, C.C.

1987-05-01

Starting in the early 1940s, Egon Lorenz and collaborators at the National Cancer Institute began an extended study of chronic low-level ionizing radiation effects in what was then the tolerance range for man. Observations on life span, body weight and radiation carcinogenesis, among others, were made in mice, guinea pigs and rabbits. At the then-permissible exposure level, 0.1 R** per 8-h day until natural death, experimental mice and guinea pigs had a slightly greater mean life span compared to control animals. In addition, there was marked weight gain during the growth phase in both species. Increased tumor incidence was alsomore » observed at the 0.1-R level in mice. The primary hypothesis for increased median life span has been rebound regenerative hyperplasia during the early part of the exposure; in the presence of continuing injury, there is physiological enhancement of defense mechanisms against intercurrent infection. The body weight gain has not been explained. 32 references.« less

Polytrauma Increases Susceptibility to Pseudomonas Pneumonia in Mature Mice.

PubMed

Turnbull, Isaiah R; Ghosh, Sarbani; Fuchs, Anja; Hilliard, Julia; Davis, Christopher G; Bochicchio, Grant V; Southard, Robert E

2016-05-01

Pneumonia is the most common complication observed in patients with severe injuries. Although the average age of injured patients is 47 years, existing studies of the effect of injury on the susceptibility to infectious complications have focused on young animals, equivalent to a late adolescent human. We hypothesized that mature adult animals are more susceptible to infection after injury than younger counterparts. To test this hypothesis, we challenged 6 to 8-month-old mature mice to a polytrauma injury followed by Pseudomonas aeruginosa pneumonia and compared them to young (8-10-week-old) animals. We demonstrate that polytrauma injury increases mortality from pneumonia in mature animals (sham-pneumonia 21% vs. polytrauma-pneumonia 62%) but not younger counterparts. After polytrauma, pneumonia in mature mice is associated with higher bacterial burden in lung, increased incidence of bacteremia, and elevated levels of bacteria in the blood, demonstrating that injury decreases the ability to control the infectious challenge. We further find that polytrauma did not induce elevations in circulating cytokine levels (TNF-alpha, IL-6, KC, and IL-10) 24  h after injury. However, mature mice subjected to polytrauma demonstrated an exaggerated circulating inflammatory cytokine response to subsequent Pseudomonas pneumonia. Additionally, whereas prior injury increases LPS-stimulated IL-6 production by peripheral blood leukocytes from young (8-10-week-old) mice, injury does not prime IL-6 production by cell from mature adult mice. We conclude that in mature mice polytrauma results in increased susceptibility to Pseudomonas pneumonia while priming an exaggerated but ineffective inflammatory response.

The contribution of animal models to the study of obesity.

PubMed

Speakman, John; Hambly, Catherine; Mitchell, Sharon; Król, Elzbieta

2008-10-01

Obesity results from prolonged imbalance of energy intake and energy expenditure. Animal models have provided a fundamental contribution to the historical development of understanding the basic parameters that regulate the components of our energy balance. Five different types of animal model have been employed in the study of the physiological and genetic basis of obesity. The first models reflect single gene mutations that have arisen spontaneously in rodent colonies and have subsequently been characterized. The second approach is to speed up the random mutation rate artificially by treating rodents with mutagens or exposing them to radiation. The third type of models are mice and rats where a specific gene has been disrupted or over-expressed as a deliberate act. Such genetically-engineered disruptions may be generated through the entire body for the entire life (global transgenic manipulations) or restricted in both time and to certain tissue or cell types. In all these genetically-engineered scenarios, there are two types of situation that lead to insights: where a specific gene hypothesized to play a role in the regulation of energy balance is targeted, and where a gene is disrupted for a different purpose, but the consequence is an unexpected obese or lean phenotype. A fourth group of animal models concern experiments where selective breeding has been utilized to derive strains of rodents that differ in their degree of fatness. Finally, studies have been made of other species including non-human primates and dogs. In addition to studies of the physiological and genetic basis of obesity, studies of animal models have also informed us about the environmental aspects of the condition. Studies in this context include exploring the responses of animals to high fat or high fat/high sugar (Cafeteria) diets, investigations of the effects of dietary restriction on body mass and fat loss, and studies of the impact of candidate pharmaceuticals on components of energy

Targeted Deletion of Kynurenine 3-Monooxygenase in Mice

PubMed Central

Giorgini, Flaviano; Huang, Shao-Yi; Sathyasaikumar, Korrapati V.; Notarangelo, Francesca M.; Thomas, Marian A. R.; Tararina, Margarita; Wu, Hui-Qiu; Schwarcz, Robert; Muchowski, Paul J.

2013-01-01

Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo−/− mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo−/− mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo−/− mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD+, did not differ between Kmo−/− and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo−/− mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo−/− mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease. PMID:24189070

Peptide Transporter 1 is Responsible for Intestinal Uptake of the Dipeptide Glycylsarcosine: Studies in Everted Jejunal Rings from Wild-type and Pept1 Null Mice

PubMed Central

Ma, Katherine; Hu, Yongjun; Smith, David E.

2010-01-01

The purpose of this study was to determine the relative importance of PEPT1 in the uptake of peptides/mimetics from mouse small intestine using glycylsarcosine (GlySar). After isolating jejunal tissue from wild-type and Pept1 null mice, 2-cm intestinal segments were everted and mounted on glass rods for tissue uptake studies. [14C]GlySar (4 μM) was studied as a function of time, temperature, sodium and pH, concentration, and potential inhibitors. Compared to wild-type animals, Pept1 null mice exhibited a 78% reduction of GlySar uptake at pH 6.0, 37°C. GlySar uptake showed pH dependence with peak values between pH 6.0-6.5 in wild-type animals, while no such tendency was observed in Pept1 null mice. GlySar exhibited Michaelis-Menten uptake kinetics and a minor nonsaturable component in wild-type animals. In contrast, GlySar uptake occurred by only a nonsaturable process in Pept1 null mice. GlySar uptake was significantly inhibited by dipeptides, aminocephalosporins, angiotensin-converting enzyme inhibitors, and the antiviral prodrug valacyclovir; these inhibitors had little, if any, effect on the uptake of GlySar in Pept1 null mice. The findings demonstrate that PEPT1 plays a critical role in the uptake of GlySar in jejunum, and suggest that PEPT1 is the major transporter responsible for the intestinal absorption of small peptides. PMID:20862774

Contemporary Animal Models For Human Gene Therapy Applications.

PubMed

Gopinath, Chitra; Nathar, Trupti Job; Ghosh, Arkasubhra; Hickstein, Dennis Durand; Nelson, Everette Jacob Remington

2015-01-01

Over the past three decades, gene therapy has been making considerable progress as an alternative strategy in the treatment of many diseases. Since 2009, several studies have been reported in humans on the successful treatment of various diseases. Animal models mimicking human disease conditions are very essential at the preclinical stage before embarking on a clinical trial. In gene therapy, for instance, they are useful in the assessment of variables related to the use of viral vectors such as safety, efficacy, dosage and localization of transgene expression. However, choosing a suitable disease-specific model is of paramount importance for successful clinical translation. This review focuses on the animal models that are most commonly used in gene therapy studies, such as murine, canine, non-human primates, rabbits, porcine, and a more recently developed humanized mice. Though small and large animals both have their own pros and cons as disease-specific models, the choice is made largely based on the type and length of study performed. While small animals with a shorter life span could be well-suited for degenerative/aging studies, large animals with longer life span could suit longitudinal studies and also help with dosage adjustments to maximize therapeutic benefit. Recently, humanized mice or mouse-human chimaeras have gained interest in the study of human tissues or cells, thereby providing a more reliable understanding of therapeutic interventions. Thus, animal models are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to a gene therapy clinical trial.

Propagation of senescent mice using nuclear transfer embryonic stem cell lines.

PubMed

Mizutani, Eiji; Ono, Tetsuo; Li, Chong; Maki-Suetsugu, Rinako; Wakayama, Teruhiko

2008-09-01

Senescent mice are often infertile, and the cloning success rate decreases with age, making it almost impossible to produce cloned progeny directly from such animals. In this study, we tried to produce offspring from such "unclonable" senescent mice using nuclear transfer techniques. Donor fibroblasts were obtained from the tail tips of mice aged up to 2 years and 9 months. Although most attempts failed to produce cloned mice by direct somatic cell nuclear transfer, we managed to establish nuclear transfer embryonic stem (ntES) cell lines from all aged mice with an establishment rate of 10-25%, irrespective of sex or strain. Finally, cloned mice were obtained from these ntES cells by a second round of nuclear transfer. In addition, healthy offspring was obtained from all aged donors via germline transmission of ntES cells in chimeric mice. This technique is thus applicable to the propagation of a variety of animals, irrespective of age or fertile potential.

Battery of behavioral tests in mice to study postoperative delirium

PubMed Central

Peng, Mian; Zhang, Ce; Dong, Yuanlin; Zhang, Yiying; Nakazawa, Harumasa; Kaneki, Masao; Zheng, Hui; Shen, Yuan; Marcantonio, Edward R.; Xie, Zhongcong

2016-01-01

Postoperative delirium is associated with increased morbidity, mortality and cost. However, its neuropathogenesis remains largely unknown, partially owing to lack of animal model(s). We therefore set out to employ a battery of behavior tests, including natural and learned behavior, in mice to determine the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on these behaviors. The mice were tested at 24 hours before and at 6, 9 and 24 hours after the Anesthesia/Surgery. Composite Z scores were calculated. Cyclosporine A, an inhibitor of mitochondria permeability transient pore, was used to determine potential mitochondria-associated mechanisms of these behavioral changes. Anesthesia/Surgery selectively impaired behaviors, including latency to eat food in buried food test, freezing time and time spent in the center in open field test, and entries and duration in the novel arm of Y maze test, with acute onset and various timecourse. The composite Z scores quantitatively demonstrated the Anesthesia/Surgery-induced behavior impairment in mice. Cyclosporine A selectively ameliorated the Anesthesia/Surgery-induced reduction in ATP levels, the increases in latency to eat food, and the decreases in entries in the novel arm. These findings suggest that we could use a battery of behavior tests to establish a mouse model to study postoperative delirium. PMID:27435513

Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD.

PubMed

Ebihara, Ken; Fujiwara, Hironori; Awale, Suresh; Dibwe, Dya Fita; Araki, Ryota; Yabe, Takeshi; Matsumoto, Kinzo

2017-09-15

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABA A receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABA A receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD. Copyright © 2017 Elsevier B.V. All rights reserved.

Social housing conditions influence morphine dependence and the extinction of morphine place preference in adolescent mice.

PubMed

Bates, M L Shawn; Emery, Michael A; Wellman, Paul J; Eitan, Shoshana

2014-09-01

Adolescent opioid abuse is on the rise, and current treatments are not effective in reducing rates of relapse. Our previous studies demonstrated that social housing conditions alter the acquisition rate of morphine conditioned place preference (CPP) in adolescent mice. Specifically, the acquisition rate of morphine CPP is slower in morphine-treated animals housed with drug-naïve animals. Thus, here we tested the effect of social housing conditions on the development of morphine dependence and the extinction rate of an acquired morphine CPP. Adolescent male mice were group-housed in one of two housing conditions. They were injected for 6 days (PND 28-33) with 20 mg/kg morphine. Morphine only mice are animals where all four mice in the cage received morphine. Morphine cage-mate mice are morphine-injected animals housed with drug-naïve animals. Mice were individually tested for spontaneous withdrawal signs by quantifying jumping behavior 4, 8, 24, and 48 h after the final morphine injection. Then, mice were conditioned to acquire morphine CPP and were tested for the rate of extinction. Morphine cage-mates express less jumping behavior during morphine withdrawal as compared to morphine only mice. As expected, morphine cage-mate animals acquired morphine CPP more slowly than the morphine only animals. Additionally, morphine cage-mates extinguished morphine CPP more readily than morphine only mice. Social housing conditions modulate morphine dependence and the extinction rate of morphine CPP. Extinction testing is relevant to human addiction because rehabilitations like extinction therapy may be used to aid human addicts in maintaining abstinence from drug use. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

MOSFET assessment of radiation dose delivered to mice using the Small Animal Radiation Research Platform (SARRP).

PubMed

Ngwa, Wilfred; Korideck, Houari; Chin, Lee M; Makrigiorgos, G Mike; Berbeco, Ross I

2011-12-01

The Small Animal Radiation Research Platform (SARRP) is a novel isocentric irradiation system that enables state-of-the-art image-guided radiotherapy research to be performed with animal models. This paper reports the results obtained from investigations assessing the radiation dose delivered by the SARRP to different anatomical target volumes in mice. Surgically implanted metal oxide semiconductor field effect transistors (MOSFET) dosimeters were employed for the dose assessment. The results reveal differences between the calculated and measured dose of -3.5 to 0.5%, -5.2 to -0.7%, -3.9 to 0.5%, -5.9 to 2.5%, -5.5 to 0.5%, and -4.3 to 0% for the left kidney, liver, pancreas, prostate, left lung, and brain, respectively. Overall, the findings show less than 6% difference between the delivered and calculated dose, without tissue heterogeneity corrections. These results provide a useful assessment of the need for tissue heterogeneity corrections in SARRP dose calculations for clinically relevant tumor model sites.

Body Weight Changes of Laboratory Animals during Transportation

PubMed Central

Lee, Sunghak; Nam, Hyunsik; Kim, Jinsung; Cho, Hyejung; Jang, Yumi; Lee, Eunjung; Choi, Eunsung; Jin, Dong Il; Moon, Hongsik

2012-01-01

The majority of laboratory animals were transported from commercial breeders to a research facility by ground transportation. During the transportation, many biological functions and systems can be affected by stress. In this experiment, the change of body weight during the transportation was measured and the recovery periods from the transportation stress established based on the body weight changes. Total 676 laboratory animals which were aged between 3 to 9 wk old were studied. The transportation time taken from container packing to unpacking the container was approximately 24 h. The temperature of animal container was constantly maintained by air-conditioning and heating equipment. Rats were found to be more sensitive than mice. The body weight of rats was significantly decreased 3.71% (p<0.05) compared to the body weight of mice which decreased 0.9% There was no significant difference between the strains in the same species. When the changes of body weights were compared between delivery days, C57BL/6 mice showed the most variable changes compared to other species and strains. Consequently, C57BL/6 was more sensitive to stress than the other strains and the transportation process needs to be standardized to reduce between day variability. To establish the recovery periods from transportation stress, the body weight changes were measured during the acclimation period. Although the body weight of animals decreased during transportation, animals recovered their weight loss after the next day. PMID:25049564

Coupler for surgery on small animals

NASA Technical Reports Server (NTRS)

Johnson, J. E., Jr.; Swartz, P. F.

1979-01-01

Minicoupler simplifies exchange of fluids with organs of laboratory animals enabling one person to perform surgery on experimental animals such as rats and mice. Innovation eliminates obstructing hands and instruments from areas of surgery.

Effects of HIV-1 on Cognition in Humanized NSG Mice

NASA Astrophysics Data System (ADS)

Akhter, Sidra Pervez

Host species specificity of human immunodeficiency virus (HIV) creates a challenge to study the pathology, diagnostic tools, and therapeutic agents. The closely related simian immunodeficiency virus and studies of neurocognitive impairments on transgenic animals expressing partial viral genome have significant limitations. The humanized mice model provides a small animal system in which a human immune system can be engrafted and immunopathobiology of HIV-1 infection can be studied. However, features of HIV-associated neurocognitive disorders (HAND) were not evaluated in this model. Open field activity test was selected to characterize behavior of original strain NOD/scid-IL-2Rgammac null (NSG) mice, effects of engraftment of human CD34+ hematopoietic stem cells (HSCs) and functional human immune system (huNSG), and finally, investigate the behavior changes induced by chronic HIV-1 infection. Long-term infected HuNSG mice showed the loss of working memory and increased anxiety in the open field. Additionally, these animals were utilized for evaluation of central nervous system metabolic and structural changes. Detected behavioral abnormalities are correlated with obtained neuroimaging and histological abnormalities published.

Social environment alters opioid-induced hyperalgesia and antinociceptive tolerance in adolescent mice.

PubMed

Bates, M L S; Emery, M A; Wellman, P J; Eitan, S

2016-07-01

Chronic opioid treatment is complicated by the development of tolerance and hyperalgesia. Social environment alters both opioid-induced behaviours and nociceptive mechanisms. Our previous studies demonstrated that, in adolescent rodents, the susceptibility to acquire opioid dependence and reward is dependent on the nature of social housing conditions. Specifically, our previous studies demonstrate that housing morphine-treated mice with drug-naïve animals mitigates the abuse liability of opioids. Thus, this study tested the effect of social housing conditions on the development of adaptive processes to morphine antinociception. Adolescent males were group-housed in different conditions. In the mixed treatment condition, mice treated with 20 mg/kg morphine (i.e. 'morphine cage-mates') and saline (i.e. 'saline cage-mates') were housed together. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'). All animals were tested for baseline pain sensitivity and for the response to morphine in the tail withdrawal, hot plate, acetone and von Frey filament tests, during and after discontinuation of opioid treatment. Both morphine cage-mate and morphine only animals developed antinociceptive tolerance. However, this effect was more robust and persistent in the morphine only group. Notably, morphine only animals, but not morphine cage-mates, developed opioid-induced hyperalgesia. This study demonstrates that housing morphine-treated mice with drug-naïve animals mitigates the development of opioid-induced hyperalgesia and antinociceptive tolerance. Thus, this study indicates that social environment influences the effectiveness of opioid pain management. © 2016 European Pain Federation - EFIC®

Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

PubMed

Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

2018-02-01

Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Bioluminescent system for dynamic imaging of cell and animal behavior

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hara-Miyauchi, Chikako; Laboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, Saitama 351-0198; Department of Biophysics and Biochemistry, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo 113-8510

2012-03-09

Highlights: Black-Right-Pointing-Pointer We combined a yellow variant of GFP and firefly luciferase to make ffLuc-cp156. Black-Right-Pointing-Pointer ffLuc-cp156 showed improved photon yield in cultured cells and transgenic mice. Black-Right-Pointing-Pointer ffLuc-cp156 enabled video-rate bioluminescence imaging of freely-moving animals. Black-Right-Pointing-Pointer ffLuc-cp156 mice enabled tracking real-time drug delivery in conscious animals. -- Abstract: The current utility of bioluminescence imaging is constrained by a low photon yield that limits temporal sensitivity. Here, we describe an imaging method that uses a chemiluminescent/fluorescent protein, ffLuc-cp156, which consists of a yellow variant of Aequorea GFP and firefly luciferase. We report an improvement in photon yield by over threemore » orders of magnitude over current bioluminescent systems. We imaged cellular movement at high resolution including neuronal growth cones and microglial cell protrusions. Transgenic ffLuc-cp156 mice enabled video-rate bioluminescence imaging of freely moving animals, which may provide a reliable assay for drug distribution in behaving animals for pre-clinical studies.« less

Comparative analysis of the intestinal flora in type 2 diabetes and nondiabetic mice

PubMed Central

Horie, Masanori; Miura, Takamasa; Hirakata, Satomi; Hosoyama, Akira; Sugino, Sakiko; Umeno, Aya; Murotomi, Kazutoshi; Yoshida, Yasukazu; Koike, Taisuke

2017-01-01

A relationship between type 2 diabetes mellitus (T2DM) and intestinal flora has been suggested since development of analysis technology for intestinal flora. An animal model of T2DM is important for investigation of T2DM. Although there are some animal models of T2DM, a comparison of the intestinal flora of healthy animals with that of T2DM animals has not yet been reported. The intestinal flora of Tsumura Suzuki Obese Diabetes (TSOD) mice was compared with that of Tsumura, Suzuki, Non Obesity (TSNO) mice in the present study. The TSOD mice showed typical type 2 diabetes symptoms, which were high-fat diet-independent. The TSOD and the TSNO mouse models were derived from the same strain, ddY. In this study, we compared the intestinal flora of TSOD mice with that if TSNO mice at 5 and 12 weeks of age. We determined that that the number of operational taxonomic units (OTUs) was significantly higher in the cecum of TSOD mice than in that of TSNO mice. The intestinal flora of the cecum and that of the feces were similar between the TSNO and the TSOD strains. The dominant bacteria in the cecum and feces were of the phyla Firmicutes and Bacteroidetes. However, the content of some bacterial species varied between the two strains. The percentage of Lactobacillus spp. within the general intestinal flora was higher in TSOD mice than in TSNO mice. In contrast, the percentages of order Bacteroidales and family Lachnospiraceae were higher in TSNO mice than in TSOD mice. Some species were observed only in TSOD mice, such as genera Turicibacter and SMB53 (family Clostridiaceae), the percentage of which were 3.8% and 2.0%, respectively. Although further analysis of the metabolism of the individual bacteria in the intestinal flora is essential, genera Turicibacter and SMB53 may be important for the abnormal metabolism of type 2 diabetes. PMID:28701620

Comparative analysis of the intestinal flora in type 2 diabetes and nondiabetic mice.

PubMed

Horie, Masanori; Miura, Takamasa; Hirakata, Satomi; Hosoyama, Akira; Sugino, Sakiko; Umeno, Aya; Murotomi, Kazutoshi; Yoshida, Yasukazu; Koike, Taisuke

2017-10-30

A relationship between type 2 diabetes mellitus (T2DM) and intestinal flora has been suggested since development of analysis technology for intestinal flora. An animal model of T2DM is important for investigation of T2DM. Although there are some animal models of T2DM, a comparison of the intestinal flora of healthy animals with that of T2DM animals has not yet been reported. The intestinal flora of Tsumura Suzuki Obese Diabetes (TSOD) mice was compared with that of Tsumura, Suzuki, Non Obesity (TSNO) mice in the present study. The TSOD mice showed typical type 2 diabetes symptoms, which were high-fat diet-independent. The TSOD and the TSNO mouse models were derived from the same strain, ddY. In this study, we compared the intestinal flora of TSOD mice with that if TSNO mice at 5 and 12 weeks of age. We determined that that the number of operational taxonomic units (OTUs) was significantly higher in the cecum of TSOD mice than in that of TSNO mice. The intestinal flora of the cecum and that of the feces were similar between the TSNO and the TSOD strains. The dominant bacteria in the cecum and feces were of the phyla Firmicutes and Bacteroidetes. However, the content of some bacterial species varied between the two strains. The percentage of Lactobacillus spp. within the general intestinal flora was higher in TSOD mice than in TSNO mice. In contrast, the percentages of order Bacteroidales and family Lachnospiraceae were higher in TSNO mice than in TSOD mice. Some species were observed only in TSOD mice, such as genera Turicibacter and SMB53 (family Clostridiaceae), the percentage of which were 3.8% and 2.0%, respectively. Although further analysis of the metabolism of the individual bacteria in the intestinal flora is essential, genera Turicibacter and SMB53 may be important for the abnormal metabolism of type 2 diabetes.

Experimental Paracoccidioidomycosis in Mice

PubMed Central

Linares, Leonor I.; Friedman, Lorraine

1972-01-01

Virulence and infectivity of nine strains of Paracoccidioides brasiliensis were investigated in groups of mice which were inoculated intranasally or intravenously, and some of each were treated with corticosteroids. Fatal infections were not often seen among untreated mice, but mortality usually occurred when corticosteroids were given, regardless of the route of fungus inoculation. Prior treatment did not uniformly increase the incidence of infection, however; only in the case of intranasally inoculated mice was this effect seen. Most strains appeared to be more virulent when administered intravenously, with the exception of a single strain which, under the influence of corticosteroids, repeatedly displayed greatest virulence when given intranasally. All animals that died early in the course of the disease, irrespective of route of inoculation, always had acute pulmonary lesions and usually no other organ was involved. Animals which died later or were sacrificed always had chronic lung lesions. Whether or not chronically diseased animals had additional organ involvement correlated with how the organisms were administered; intravenously inoculated animals usually had extrapulmonary as well as pulmonary lesions, but lesions of those inoculated intranasally were almost exclusively pulmonary. Corticosteroids did not alter the histologic characteristics of either the acute or the chronic type of lesion, but the lesions of treated animals were usually more extensive. Most of the survivors appeared healthy even when infection was extensive. Images PMID:4637603

Investigation of Aspergillus flavus in animal virulence.

PubMed

Lan, Huahui; Wu, Lianghuan; Sun, Ruilin; Yang, Kunlong; Liu, Yinghang; Wu, Jiefei; Geng, Longpo; Huang, Chuanzhong; Wang, Shihua

2018-04-01

Aspergillus flavus is a common fungal pathogen of plants, animals and humans. Recently, many genes of A. flavus have been reported involving in regulation of pathogenesis in crops, but whether these genes are involved in animal virulence is still unknown. Here, we used a previous easy-to-use infection model for A. flavus based on mouse model by intravenous inoculation of A. flavus conidia. The outcome of infections in mice model showed that A. flavus NRRL3357 and laboratory strain CA14 PTS were both in dose dependent manner and highly reproducible. The progress of disease could be monitored by mice survival and histology analysis. Fungal burden analysis indicated it was gradually decreased within 7 days after infection. Moreover, aspergillosis caused by A. flavus significantly up-regulated gene expression levels of immune response mediators, including INF-γ, TNF-α, Dectin-1 and TLR2. Furthermore, the defined deletion A. flavus strains that previously displayed virulence in crop infection were also determined in this mouse model, and the results showed comparable degrees of infection in mice. Our results suggested that intravenous inoculation of conidia could be a suitable model for testing different A. flavus mutants in animal virulence. We hope to use this model to determine distinct A. flavus strains virulence in animals and study novel therapeutic methods to help control fungus diseases in the future. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Mice are not Men and yet… how humanized mice inform us about human infectious diseases].

PubMed

Cachat, Anne; Villaudy, Julien; Rigal, Dominique; Gazzolo, Louis; Duc Dodon, Madeleine

2012-01-01

The study of human pathologies is often limited by the absence of animal models which are robust, cost-effective and reproduce the hallmarks of human infections. While mice have been frequently employed to study human diseases, many of important pathogens display unique human tropism. These last two decades the graft of human progenitor cells or tissues into -immunodeficient mice has allowed the elaboration of so called humanized mice. Humanized mouse technology has made rapid progress, and it is now possible to achieve high levels of human chimerism in various organs and tissues, particularly the immune system and the liver. The review briefly summarizes the different models of humanized mice available for in vivo experiments. With a focus on lymphotropic, monocytotropic and hepatotropic viruses, we here discuss the current status and future prospects of these models for studying the pathogenesis of infectious diseases. Furthermore, they provide a powerful tool for the development of innovative therapies. © 2012 médecine/sciences – Inserm / SRMS.

Evaluation of anxiolytic activity of aqueous extract of Coriandrum sativum Linn. in mice: A preliminary experimental study

PubMed Central

Latha, K.; Rammohan, B.; Sunanda, B. P. V.; Maheswari, M. S. Uma; Mohan, Surapaneni Krishna

2015-01-01

Objectives: To evaluate the anxiolytic effect of Coriandrum sativum (CS) aqueous extract in mice. To compare the antianxiety activity of CS against standard drug diazepam (3 mg/kg). Materials and Methods: After obtaining Institutional Animal Ethics Committee approval, Swiss albino mice (18–25 g) of either sex were randomly divided into five groups of six animals each. Dried powder of CS leaves was boiled with distilled water, cooled, filtered, placed on a hotplate for complete evaporation, finally weighed and stored. The control group, test group, and standard drugs group received saline, CS extract (50, 100, and 200 mg/kg), diazepam (3 mg/kg), respectively, by oral feeding. The antianxiety effect was assessed by elevated plus maze (EPM) in mice. Results: In EPM, it implied that CS 50 mg/kg (Group III), 100 mg/kg (Group IV), and 200 mg/kg (Group V) significantly (P < 0.001) increases the number of entries in open arms compared to control. The time spent in open arms also increased in all the doses of CS extract significantly. Conclusion: The current study demonstrates statistically significant dose-dependent antianxiety activity of CS leaves. PMID:26109787

Lepidium meyenii (Maca) increases litter size in normal adult female mice

PubMed Central

Ruiz-Luna, Ana C; Salazar, Stephanie; Aspajo, Norma J; Rubio, Julio; Gasco, Manuel; Gonzales, Gustavo F

2005-01-01

Background Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. Methods Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. Results Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. Conclusion Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility. PMID

Lepidium meyenii (Maca) increases litter size in normal adult female mice.

PubMed

Ruiz-Luna, Ana C; Salazar, Stephanie; Aspajo, Norma J; Rubio, Julio; Gasco, Manuel; Gonzales, Gustavo F

2005-05-03

Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility.

A small animal peripheral challenge model of yellow fever using interferon-receptor deficient mice and the 17D-204 vaccine strain.

PubMed

Thibodeaux, Brett A; Garbino, Nina C; Liss, Nathan M; Piper, Joseph; Blair, Carol D; Roehrig, John T

2012-05-02

Yellow fever virus (YFV), a member of the genus Flavivirus, is a mosquito-borne pathogen that requires wild-type (wt), virulent strains to be handled at biosafety level (BSL) 3, with HEPA-filtration of room air exhaust (BSL3+). YFV is found in tropical regions of Africa and South America and causes severe hepatic disease and death in humans. Despite the availability of effective vaccines (17D-204 or 17DD), YFV is still responsible for an estimated 200,000 cases of illness and 30,000 deaths annually. Besides vaccination, there are no other prophylactic or therapeutic strategies approved for use in human YF. Current small animal models of YF require either intra-cranial inoculation of YF vaccine to establish infection, or use of wt strains (e.g., Asibi) in order to achieve pathology. We have developed and characterized a BSL2, adult mouse peripheral challenge model for YFV infection in mice lacking receptors for interferons α, β, and γ (strain AG129). Intraperitoneal challenge of AG129 mice with 17D-204 is a uniformly lethal in a dose-dependent manner, and 17D-204-infected AG129 mice exhibit high viral titers in both brain and liver suggesting this infection is both neurotropic and viscerotropic. Furthermore the use of a mouse model permitted the construction of a 59-biomarker multi-analyte profile (MAP) using samples of brain, liver, and serum taken at multiple time points over the course of infection. This MAP serves as a baseline for evaluating novel therapeutics and their effect on disease progression. Changes (4-fold or greater) in serum and tissue levels of pro- and anti-inflammatory mediators as well as other factors associated with tissue damage were noted in AG129 mice infected with 17D-204 as compared to mock-infected control animals. Published by Elsevier Ltd.

Preflight studies on tolerance of pocket mice to oxygen and heat. II - Effects on lungs

NASA Technical Reports Server (NTRS)

Harrison, G. A.; Corbett, R. L.; Klein, G.

1975-01-01

An electron microscope examination was carried out on the lungs of 11 pocket mice (Perognathus longimembris) that breathed oxygen at 10 psi or 12 psi partial pressure over a period of 7 d, at the end of which time they were decompressed to sea-level O2 pressure, either suddenly or in 30, 60, or 90 min. Vesiculation was noted in the endothelium of the alveolar-capillary wall in most of the animals and, occasionally, blebbing. Some mitochrondria were swollen in a few of the animals. Alveolar exudate was, in general, sparse. Compared with the lungs of other rodents, the lungs of pocket mice appeared relatively resistant to the toxic effects of oxygen. This conclusion needs, however, to be tempered by the fact that 5% N2 was used in the tests reported here. Nonetheless, the results suggest that the oxygen pressures anticipated on the flight of Apollo XVII should be well tolerated by the pocket mice.

Characterizing interspecies uncertainty using data from studies of anti-neoplastic agents in animals and humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, Paul S.; Keenan, Russell E.; Swartout, Jeffrey C.

For most chemicals, the Reference Dose (RfD) is based on data from animal testing. The uncertainty introduced by the use of animal models has been termed interspecies uncertainty. The magnitude of the differences between the toxicity of a chemical in humans and test animals and its uncertainty can be investigated by evaluating the inter-chemical variation in the ratios of the doses associated with similar toxicological endpoints in test animals and humans. This study performs such an evaluation on a data set of 64 anti-neoplastic drugs. The data set provides matched responses in humans and four species of test animals: mice,more » rats, monkeys, and dogs. While the data have a number of limitations, the data show that when the drugs are evaluated on a body weight basis: 1) toxicity generally increases with a species' body weight; however, humans are not always more sensitive than test animals; 2) the animal to human dose ratios were less than 10 for most, but not all, drugs; 3) the current practice of using data from multiple species when setting RfDs lowers the probability of having a large value for the ratio. These findings provide insight into inter-chemical variation in animal to human extrapolations and suggest the need for additional collection and analysis of matched toxicity data in humans and test animals.« less

[Establishment of the experimental animal model of Babesia microti].

PubMed

Lu, Yan; Cai, Yu-Chun; Chen, Shao-Hong; Chen, Jia-Xu; Guo, Jian; Chen, Mu-Xin; Ai, Lin; Chu, Yan-Hong; Chen, Zhuo; Zhou, Xiao-Nong

2012-12-30

To establish the experimental animal model for the study of Babesia microti. BALB/c mice, immunosuppressive BALB/c mice, SCID mice and NOD-SCID mice were inoculated with B. microti-infected red blood cells (RBC) by intraperitoneal injection respectively. After inoculation, thin blood smears were prepared every day, stained with Giemsa staining and examined for the presence of parasitemia. Three mice were dissected to examine the infectivity in bone marrow, brain, spleen, heart, lung, kidney and liver tissues. The infection rate of erythrocytes in different tissues was recorded, and the relationship between the infectivity of tissues and infection rate in peripheral blood was analyzed. Blood samples infected with B. microti were preserved in liquid nitrogen with dimethyl sulfoxide (DMSO) for 2 months. The thawed parasitized blood was injected into the BALB/c mice by same route and the parasitemia was monitored. The four kinds of mice were all infected by B. microti with parasitemia. The percentage of parasitized red blood cells from peripheral blood were 82.4% (BALB/c mice, d7), 73.2% (immunosuppressive BALB/c mice, d5), 86.4% (SCID mice, d8) and 72.5% (NOD-SCID mice, d8) at the maximum, respectively. Parasitemia decreased rapidly in BALB/c mice, whereas decreased slowly in immunosuppressive BALB/c mice. Only the parasitemia in SCID mice and NOD-SCID mice decreased significantly and tended to picking up again. The parasites were observed in RBCs from bone marrow, brain, spleen, heart, lung, kidney and liver tissues. The infection rate of erythrocytes in tissues increased with an increase of infection in peripheral blood. After cryopreservation, the parasites proliferated in BALB/c mice. Parasitemia appeared after inoculation with frozen infected blood two days later than that of fresh infected blood. The infection rate reached its peak after inoculation with frozen infected blood one day later than that of fresh infected blood. The experimental animal model of B

Transgenic mice as an alternative to monkeys for neurovirulence testing of live oral poliovirus vaccine: validation by a WHO collaborative study.

PubMed Central

Dragunsky, Eugenia; Nomura, Tatsuji; Karpinski, Kazimir; Furesz, John; Wood, David J.; Pervikov, Yuri; Abe, Shinobu; Kurata, Takeshi; Vanloocke, Olivier; Karganova, Galina; Taffs, Rolf; Heath, Alan; Ivshina, Anna; Levenbook, Inessa

2003-01-01

OBJECTIVE: Extensive WHO collaborative studies were performed to evaluate the suitability of transgenic mice susceptible to poliovirus (TgPVR mice, strain 21, bred and provided by the Central Institute for Experimental Animals, Japan) as an alternative to monkeys in the neurovirulence test (NVT) of oral poliovirus vaccine (OPV). METHODS: Nine laboratories participated in the collaborative study on testing neurovirulence of 94 preparations of OPV and vaccine derivatives of all three serotypes in TgPVR21 mice. FINDINGS: Statistical analysis of the data demonstrated that the TgPVR21 mouse NVT was of comparable sensitivity and reproducibility to the conventional WHO NVT in simians. A statistical model for acceptance/rejection of OPV lots in the mouse test was developed, validated, and shown to be suitable for all three vaccine types. The assessment of the transgenic mouse NVT is based on clinical evaluation of paralysed mice. Unlike the monkey NVT, histological examination of central nervous system tissue of each mouse offered no advantage over careful and detailed clinical observation. CONCLUSIONS: Based on data from the collaborative studies the WHO Expert Committee for Biological Standardization approved the mouse NVT as an alternative to the monkey test for all three OPV types and defined a standard implementation process for laboratories that wish to use the test. This represents the first successful introduction of transgenic animals into control of biologicals. PMID:12764491

The effects of repeated antibiotic administration to juvenile BALB/c mice on the microbiota status and animal behavior at the adult age.

PubMed

Ceylani, Taha; Jakubowska-Doğru, Ewa; Gurbanov, Rafig; Teker, Hikmet Taner; Gozen, Ayse Gul

2018-06-01

Recent studies carried on germ -free (GF) animal models suggest that the gut microbiota (GM) may play a role in the regulation of anxiety, mood, and cognitive abilities such as memory and learning processes. Consistently, any treatment disturbing the gut microbiota, including the overuse of antibiotics, may influence the brain functions and impact behavior. In the present study, to address this issue, two wide-spectrum antibiotics (ampicillin and cefoperazone, 1 g/l) were repeatedly applied throughout a 6-week period to initially 21-day-old male BALB/c mice. Antibiotics were administered separately or in a mixed fashion. On the completion of the antibiotic treatment, all mice were subjected to the behavioral tests. The serum levels of corticosterone and brain-derived neurotropic factor (BDNF) were assessed. Gut microbiota profiles were obtained by using denaturing gradient gel electrophoresis system, DGGE, from fecal samples. Ampicillin had a greater impact on both, gut microbiota composition and mice behavior compared to cefoperazone. All antibiotic-treated groups manifested a decrease in the locomotor activity and reduced recognition memory. However, the ampicillin-treated groups showed a higher anxiety level as assessed by the open field and the elevated plus maze tests and an increased immobility (behavioral despair) in the forced swim test. Obtained results evidently show that in mice, a repeated antibiotic treatment applied during adolescence, parallel to the changes in GM, affects locomotor activity, affective behavior and cognitive skills in young adults with ampicillin specifically enhancing anxiety- and depressive-like responses. Lower levels of serum BDNF were not associated with cognitive impairment but with changes in affective-like behaviors. Repeated administration of neither ampicillin nor cefoperazone affected basal serum corticosterone levels. This is one of the few studies demonstrating changes in a behavioral phenotype of young-adult subjects

Operant ethanol self-administration in ethanol dependent mice.

PubMed

Lopez, Marcelo F; Becker, Howard C

2014-05-01

While rats have been predominantly used to study operant ethanol self-administration behavior in the context of dependence, several studies have employed operant conditioning procedures to examine changes in ethanol self-administration behavior as a function of chronic ethanol exposure and withdrawal experience in mice. This review highlights some of the advantages of using operant conditioning procedures for examining the motivational effects of ethanol in animals with a history of dependence. As reported in rats, studies using various operant conditioning procedures in mice have demonstrated significant escalation of ethanol self-administration behavior in mice rendered dependent via forced chronic ethanol exposure in comparison to nondependent mice. This paper also presents a summary of these findings, as well as suggestions for future studies. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of Cage-Change Frequency and Bedding Volume on Mice and Their Microenvironment

PubMed Central

Rosenbaum, Matthew D; VandeWoude, Susan; Johnson, Thomas E

2009-01-01

The frequency at which mouse cages are changed has important implications for the animals, animal care personnel, and facility managers. The objective of this study was to determine how bedding volume and the interval between changes affect microenvironmental conditions, health, and behavior of mice housed in individually ventilated cages (IVC). A total of 15 cages (n = 5 cages per bedding volume) housing ICR female mice (n = 5 animals per cage) were monitored for 17 d. Parameters monitored included clinical evaluation of each animal, appearance of the cage, fecal corticosterone levels, bedding weight, and mouse mass. Atmospheric analysis was performed daily to determine intracage ammonia cage humidity and temperature on a daily basis. Mice were videotaped for 10 min on days 1, 8, and 15, and videos were analyzed for abnormal behaviors. On day 17, 1 mouse from each cage was euthanized, and bronchoalveolar lavage was performed. Statistical differences in parameters were most often noted between low- and high-volume bedding groups. Correlation between visual appearance and actual intracage environmental conditions and mouse health and behavior at specific time points indicated cages that appear dirty to most observers did not have measurably adverse effects on the animals for any of the many parameters evaluated in this study. This study demonstrated that a 2-wk interval between cage changes for ICR female mice housed in IVC caging (with approximately 90 air changes per hour) and aspen chip bedding did not significantly affect measures of animal well-being in this study. This lack of effect occurred despite the appearance of excessive soiling by the 2-wk time point. PMID:19930825

A miniature mechanical ventilator for newborn mice.

PubMed

Kolandaivelu, K; Poon, C S

1998-02-01

Transgenic/knockout mice with pre-defined mutations have become increasingly popular in biomedical research as models of human diseases. In some instances, the resulting mutation may cause cardiorespiratory distress in the neonatal or adult animals and may necessitate resuscitation. Here we describe the design and testing of a miniature and versatile ventilator that can deliver varying ventilatory support modes, including conventional mechanical ventilation and high-frequency ventilation, to animals as small as the newborn mouse. With a double-piston body chamber design, the device circumvents the problem of air leakage and obviates the need for invasive procedures such as endotracheal intubation, which are particularly important in ventilating small animals. Preliminary tests on newborn mice as early as postnatal day O demonstrated satisfactory restoration of pulmonary ventilation and the prevention of respiratory failure in mutant mice that are prone to respiratory depression. This device may prove useful in the postnatal management of transgenic/knockout mice with genetically inflicted respiratory disorders.

Toxicology and carcinogenesis studies of a nondecolorized [corrected] whole leaf extract of Aloe barbadensis Miller (Aloe vera) in F344/N rats and B6C3F1 mice (drinking water study).

PubMed

Boudreau, M D; Beland, F A; Nichols, J A; Pogribna, M

2013-08-01

Extracts from the leaves of the Aloe vera plant (Aloe barbadensis Miller) have long been used as herbal remedies and are also now promoted as a dietary supplement, in liquid tonics, powders or tablets, as a laxative and to prevent a variety of illnesses. We studied the effects of Aloe vera extract on rats and mice to identify potential toxic or cancer-related hazards. We gave solutions of nondecolorized extracts of Aloe vera leaves in the drinking water to groups of rats and mice for 2 years. Groups of 48 rats received solutions containing 0.5%, 1% or 1.5% of Aloe vera extract in the drinking water, and groups of mice received solutions containing 1%, 2%, or 3% of Aloe vera extract. Similar groups of animals were given plain drinking water and served as the control groups. At the end of the study tissues from more than 40 sites were examined for every animal. In all groups of rats and mice receiving the Aloe vera extract, the rates of hyperplasia in the large intestine were markedly increased compared to the control animals. There were also increases in hyperplasia in the small intestine in rats receiving the Aloe vera extract, increases in hyperplasia of the stomach in male and female rats and female mice receiving the Aloe vera extract, and increases in hyperplasia of the mesenteric lymph nodes in male and female rats and male mice receiving the Aloe vera extract. In addition, cancers of the large intestine occurred in male and female rats given the Aloe vera extract, though none had been seen in the control groups of rats for this and other studies at this laboratory. We conclude that nondecolorized Aloe vera caused cancers of the large intestine in male and female rats and also caused hyperplasia of the large intestine, small intestine, stomach, and lymph nodes in male and female rats. Aloe vera extract also caused hyperplasia of the large intestine in male and female mice and hyperplasia of the mesenteric lymph node in male mice and hyperplasia of the stomach

Two-Photon Microscopy Imaging of thy1GFP-M Transgenic Mice: A Novel Animal Model to Investigate Brain Dendritic Cell Subsets In Vivo

PubMed Central

Laperchia, Claudia; Allegra Mascaro, Anna L.; Sacconi, Leonardo; Andrioli, Anna; Mattè, Alessandro; De Franceschi, Lucia; Grassi-Zucconi, Gigliola; Bentivoglio, Marina; Buffelli, Mario; Pavone, Francesco S.

2013-01-01

Transgenic mice expressing fluorescent proteins in specific cell populations are widely used for in vivo brain studies with two-photon fluorescence (TPF) microscopy. Mice of the thy1GFP-M line have been engineered for selective expression of green fluorescent protein (GFP) in neuronal populations. Here, we report that TPF microscopy reveals, at the brain surface of these mice, also motile non-neuronal GFP+ cells. We have analyzed the behavior of these cells in vivo and characterized in brain sections their immunophenotype. With TPF imaging, motile GFP+ cells were found in the meninges, subarachnoid space and upper cortical layers. The striking feature of these cells was their ability to move across the brain parenchyma, exhibiting evident shape changes during their scanning-like motion. In brain sections, GFP+ cells were immunonegative to antigens recognizing motile cells such as migratory neuroblasts, neuronal and glial precursors, mast cells, and fibroblasts. GFP+ non-neuronal cells exhibited instead the characteristic features and immunophenotype (CD11c and major histocompatibility complex molecule class II immunopositivity) of dendritic cells (DCs), and were immunonegative to the microglial marker Iba-1. GFP+ cells were also identified in lymph nodes and blood of thy1GFP-M mice, supporting their identity as DCs. Thus, TPF microscopy has here allowed the visualization for the first time of the motile behavior of brain DCs in situ. The results indicate that the thy1GFP-M mouse line provides a novel animal model for the study of subsets of these professional antigen-presenting cells in the brain. Information on brain DCs is still very limited and imaging in thy1GFP-M mice has a great potential for analyses of DC-neuron interaction in normal and pathological conditions. PMID:23409142

Transgenic mice in developmental toxicology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woychik, R.P.

1992-12-31

Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areasmore » of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.« less

Transgenic mice in developmental toxicology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woychik, R.P.

1992-01-01

Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areasmore » of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.« less

Hypothyroidism Compromises Hypothalamic Leptin Signaling in Mice

PubMed Central

Groba, Claudia; Mayerl, Steffen; van Mullem, Alies A.; Visser, Theo J.; Darras, Veerle M.; Habenicht, Andreas J.

2013-01-01

The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing, particularly in the central nervous system, is only poorly defined. Here, we studied the consequences of hypothyroidism on leptin production as well as leptin sensing in congenital hypothyroid TRH receptor 1 knockout (Trhr1 ko) mice and euthyroid control animals. Hypothyroid mice exhibited decreased circulating leptin levels due to a decrease in fat mass and reduced leptin expression in white adipose tissue. In neurons of the hypothalamic arcuate nucleus, hypothyroid mice showed increased leptin receptor Ob-R expression and decreased suppressor of cytokine signaling 3 transcript levels. In order to monitor putative changes in central leptin sensing, we generated hypothyroid and leptin-deficient animals by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob/ob mice. Hypothyroid Trhr1/ob double knockout mice showed a blunted response to leptin treatment with respect to body weight and food intake and exhibited a decreased activation of phospho-signal transducer and activator of transcription 3 as well as a up-regulation of suppressor of cytokine signaling 3 upon leptin treatment, particularly in the arcuate nucleus. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism. PMID:23518925

Continuous monitoring of arthritis in animal models using optical imaging modalities

NASA Astrophysics Data System (ADS)

Son, Taeyoon; Yoon, Hyung-Ju; Lee, Saseong; Jang, Won Seuk; Jung, Byungjo; Kim, Wan-Uk

2014-10-01

Given the several difficulties associated with histology, including difficulty in continuous monitoring, this study aimed to investigate the feasibility of optical imaging modalities-cross-polarization color (CPC) imaging, erythema index (EI) imaging, and laser speckle contrast (LSC) imaging-for continuous evaluation and monitoring of arthritis in animal models. C57BL/6 mice, used for the evaluation of arthritis, were divided into three groups: arthritic mice group (AMG), positive control mice group (PCMG), and negative control mice group (NCMG). Complete Freund's adjuvant, mineral oil, and saline were injected into the footpad for AMG, PCMG, and NCMG, respectively. LSC and CPC images were acquired from 0 through 144 h after injection for all groups. EI images were calculated from CPC images. Variations in feet area, EI, and speckle index for each mice group over time were calculated for quantitative evaluation of arthritis. Histological examinations were performed, and the results were found to be consistent with those from optical imaging analysis. Thus, optical imaging modalities may be successfully applied for continuous evaluation and monitoring of arthritis in animal models.

Increased mitogenic response in lymphocytes from chronically centrifuged mice

NASA Technical Reports Server (NTRS)

Mueller, Otfried; Hunzinger, E.; Cogoli, Augusto; Bechler, B.; Lee, J.; Moore, J.; Duke, J.

1990-01-01

The effects upon the mitogenic response of splenic lymphocytes when exposing mice to prolonged hypergravity conditions (3.5 G for 1 year) were studied. Cultures of splenic lymphocytes isolated from both centrifuged and control (1 G) animals were stimulated with Concanavalin A and the response measured using both morphological and biochemical means. Lymphocytes obtained from centrifuged mice exhibited much higher activation rates (as measured by the incorporation of H-3 thymidine) and larger cell aggregates consisting of more lymphoblasts and mitotic figures than those observed in non centrifuged control animals. Isolated splenic lymphocytes thus appear to have been conditioned by hypergravity state.

Subcutaneous Implants of Buprenorphine-Cholesterol-Triglyceride Powder in Mice.

PubMed

DeTolla, L; Sanchez, R; Khan, E; Tyler, B; Guarnieri, M

2014-01-01

Subcutaneous drug implants are convenient systems for the long-term delivery of drugs in animals. Lipid carriers are logical tools because they generally allow for higher doses and low toxicity. The present study used an US Food and Drug Administration Target Animal Safety test system to evaluate the safety of a subcutaneous implant of a cholesterol-triglyceride-buprenorphine powder in 120 BALB/c mice. Mice were evaluated in 4- and 12-day trials with 1- and 5-fold doses of the intended 3 mg/kg dose of drug. One male mouse treated with three 3 mg/kg doses and surgery on days 0, 4, and 8 died on day 9. The cause of death was not determined. In the surviving 119 mice there was no evidence of skin reaction at the site of the implant. Compared to control animals treated with saline, weight measurements, clinical pathology, histopathology, and clinical observations were unremarkable. These results demonstrate that the lipid carrier is substantially safe. Cholesterol-triglyceride-drug powders may provide a valuable research tool for studies of analgesic and inflammatory drug implants in veterinary medicine.

Subcutaneous Implants of Buprenorphine-Cholesterol-Triglyceride Powder in Mice

PubMed Central

DeTolla, L.; Sanchez, R.; Khan, E.; Tyler, B.; Guarnieri, M.

2014-01-01

Subcutaneous drug implants are convenient systems for the long-term delivery of drugs in animals. Lipid carriers are logical tools because they generally allow for higher doses and low toxicity. The present study used an US Food and Drug Administration Target Animal Safety test system to evaluate the safety of a subcutaneous implant of a cholesterol-triglyceride-buprenorphine powder in 120 BALB/c mice. Mice were evaluated in 4- and 12-day trials with 1- and 5-fold doses of the intended 3 mg/kg dose of drug. One male mouse treated with three 3 mg/kg doses and surgery on days 0, 4, and 8 died on day 9. The cause of death was not determined. In the surviving 119 mice there was no evidence of skin reaction at the site of the implant. Compared to control animals treated with saline, weight measurements, clinical pathology, histopathology, and clinical observations were unremarkable. These results demonstrate that the lipid carrier is substantially safe. Cholesterol-triglyceride-drug powders may provide a valuable research tool for studies of analgesic and inflammatory drug implants in veterinary medicine. PMID:26464927

Design and development of biomimetic quadruped robot for behavior studies of rats and mice.

PubMed

Ishii, Hiroyuki; Masuda, Yuichi; Miyagishima, Syunsuke; Fumino, Shogo; Takanishi, Atsuo; Laschi, Cecilia; Mazzolai, Barbara; Mattoli, Virgilio; Dario, Paolo

2009-01-01

This paper presents the design and development of a novel biomimetic quadruped robot for behavior studies of rats and mice. Many studies have been performed using these animals for the purpose of understanding human mind in psychology, pharmacology and brain science. In these fields, several experiments on social interactions have been performed using rats as basic studies of mental disorders or social learning. However, some researchers mention that the experiments on social interactions using animals are poorly-reproducible. Therefore, we consider that reproducibility of these experiments can be improved by using a robotic agent that interacts with an animal subject. Thus, we developed a small quadruped robot WR-2 (Waseda Rat No. 2) that behaves like a real rat. Proportion and DOF arrangement of WR-2 are designed based on those of a mature rat. This robot has four 3-DOF legs, a 2-DOF waist and a 1-DOF neck. A microcontroller and a wireless communication module are implemented on it. A battery is also implemented. Thus, it can walk, rear by limbs and groom its body.

Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice.

PubMed

Nishchal, B S; Rai, S; Prabhu, M N; Ullal, Sheetal D; Rajeswari, S; Gopalakrishna, H N

2014-01-01

Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects.

Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice

PubMed Central

Nishchal, B. S.; Rai, S.; Prabhu, M. N.; Ullal, Sheetal D.; Rajeswari, S.; Gopalakrishna, H. N.

2014-01-01

Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects. PMID:25593394

The development of response surface pathway design to reduce animal numbers in toxicity studies

PubMed Central

2014-01-01

Background This study describes the development of Response Surface Pathway (RSP) design, assesses its performance and effectiveness in estimating LD50, and compares RSP with Up and Down Procedures (UDPs) and Random Walk (RW) design. Methods A basic 4-level RSP design was used on 36 male ICR mice given intraperitoneal doses of Yessotoxin. Simulations were performed to optimise the design. A k-adjustment factor was introduced to ensure coverage of the dose window and calculate the dose steps. Instead of using equal numbers of mice on all levels, the number of mice was increased at each design level. Additionally, the binomial outcome variable was changed to multinomial. The performance of the RSP designs and a comparison of UDPs and RW were assessed by simulations. The optimised 4-level RSP design was used on 24 female NMRI mice given Azaspiracid-1 intraperitoneally. Results The in vivo experiment with basic 4-level RSP design estimated the LD50 of Yessotoxin to be 463 μg/kgBW (95% CI: 383–535). By inclusion of the k-adjustment factor with equal or increasing numbers of mice on increasing dose levels, the estimate changed to 481 μg/kgBW (95% CI: 362–566) and 447 μg/kgBW (95% CI: 378–504 μg/kgBW), respectively. The optimised 4-level RSP estimated the LD50 to be 473 μg/kgBW (95% CI: 442–517). A similar increase in power was demonstrated using the optimised RSP design on real Azaspiracid-1 data. The simulations showed that the inclusion of the k-adjustment factor, reduction in sample size by increasing the number of mice on higher design levels and incorporation of a multinomial outcome gave estimates of the LD50 that were as good as those with the basic RSP design. Furthermore, optimised RSP design performed on just three levels reduced the number of animals from 36 to 15 without loss of information, when compared with the 4-level designs. Simulated comparison of the RSP design with UDPs and RW design demonstrated the superiority of RSP. Conclusion

Identification of an Astrovirus Commonly Infecting Laboratory Mice in the US and Japan

PubMed Central

Ng, Terry Fei Fan; Kondov, Nikola O.; Hayashimoto, Nobuhito; Uchida, Ritsuki; Cha, Yunhee; Beyer, Ashley I.; Wong, Walt; Pesavento, Patricia A.; Suemizu, Hiroshi; Muench, Marcus O.; Delwart, Eric

2013-01-01

Mice (Mus musculus) are the most commonly used laboratory animals. Viral metagenomics on tissues of immunodeficient mice revealed sequences of a novel mammalian astrovirus. Using PCR, we screened mice from 4 breeders, 4 pharmaceutical companies, 14 research institutes and 30 universities in the US and Japan. Mice from one US breeder tested positive while none from Japanese breeders were positive for MuAstV. Mice in over half of the universities (19/30), institutes (7/14) and pharmaceutical animal facilities (2/4) investigated revealed the presence of MuAstV. Nine mice strains tested positive including both immunodeficient strains (NSG, NOD-SCID, NSG-3GS, C57BL6-Timp-3 −/−, and uPA-NOG) and immunocompetent strains (B6J, ICR, Bash2, BALB/c). Our data indicates that MuAstV has a wide geographical, institutional and host strain distribution. Comparison of the MuAstV RdRp sequences showed numerous mutations indicating ongoing viral divergence in different facilities. This study demonstrates the need for metagenomic screening of laboratory animals to identify adventitious infections that may affect experimental outcomes. PMID:23825590

Supplementation with macular carotenoids improves visual performance of transgenic mice.

PubMed

Li, Binxing; Rognon, Gregory T; Mattinson, Ty; Vachali, Preejith P; Gorusupudi, Aruna; Chang, Fu-Yen; Ranganathan, Arunkumar; Nelson, Kelly; George, Evan W; Frederick, Jeanne M; Bernstein, Paul S

2018-07-01

Carotenoid supplementation can improve human visual performance, but there is still no validated rodent model to test their effects on visual function in laboratory animals. We recently showed that mice deficient in β-carotene oxygenase 2 (BCO2) and/or β-carotene oxygenase 1 (BCO1) enzymes can accumulate carotenoids in their retinas, allowing us to investigate the effects of carotenoids on the visual performance of mice. Using OptoMotry, a device to measure visual function in rodents, we examined the effect of zeaxanthin, lutein, and β-carotene on visual performance of various BCO knockout mice. We then transgenically expressed the human zeaxanthin-binding protein GSTP1 (hGSTP1) in the rods of bco2 -/- mice to examine if delivering more zeaxanthin to retina will improve their visual function further. The visual performance of bco2 -/- mice fed with zeaxanthin or lutein was significantly improved relative to control mice fed with placebo beadlets. β-Carotene had no significant effect in bco2 -/- mice but modestly improved cone visual function of bco1 -/- mice. Expression of hGSTP1 in the rods of bco2 -/- mice resulted in a 40% increase of retinal zeaxanthin and further improvement of visual performance. This work demonstrates that these "macular pigment mice" may serve as animal models to study carotenoid function in the retina. Copyright © 2018 Elsevier Inc. All rights reserved.

Generation of genetically-engineered animals using engineered endonucleases.

PubMed

Lee, Jong Geol; Sung, Young Hoon; Baek, In-Jeoung

2018-05-17

The key to successful drug discovery and development is to find the most suitable animal model of human diseases for the preclinical studies. The recent emergence of engineered endonucleases is allowing for efficient and precise genome editing, which can be used to develop potentially useful animal models for human diseases. In particular, zinc finger nucleases, transcription activator-like effector nucleases, and the clustered regularly interspaced short palindromic repeat systems are revolutionizing the generation of diverse genetically-engineered experimental animals including mice, rats, rabbits, dogs, pigs, and even non-human primates that are commonly used for preclinical studies of the drug discovery. Here, we describe recent advances in engineered endonucleases and their application in various laboratory animals. We also discuss the importance of genome editing in animal models for more closely mimicking human diseases.

[EFFECTIVENESS OF FULLERENE-(TRIS-AMINOCAPRONIC ACID) HYDRATE IN THE MODEL OF EXPERIMENTAL VIRAL-BACTERIAL PNEUMONIA OF MICE].

PubMed

Falynskova, I N; Leonova, E I; Fedyakina, I T; Makhmudova, N R; Lepekha, L N; Mikhailova, N A; Rasnetsov, L D; Zverev, V V; Leneva, I A

2015-01-01

Study the effectiveness of the substance and various drug formulations of fullerene-(tris-aminocapronic acid) hydrate (FTAAH onwards) in the model of experimental viral-bacterial pneumonia of mice. BALB/c mice were infected with influenza virus A/California/04/2009 and subsequently infected with Staphylococcus aureus. The animals were treated after viral infection with the substance and various drug forms of FTAAH, as well as comparative preparations--oseltamivir and arbidol. Therapy effectiveness was evaluated by clinical indicators (survival, lifespan, animal mass decrease reduction), virological (virus titer), microbiological (density of bacteria in lungs) parameters, confirmed by pathomorphological characteristics of lungs. FTAAH therapy in injectable form was effective in the model of a combined viral-bacterial pneumonia of mice by all the studied criteria: treatment increased mice survival, reduced the decrease of their body weight, resulted in a reduction of virus titers and density of bacteria in lungs, that correlated with the data from morphological study and signs of bronchopneumonia resolution in mice. FTAAH therapy in rectal form depended on animal infection schemes, as well as preparation dose, increasing with its increase. FTAAH substance is effective in the model of experimental viral-bacterial pneumonia of mice.

Morphologic and Histologic Comparison of Hypertrophic Scar in Nude Mice, T-Cell Receptor, and Recombination Activating Gene Knockout Mice.

PubMed

Momtazi, Moein; Ding, Jie; Kwan, Peter; Anderson, Colin C; Honardoust, Dariush; Goekjian, Serge; Tredget, Edward E

2015-12-01

Proliferative scars in nude mice have demonstrated morphologic and histologic similarities to human hypertrophic scar. Gene knockout technology provides the opportunity to study the effect of deleting immune cells in various disease processes. The authors' objective was to test whether grafting human skin onto T-cell receptor (TCR) αβ-/-γδ-/-, recombination activating gene (RAG)-1-/-, and RAG-2γ-/-c-/- mice results in proliferative scars consistent with human hypertrophic scar and to characterize the morphologic, histologic, and cellular changes that occur after removing immune cells. Nude TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice (n = 20 per strain) were grafted with human skin and euthanized at 30, 60, 120, and 180 days. Controls (n = 5 per strain) were autografted with mouse skin. Scars and normal skin were harvested at each time point. Sections were stained with hematoxylin and eosin, Masson's trichrome, and immunohistochemistry for anti-human leukocyte antigen-ABC, α-smooth muscle actin, decorin, and biglycan. TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice grafted with human skin developed firm, elevated scars with histologic and immunohistochemical similarities to human hypertrophic scar. Autografted controls showed no evidence of pathologic scarring. Knockout animals demonstrated a capacity for scar remodeling not observed in nude mice where reductions in α-smooth muscle actin staining pattern and scar thickness occurred over time. Human skin transplanted onto TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice results in proliferative scars with morphologic and histologic features of human hypertrophic scar. Remodeling of proliferative scars generated in knockout animals is analogous to changes in human hypertrophic scar. These animal models may better represent the natural history of human hypertrophic scar.

Diabetes Associated Metabolomic Perturbations in NOD Mice

PubMed Central

Hwang, Jessica; Poudel, Ananta; Jo, Junghyo; Periwal, Vipul; Fiehn, Oliver; Hara, Manami

2014-01-01

Non-obese diabetic (NOD) mice are a widely-used model oftype1 diabetes (T1D). However, not all animals develop overt diabetes. This study examined the circulating metabolomic profiles of NOD mice progressing or not progressing to T1D. Total beta-cell mass was quantified in the intact pancreas using transgenic NOD mice expressinggreen fluorescent protein under the control of mouse insulin I promoter.While both progressor and non-progressor animals displayed lymphocyte infiltration and endoplasmic reticulum stress in the pancreas tissue;overt T1D did not develop until animals lost ~70% of the total beta-cell mass.Gas chromatography time of flight mass spectrometry (GC-TOF) was used to measure >470 circulating metabolites in male and female progressor and non-progressor animals (n=76) across a wide range of ages (neonates to >40-wk).Statistical and multivariate analyses were used to identify age and sex independent metabolic markers which best differentiated progressor and non-progressor animals’ metabolic profiles. Key T1D-associated perturbations were related with: (1) increased plasma glucose and reduced 1,5-anhydroglucitol markers of glycemic control; (2) increased allantoin, gluconic acid and nitric oxide-derived saccharic acid markers of oxidative stress; (3) reduced lysine, an insulin secretagogue; (4) increased branched-chain amino acids, isoleucine and valine; (5) reduced unsaturated fatty acids including arachidonic acid; and (6)perturbations in urea cycle intermediates suggesting increased arginine-dependent NO synthesis. Together these findings highlight the strength of the unique approach of comparing progressor and non-progressor NOD mice to identify metabolic perturbations involved in T1D progression. PMID:25755629

[Preliminary establishment of transplanted human chronic myeloid leukemia model in nude mice].

PubMed

Li, Xian-Min; Ding, Xin; Zhang, Long-Zhen; Cen, Jian-Nong; Chen, Zi-Xing

2011-12-01

Chronic myeloid leukemia (CML) is a malignant clonal disease derived from hematopoietic stem cells. CML stem cells were thought to be the root which could lead disease development and ultimately rapid change. However, a stable animal model for studying the characteristics of CML stem cells is currently lacking. This study was aimed to establish a transplanted human CML nude-mice model to further explore the biological behavior of CML stem cells in vivo, and to enrich CML stem cells in nude mice by series transplantation. The 4 - 6 weeks old BALB/c nude mice pretreated by splenectomy (S), cytoxan intraperitoneal injection (C) and sublethal irradiation (I) were transplanted intravenously with (5 - 7) × 10(7) of bone marrow mononuclear cells from CML patients in chronic phase. Alternatively, 4 - 6 weeks old BALB/c nude mice pretreated by lethal irradiation were transplanted intravenously with 5 × 10(6) homologous bone marrow cells of BALB/c nude mice together with (5 - 7) × 10(7) of bone marrow mononuclear cells from CML patients in chronic phase simultaneously. The leukemic cells engrafted and infiltrated in organs and bone marrow of the mice were tracked by reverse transcription-polymerase chain reaction (RT-PCR), plastic-embedded biopsy and flow cytometry. The results of these two methods were compared. The results showed that human CML cells engrafted and infiltrating into the bone marrow of two nude mice pretreated with SCI could be detected. In spite of the low successful rate, results suggested the feasibility of this method by using BALB/c nude mice as a human CML animal model. In contrast, in nude mice pretreated by the lethal dose irradiation, CML cells in the bone marrow could not be found. It is concluded that human bone marrow CML cells can results in leukemia in nude mice pretreated by SCI. Thus this study provides a new strategy for establishment of CML animal models which deserves further elaboration.

Mouse Drawer System (MDS): An autonomous hardware for supporting mice space research

NASA Astrophysics Data System (ADS)

Liu, Y.; Biticchi, R.; Alberici, G.; Tenconi, C.; Cilli, M.; Fontana, V.; Cancedda, R.; Falcetti, G.

2005-08-01

For the scientific community the ability of flying mice under weightless conditions in space, compared to other rodents, offers many valuable advantages. These include the option of testing a wide range of wild-type and mutant animals, an increased animal number for flight, and a reduced demand on shuttle resources and crew time. In this study, we describe a spaceflight hardware for mice, the Mouse Drawer System (MDS). MDS can interface with Space Shuttle middeck and International Space Station Express Rack. It consists of Mice Chamber, Liquid Handling Subsystem, Food Delivery Subsystem, Air Conditioning Subsystem, Illumination Subsystem, Observation Subsystem and Payload Control Unit. It offers single or paired containment for 6-8 mice with a mean weight of 40 grams/mouse for a period of up to 3 months. Animal tests were conducted in a MDS breadboard to validate the biocompatibility of various subsystems. Mice survived in all tests of short and long duration. Results of blood parameters, histology and air/waste composition analysis showed that MDS subsystems meet the NIH guidelines for temperature, humidity, food and water access, air quality, odour and waste management.

NITROBENZENE CARCINOGENICITY IN ANIMALS AND HUMAN HAZARD EVALUATION

EPA Science Inventory

Nitrobenzene (NB) human cancer studies have not been reported, but animals studies have. Three rodent strains inhaling NB produce cancer at eight sites. B6C3F1 mice respond with mammary gland malignant tumors and male lung and thyroid benign tumors, F344/N male rats respond with ...

[The battery of tests for behavioral phenotyping of aging animals in the experiment].

PubMed

Gorina, Ya V; Komleva, Yu K; Lopatina, O L; Volkova, V V; Chernykh, A I; Shabalova, A A; Semenchukov, A A; Olovyannikova, R Ya; Salmina, A B

2017-01-01

The purpose of the study was to develop a battery of tests to study social and cognitive impairments for behavioral phenotyping of aging experimental animals with physiological neurodegeneration. Object of the study were outbred CD1 mice in the following groups: 1st group - 12-month old male mice (physiological aging); 2nd group - 2-month old male mice (control group). Social recognition test, elevated plus maze test (EPM), open field test, light-dark box test, and Fear conditioning protocol were used to estimate the neurological status of experimental animals. We found that aging male mice in a contrast to young ones have demonstrated lower social interest to female mice in the social recognition task. EPM and light-dark box tests showed increased level of anxiety in the group of aged mice comparing to the control group. Fear conditioning protocol revealed impairment of associative learning and memory in the group of aged mice, particularly, fear memory consolidation was dramatically suppressed. Analysis of behavioral factors, social interactions and anxiety level in the experimental mice has confirmed age-related neurodegeneration in the 1st group. We found that the most informative approach to identifying neurological impairments in aging mice (social interaction deficit, limitation of interests, increased level of anxiety) should be based on the open field test light-dark box test, and Fear conditioning protocol. Such combination allows obtaining new data on behavioral alterations in the age-associated of neurodegeneration and to develop novel therapeutic strategies for the treatment of age-related brain pathology.

Gravity receptor function in mice with graded otoconial deficiencies.

PubMed

Jones, Sherri M; Erway, Lawrence C; Johnson, Kenneth R; Yu, Heping; Jones, Timothy A

2004-05-01

The purpose of the present study was to examine gravity receptor function in mutant mouse strains with variable deficits in otoconia: lethal milk (lm), pallid (pa), tilted (tlt), mocha (mh), and muted (mu). Control animals were either age-matched heterozygotes or C57BL/6J (abbr. B6) mice. Gravity receptor function was measured using linear vestibular evoked potentials (VsEPs). Cage and swimming behaviors were also documented. Temporal bones were cleared to assess the overall otoconial deficit and to correlate structure and function for lm mice. Results confirmed the absence of VsEPs for mice that lacked otoconia completely. VsEP thresholds and amplitudes varied in mouse strains with variable loss of otoconia. Some heterozygotes also showed elevated VsEP thresholds in comparison to B6 mice. In lm mice, which have absent otoconia in the utricle and a variable loss of otoconia in the saccule, VsEPs were present and average P1/N1 amplitudes were highly correlated with the average loss of saccular otoconia (R = 0.77,p < 0.001). Cage and swimming behavior were not adversely affected in those animals with recordable VsEPs. Most, but not all, mice with absent VsEPs were unable to swim. Some animals were able to swim despite having no measurable gravity receptor response. The latter finding underscores the remarkable adaptive potential exhibited by neurobehavioral systems following profound sensory loss. It also shows that behavior alone may be an unreliable indicator of the extent of gravity receptor deficits.

Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals.

PubMed

Bonsall, David R; Kim, Hyunji; Tocci, Catherine; Ndiaye, Awa; Petronzio, Abbey; McKay-Corkum, Grace; Molyneux, Penny C; Scammell, Thomas E; Harrington, Mary E

2015-01-01

Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson's Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively), all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel treatments for

Animal Models for the Study of the Relationships between Diet and Obesity: A Focus on Dietary Protein and Estrogen Deficiency

PubMed Central

Chalvon-Demersay, Tristan; Blachier, François; Tomé, Daniel; Blais, Anne

2017-01-01

Obesity is an increasing major public health concern asking for dietary strategies to limit weight gain and associated comorbidities. In this review, we present animal models, particularly rats and mice, which have been extensively used by scientists to understand the consequences of diet quality on weight gain and health. Notably, modulation of dietary protein quantity and/or quality has been shown to exert huge effects on body composition homeostasis through the modulation of food intake, energy expenditure, and metabolic pathways. Interestingly, the perinatal window appears to represent a critical period during which the protein intake of the dam can impact the offspring’s weight gain and feeding behavior. Animal models are also widely used to understand the processes and mechanisms that contribute to obesity at different physiological and pathophysiological stages. An interesting example of such aspect is the situation of decreased estrogen level occurring at menopause, which is linked to weight gain and decreased energy expenditure. To study metabolic disorders associated with such situation, estrogen withdrawal in ovariectomized animal models to mimic menopause are frequently used. According to many studies, clear species-specific differences exist between rats and mice that need to be taken into account when results are extrapolated to humans. PMID:28373974

Effects of ethanol on immune response in the brain: region-specific changes in aged mice.

PubMed

Kane, Cynthia J M; Phelan, Kevin D; Douglas, James C; Wagoner, Gail; Johnson, Jennifer Walker; Xu, Jihong; Drew, Paul D

2013-05-23

Alcohol abuse has dramatic effects on the health of the elderly. Recent studies indicate that ethanol increases immune activity in younger animals and that some of these proinflammatory molecules alter alcohol consumption and addiction. However, the effects of alcohol on immune activation in aged animals have not been thoroughly investigated. We compared the effects of ethanol on chemokine and cytokine expression in the hippocampus, cerebellum, and cerebral cortex of aged C57BL/6 mice. Mice were treated via gavage with 6 g/kg ethanol for 10 days and tissue was harvested 1 day post-treatment. Ethanol selectively increased mRNA levels of the chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 in the hippocampus and cerebellum, but not in the cortex of aged mice relative to control animals. In this paradigm, ethanol did not affect mRNA levels of the cytokines IL-6 or TNF-α in any of these brain regions in aged animals. Collectively, these data indicate a region-specific susceptibility to ethanol regulation of neuroinflammatory and addiction-related molecules in aged mice. These studies could have important implications concerning alcohol-induced neuropathology and alcohol addiction in the elderly.

Evaluating the dose effects of a longitudinal micro-CT study on pulmonary tissue in C57BL/6 mice

NASA Astrophysics Data System (ADS)

Detombe, Sarah A.; Dunmore-Buyze, Joy; Petrov, Ivailo E.; Drangova, Maria

2012-03-01

Background: Micro-computed tomography offers numerous advantages for small animal imaging, including the ability to monitor the same animals throughout a longitudinal study. However, concerns are often raised regarding the effects of x-ray dose accumulated over the course of the experiment. In this study, we scan C57BL/6 mice multiple times per week for six weeks, to determine the effect of the cumulative dose on pulmonary tissue at the end of the study. Methods/Results: C57BL/6 male mice were split into two groups (irradiated group=10, control group=10). The irradiated group was scanned (80kVp/50mA) each week for 6 weeks; the weekly scan session had three scans. This resulted in a weekly dose of 0.84 Gy, and a total study dose of 5.04 Gy. The control group was scanned on the final week. Scans from weeks 1 and 6 were reconstructed and analyzed: overall, there was no significant difference in lung volume or lung density between the control group and the irradiated group. Similarly, there were no significant differences between the week 1 and week 6 scans in the irradiated group. Histological samples taken from excised lung tissue also showed no evidence of inflammation or fibrosis in the irradiated group. Conclusion: This study demonstrates that a 5 Gy x-ray dose accumulated over six weeks during a longitudinal micro-CT study has no significant effects on the pulmonary tissue of C57BL/6 mice. As a result, the many advantages of micro- CT imaging, including rapid acquisition of high-resolution, isotropic images in free-breathing mice, can be taken advantage of in longitudinal studies without concern for negative dose-related effects.

Animal Models of Hemophilia

PubMed Central

Sabatino, Denise E.; Nichols, Timothy C.; Merricks, Elizabeth; Bellinger, Dwight A.; Herzog, Roland W.; Monahan, Paul E.

2013-01-01

The X-linked bleeding disorder hemophilia is caused by mutations in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Unless prophylactic treatment is provided, patients with severe disease (less than 1% clotting activity) typically experience frequent spontaneous bleeds. Current treatment is largely based on intravenous infusion of recombinant or plasma-derived coagulation factor concentrate. More effective factor products are being developed. Moreover, gene therapies for sustained correction of hemophilia are showing much promise in pre-clinical studies and in clinical trials. These advances in molecular medicine heavily depend on availability of well-characterized small and large animal models of hemophilia, primarily hemophilia mice and dogs. Experiments in these animals represent important early and intermediate steps of translational research aimed at development of better and safer treatments for hemophilia, such a protein and gene therapies or immune tolerance protocols. While murine models are excellent for studies of large groups of animals using genetically defined strains, canine models are important for testing scale-up and for longer-term follow-up as well as for studies that require larger blood volumes. PMID:22137432

Effects of social isolation, re-socialization and age on cognitive and aggressive behaviors of Kunming mice and BALB/c mice.

PubMed

An, Dong; Chen, Wei; Yu, De-Qin; Wang, Shi-Wei; Yu, Wei-Zhi; Xu, Hong; Wang, Dong-Mei; Zhao, Dan; Sun, Yi-Ping; Wu, Jun-Cheng; Tang, Yi-Yuan; Yin, Sheng-Ming

2017-05-01

Both Kunming (KM) mice and BALB/c mice have been widely used as rodent models to investigate stress-associated mental diseases. However, little is known about the different behaviors of KM mice and BALB/c mice after social isolation, particularly cognitive and aggressive behaviors. In this study, the behaviors of KM and BALB/c mice isolated for 2, 4 and 8 weeks and age-matched controls were evaluated using object recognition, object location and resident-intruder tests. The recovery of behavioral deficits by re-socialization was also examined for the isolated mice in adolescence. Our study showed that isolation for 2, 4 and 8 weeks led to cognitive deficits and increased aggressiveness for both KM and BALB/c mice. An important finding is that re-socialization could completely recover spatial/non-spatial cognitive deficits resulted from social isolation for both KM and BALB/c mice. In addition, age only impacted aggressiveness of KM mice. Moreover, isolation duration showed different impacts on cognitive and aggressive behaviors for both KM and BALB/c mice. Furthermore, BALB/c mice showed weak spatial/non-spatial memory and low aggressiveness when they were at the same age and isolation duration, compared to KM mice. In conclusion, KM mice and BALB/c mice behaved characteristically under physiology and isolation conditions. © 2016 Japanese Society of Animal Science.

Animal models of pituitary neoplasia

PubMed Central

Lines, K.E.; Stevenson, M.; Thakker, R.V.

2016-01-01

Pituitary neoplasias can occur as part of a complex inherited disorder, or more commonly as sporadic (non-familial) disease. Studies of the molecular and genetic mechanisms causing such pituitary tumours have identified dysregulation of >35 genes, with many revealed by studies in mice, rats and zebrafish. Strategies used to generate these animal models have included gene knockout, gene knockin and transgenic over-expression, as well as chemical mutagenesis and drug induction. These animal models provide an important resource for investigation of tissue-specific tumourigenic mechanisms, and evaluations of novel therapies, illustrated by studies into multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome in which ∼30% of patients develop pituitary adenomas. This review describes animal models of pituitary neoplasia that have been generated, together with some recent advances in gene editing technologies, and an illustration of the use of the Men1 mouse as a pre clinical model for evaluating novel therapies. PMID:26320859

[Establishment of endometriosis subcutaneous model in immunodeficient nude mice].

PubMed

Ni, H J; Zhang, Z; Dai, Y D; Zhang, S Y

2016-09-06

Objective: To establish a model of endometriosis in immunodeficient nude mice and compare the outcome of the model construction between two different techniques. Methods: Eighteen nude mice were divided into 2 groups, with 9 mice in each group. All nude mice received a subcutaneous transplantation of endometrial fragments, followed by sutured the wounded skin (sutured group) or not (no-sutured group). Then the success rate of the model construction, inflammation of the wounds and the animal survival rate in the two groups were analyzed. Result: In no-sutured group, the survival rate of animal and the success rate of the model construction were 9/9 and 8/9 respectively, with 8/9 survival rate and 7/9 success rate in sutured group. No significant difference was found between the two groups. And no obvious inflammation was presented in the wounds for both groups. Conclusion: It is an effective method to establish animal model of endometriosis by subcutaneous transplantation in nude mice. After transplantation, it does not affect the outcome of the survival rate of the animal and the success rate of the model construction whether we suture the wounded skin. Considering the shorter operation time, we found it's a simpler and time saving method to establish endometriosis by subcutaneously transplanting endometrial fragments in nude mice with no skin-sutured. And this model is worth of promotion.

Does Telomere Shortening Precede the Onset of Hypertension in Spontaneously Hypertensive Mice?

PubMed

Chiu, Christine L; Hearn, Nerissa L; Paine, Devin; Steiner, Nicole; Lind, Joanne M

2016-10-01

Telomere length is widely considered as a marker of biological aging. Clinical studies have reported associations between reduced telomere length and hypertension. The aim of this study was to compare telomere length in hypertensive and normotensive mice at pre-disease and established disease time points to determine whether telomere length differs between the strains before and after the onset of disease. Genomic DNA was extracted from kidney and heart tissues of 4-, 12-, and 20-week-old male hypertensive (BPH/2J) and normotensive (BPN/3J) mice. Relative telomere length (T/S) was measured using quantitative PCR. Age was inversely correlated with telomere length in both strains. In 4-week-old pre-hypertensive animals, no difference in T/S was observed between BPH/2J and BPN/3J animals in kidney or heart tissue (kidney p = 0.14, heart p = 0.06). Once the animals had established disease, at 12 and 20 weeks, BPH/2J mice had significantly shorter telomeres when compared to their age-matched controls in both kidney (12 weeks p < 0.001 and 20 weeks p = 0.004) and heart tissues (12 weeks p < 0.001 and 20 weeks p < 0.001). This is the first study to show that differences in telomere lengths between BPH/2J and BPN/3J mice occur after the development of hypertension and do not cause hypertension in the BPH/2J mice.

From psychiatric disorders to animal models: a bidirectional and dimensional approach

PubMed Central

Donaldson, Zoe. R.; Hen, René

2014-01-01

Psychiatric genetics research is bidirectional in nature, with human and animal studies becoming more closely integrated as techniques for genetic manipulations allow for more subtle exploration of disease phenotypes. This synergy, however, highlights the importance of considering the way in which we approach the genotype-phenotype relationship. In particular, the nosological divide of psychiatric illness, while clinically relevant, is not directly translatable in animal models. For instance, mice will never fully re-capitulate the broad criteria for many psychiatric disorders; nor will they have guilty ruminations, suicidal thoughts, or rapid speech. Instead, animal models have been and continue to provide a means to explore dimensions of psychiatric disorders in order to identify neural circuits and mechanisms underlying disease-relevant phenotypes. Thus, the genetic investigation of psychiatric illness will yield the greatest insights if efforts continue to identify and utilize biologically valid phenotypes across species. In this review we discuss the progress to date and the future efforts that will enhance translation between human and animal studies, including the identification of intermediate phenotypes that can be studied across species, as well as the importance of refined modeling of human disease-associated genetic variation in mice and other animal models. PMID:24650688

Voluntary exercise under a food restriction condition decreases blood branched-chain amino acid levels, in addition to improvement of glucose and lipid metabolism, in db mice, animal model of type 2 diabetes.

PubMed

Marchianti, Ancah Caesarina Novi; Arimura, Emi; Ushikai, Miharu; Horiuchi, Masahisa

2014-09-01

Exercise is effective for preventing the onset and development of type 2 diabetes mellitus (T2DM) in human cases; however, the effect of exercise on the pathophysiology using animal models of T2DM has not been fully evaluated. We applied voluntary exercise under pair-fed (P) conditions in db mice, an animal model of T2DM. Exercising (Ex) and sedentary (Se) mice were placed in a cage, equipped with a free or locked running wheel, for 4 weeks, respectively. The amount of food consumed by ad libitum-fed wild-type mice under the Se condition (ad-WT) was supplied to all mice, except ad libitum db mice (ad-db). Blood parameters and expression of the genes involved in nutrient metabolism were analyzed. PEx-db (pair-fed and exercising) mice showed significantly lower HbA1c, body weight and liver weight than PSe-db and ad-db mice. Decreased hepatic triglycerides in PEx-db mice corresponded to a lower expression of lipogenic enzyme genes in the liver. Moreover, PEx-db mice showed significantly lower plasma branched-chain amino acids (BCAA), arginine, proline, and tyrosine, in addition to increased skeletal muscle (SM) weight, than PSe-db and ad-db mice, in spite of little influence on the expression of the BCAA transaminase gene, in SM and WAT. We found that exercise under a food restriction condition decreases several amino acids, including BCAA, and may improve insulin sensitivity more than mere food restriction. We propose that the decreased concentration of blood amino acids may be a valuable marker evaluating the effects of exercise on diabetic conditions.

Animal studies of addictive behavior.

PubMed

Vanderschuren, Louk J M J; Ahmed, Serge H

2013-04-01

It is increasingly recognized that studying drug taking in laboratory animals does not equate to studying genuine addiction, characterized by loss of control over drug use. This has inspired recent work aimed at capturing genuine addiction-like behavior in animals. In this work, we summarize empirical evidence for the occurrence of several DSM-IV-like symptoms of addiction in animals after extended drug use. These symptoms include escalation of drug use, neurocognitive deficits, resistance to extinction, increased motivation for drugs, preference for drugs over nondrug rewards, and resistance to punishment. The fact that addiction-like behavior can occur and be studied in animals gives us the exciting opportunity to investigate the neural and genetic background of drug addiction, which we hope will ultimately lead to the development of more effective treatments for this devastating disorder.

Sex-specific phenotypes of hyperthyroidism and hypothyroidism in aged mice.

PubMed

Rakov, Helena; Engels, Kathrin; Hönes, Georg Sebastian; Brix, Klaudia; Köhrle, Josef; Moeller, Lars Christian; Zwanziger, Denise; Führer, Dagmar

2017-12-22

Sex and age play a role in the prevalence of thyroid dysfunction (TD), but their interrelationship for manifestation of hyper- and hypothyroidism is still not well understood. Using a murine model, we asked whether sex impacts the phenotypes of hyper- and hypothyroidism at two life stages. Hyper- and hypothyroidism were induced by i.p. T4 or MMI/ClO 4 -/LoI treatment over 7 weeks in 12- and 20-months-old female and male C57BL/6N mice. Control animals underwent PBS treatment (n = 7-11 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination and strength) and serum thyroid hormone (TH) status. Distinct sex impact was found in eu- and hyperthyroid mice, while phenotypic traits of hypothyroidism were similar in male and female mice. No sex difference was found in TH status of euthyroid mice; however, T4 treatment resulted in twofold higher TT4, FT4 and FT3 serum concentrations in adult and old females compared to male animals. Hyperthyroid females consistently showed higher locomotor activity and better coordination but more impairment of muscle function by TH excess at adult age. Importantly and in contrast to male mice, adult and old hyperthyroid female mice showed increased body weight. Higher body temperature in female mice was confirmed in all age groups. No sex impact was found on heart rate irrespective of TH status in adult and old mice. By comparison of male and female mice with TD at two life stages, we found that sex modulates TH action in an organ- and function-specific manner. Sex differences were more pronounced under hyperthyroid conditions. Importantly, sex-specific differences in features of TD in adult and old mice were not conclusively explained by serum TH status in mice.

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

PubMed Central

Koboziev, Iurii; Jones-Hall, Yava; Valentine, John F.; Webb, Cynthia Reinoso; Furr, Kathryn L.; Grisham, Matthew B.

2015-01-01

Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases as well as assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically-effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient’s bedside, it is becoming increasingly apparent that the mouse immune system may not adequately recapitulate the immuno-pathological mechanisms observed in human diseases. Indeed, it is well-known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system in order to address important, human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hemato-lymphoid cells in mice would provide investigators with a relatively inexpensive, small animal model to study clinically-relevant mechanisms as well as facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic

Preflight studies on tolerance of pocket mice to oxygen and heat. IV - Observations on the brain

NASA Technical Reports Server (NTRS)

Bailey, O. T.; Ordy, J. M.; Haymaker, W.

1975-01-01

Experiments designed to ascertain the effects of oxygen at 8, 10, and 12 psi partial pressure on the brains of pocket mice (Perognathus longimembris) were carried out at room temperature (24 C, 75 F) and at 32 C (90 F). The animals exposed to 8-12 psi at 32 C had been in earlier KO2 oxygen tests. Five animals exposed either to 10 or 12 psi (517 mm or 620 mm Hg) O2 partial pressure at 32 C died during the course of the tests, possibly as a consequence of injury sustained by the earlier O2 partial pressure testing. Autopsy was not carried out. In the other 36 exposed animals, no pathological changes were observed in the brain. It is thus highly probable that oxygen pressures at the hyperbaric levels to which the pocket mice would be exposed during the Apollo XVII mission would not result in any lesions in the brain.

Principles of Economic Rationality in Mice.

PubMed

Rivalan, Marion; Winter, York; Nachev, Vladislav

2017-12-12

Humans and non-human animals frequently violate principles of economic rationality, such as transitivity, independence of irrelevant alternatives, and regularity. The conditions that lead to these violations are not completely understood. Here we report a study on mice tested in automated home-cage setups using rewards of drinking water. Rewards differed in one of two dimensions, volume or probability. Our results suggest that mouse choice conforms to the principles of economic rationality for options that differ along a single reward dimension. A psychometric analysis of mouse choices further revealed that mice responded more strongly to differences in probability than to differences in volume, despite equivalence in return rates. This study also demonstrates the synergistic effect between the principles of economic rationality and psychophysics in making quantitative predictions about choices of healthy laboratory mice. This opens up new possibilities for the analyses of multi-dimensional choice and the use of mice with cognitive impairments that may violate economic rationality.

In utero exposure to valproic acid and autism--a current review of clinical and animal studies.

PubMed

Roullet, Florence I; Lai, Jonathan K Y; Foster, Jane A

2013-01-01

Valproic acid (VPA) is both an anti-convulsant and a mood stabilizer. Clinical studies over the past 40 years have shown that exposure to VPA in utero is associated with birth defects, cognitive deficits, and increased risk of autism. Two recent FDA warnings related to use of VPA in pregnancy emphasize the need to reevaluate its use clinically during child-bearing years. The emerging clinical evidence showing a link between VPA exposure and both cognitive function and risk of autism brings to the forefront the importance of understanding how VPA exposure influences neurodevelopment. In the past 10 years, animal studies have investigated anatomical, behavioral, molecular, and physiological outcomes related to in utero VPA exposure. Behavioral studies show that VPA exposure in both rats and mice leads to autistic-like behaviors in the offspring, including social behavior deficits, increased repetitive behaviors, and deficits in communication. Based on this work VPA maternal challenge in rodents has been proposed as an animal model to study autism. This model has both face and construct validity; however, like all animal models there are limitations to its translation to the clinical setting. Here we provide a review of clinical studies that examined pregnancy outcomes of VPA use as well as the related animal studies. Copyright © 2013 Elsevier Inc. All rights reserved.

Establishment of an inflamed animal model of diabetic nephropathy.

PubMed

Ma, Kun Ling; Zhang, Yang; Liu, Jing; Wu, Yu; Hu, Ze Bo; Ruan, Xiong Zhong; Liu, Bi Cheng

2014-01-01

Inflammatory stress plays a crucial role in the progression of diabetic nephropathy (DN). This study aimed to establish a novel inflamed animal model of DN and to evaluate its significance in DN. Nondiabetic db/m mice and diabetic db/db mice were randomly divided into four groups: db/m, db/m+casein, db/db, and db/db+casein for eight weeks. Casein was subcutaneously injected to induce chronic inflammation. Body weight and albumin to creatinine ratio (ACR) in the urine were measured every week. The plasma levels of serum amyloid protein A (SAA) and tumour necrotic factor-α (TNF-α) were determined with the enzyme-linked immunosorbent assay. The morphological changes to the renal pathology and ultra-microstructures were checked by pathological staining and electron microscopy. Immunofluorescent staining and Western blotting were used to determine the protein expression of podocyte-specific molecules and inflammatory cytokines in kidneys. ACR, plasma levels of SAA and TNF-α, protein expression of inflammatory cytokines, mesangial expansion, collagen accumulation, and foot process effacement in kidneys of casein-injected db/db mice were significantly increased compared with the db/db mice. Casein injection markedly decreased the protein expression of Wilms' tumor-1 and nephrin in kidneys of db/db mice, which are specific podocyte biomarkers, suggesting that chronic inflammation accelerates podocyte injuries in db/db mice. Interestingly, no obvious urinary protein, inflammatory cytokine expression, or histological changes in the kidneys of casein-injected db/m mice were found compared with the db/m mice. An inflamed animal model of DN was successfully established and may provide a useful tool for investigating the pathogenesis of DN under inflammatory stress.

Using Dried Blood Spot Sampling to Improve Data Quality and Reduce Animal Use in Mouse Pharmacokinetic Studies

PubMed Central

Wickremsinhe, Enaksha R; Perkins, Everett J

2015-01-01

Traditional pharmacokinetic analysis in nonclinical studies is based on the concentration of a test compound in plasma and requires approximately 100 to 200 µL blood collected per time point. However, the total blood volume of mice limits the number of samples that can be collected from an individual animal—often to a single collection per mouse—thus necessitating dosing multiple mice to generate a pharmacokinetic profile in a sparse-sampling design. Compared with traditional methods, dried blood spot (DBS) analysis requires smaller volumes of blood (15 to 20 µL), thus supporting serial blood sampling and the generation of a complete pharmacokinetic profile from a single mouse. Here we compare plasma-derived data with DBS-derived data, explain how to adopt DBS sampling to support discovery mouse studies, and describe how to generate pharmacokinetic and pharmacodynamic data from a single mouse. Executing novel study designs that use DBS enhances the ability to identify and streamline better drug candidates during drug discovery. Implementing DBS sampling can reduce the number of mice needed in a drug discovery program. In addition, the simplicity of DBS sampling and the smaller numbers of mice needed translate to decreased study costs. Overall, DBS sampling is consistent with 3Rs principles by achieving reductions in the number of animals used, decreased restraint-associated stress, improved data quality, direct comparison of interanimal variability, and the generation of multiple endpoints from a single study. PMID:25836959

Combinations of chromosome transfer and genome editing for the development of cell/animal models of human disease and humanized animal models.

PubMed

Uno, Narumi; Abe, Satoshi; Oshimura, Mitsuo; Kazuki, Yasuhiro

2018-02-01

Chromosome transfer technology, including chromosome modification, enables the introduction of Mb-sized or multiple genes to desired cells or animals. This technology has allowed innovative developments to be made for models of human disease and humanized animals, including Down syndrome model mice and humanized transchromosomic (Tc) immunoglobulin mice. Genome editing techniques are developing rapidly, and permit modifications such as gene knockout and knockin to be performed in various cell lines and animals. This review summarizes chromosome transfer-related technologies and the combined technologies of chromosome transfer and genome editing mainly for the production of cell/animal models of human disease and humanized animal models. Specifically, these include: (1) chromosome modification with genome editing in Chinese hamster ovary cells and mouse A9 cells for efficient transfer to desired cell types; (2) single-nucleotide polymorphism modification in humanized Tc mice with genome editing; and (3) generation of a disease model of Down syndrome-associated hematopoiesis abnormalities by the transfer of human chromosome 21 to normal human embryonic stem cells and the induction of mutation(s) in the endogenous gene(s) with genome editing. These combinations of chromosome transfer and genome editing open up new avenues for drug development and therapy as well as for basic research.

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice.

PubMed

Jackson, Kathryn C; Wohlers, Lindsay M; Lovering, Richard M; Schuh, Rosemary A; Maher, Amy C; Bonen, Arend; Koves, Timothy R; Ilkayeva, Olga; Thomson, David M; Muoio, Deborah M; Spangenburg, Espen E

2013-02-01

Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile.

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

PubMed Central

Jackson, Kathryn C.; Wohlers, Lindsay M.; Lovering, Richard M.; Schuh, Rosemary A.; Maher, Amy C.; Bonen, Arend; Koves, Timothy R.; Ilkayeva, Olga; Thomson, David M.; Muoio, Deborah M.

2013-01-01

Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile. PMID:23193112

Institutional transparency improves public perception of lab animal technicians and support for animal research.

PubMed

Mills, Katelyn E; Han, Zetta; Robbins, Jesse; Weary, Daniel M

2018-01-01

The use of animals in research is controversial and often takes place under a veil of secrecy. Lab animal technicians responsible for the care of animals at research institutions are sometimes described as performing 'dirty work' (i.e. professions that are viewed as morally tainted), and may be stigmatized by negative perceptions of their job. This study assessed if transparency affects public perceptions of lab animal technicians and support for animal research. Participants (n = 550) were randomly assigned to one of six scenarios (using a 3x2 design) that described identical research varying only the transparency of the facility (low, high) and the species used (mice, dogs, cows). Participants provided Likert-type and open-ended responses to questions about the personal characteristics (warmth, competence) of a hypothetical lab technician 'Cathy' and their support for the described research. Quantitative analysis showed participants in the low-transparency condition perceived Cathy to be less warm and were less supportive of the research regardless of animal species. Qualitative responses varied greatly, with some participants expressing support for both Cathy and the research. These results suggest that increasing transparency in lab animal institutions could result in a more positive perception of lab animal researchers and the work that they do.

Institutional transparency improves public perception of lab animal technicians and support for animal research

PubMed Central

Mills, Katelyn E.; Han, Zetta; Robbins, Jesse

2018-01-01

The use of animals in research is controversial and often takes place under a veil of secrecy. Lab animal technicians responsible for the care of animals at research institutions are sometimes described as performing ‘dirty work’ (i.e. professions that are viewed as morally tainted), and may be stigmatized by negative perceptions of their job. This study assessed if transparency affects public perceptions of lab animal technicians and support for animal research. Participants (n = 550) were randomly assigned to one of six scenarios (using a 3x2 design) that described identical research varying only the transparency of the facility (low, high) and the species used (mice, dogs, cows). Participants provided Likert-type and open-ended responses to questions about the personal characteristics (warmth, competence) of a hypothetical lab technician ‘Cathy’ and their support for the described research. Quantitative analysis showed participants in the low-transparency condition perceived Cathy to be less warm and were less supportive of the research regardless of animal species. Qualitative responses varied greatly, with some participants expressing support for both Cathy and the research. These results suggest that increasing transparency in lab animal institutions could result in a more positive perception of lab animal researchers and the work that they do. PMID:29466425

Evaluation of Taterapox Virus in Small Animals.

PubMed

Parker, Scott; Crump, Ryan; Hartzler, Hollyce; Buller, R Mark

2017-08-01

Taterapox virus (TATV), which was isolated from an African gerbil ( Tatera kempi ) in 1975, is the most closely related virus to variola; however, only the original report has examined its virology. We have evaluated the tropism of TATV in vivo in small animals. We found that TATV does not infect Graphiurus kelleni , a species of African dormouse, but does induce seroconversion in the Mongolian gerbil ( Meriones unguiculatus ) and in mice; however, in wild-type mice and gerbils, the virus produces an unapparent infection. Following intranasal and footpad inoculations with 1 × 10⁶ plaque forming units (PFU) of TATV, immunocompromised stat1 -/- mice showed signs of disease but did not die; however, SCID mice were susceptible to intranasal and footpad infections with 100% mortality observed by Day 35 and Day 54, respectively. We show that death is unlikely to be a result of the virus mutating to have increased virulence and that SCID mice are capable of transmitting TATV to C57BL/6 and C57BL/6 stat1 -/- animals; however, transmission did not occur from TATV inoculated wild-type or stat1 -/- mice. Comparisons with ectromelia (the etiological agent of mousepox) suggest that TATV behaves differently both at the site of inoculation and in the immune response that it triggers.

Effects of a ketogenic diet on auditory gating in DBA/2 mice: A proof-of-concept study.

PubMed

Tregellas, Jason R; Smucny, Jason; Legget, Kristina T; Stevens, Karen E

2015-12-01

Although the ketogenic diet has shown promise in a pilot study and case report in schizophrenia, its effects in animal models of hypothesized disease mechanisms are unknown. This study examined effects of treatment with the ketogenic diet on hippocampal P20/N40 gating in DBA/2 mice, a translational endophenotype that mirrors inhibitory deficits in P50 sensory gating in schizophrenia patients. As expected, the diet increased blood ketone levels. Animals with the highest ketone levels showed the lowest P20/N40 gating ratios. These preliminary results suggest that the ketogenic diet may effectively target sensory gating deficits and is a promising area for additional research in schizophrenia. Published by Elsevier B.V.

Animal Studies of Addictive Behavior

PubMed Central

Ahmed, Serge H.

2013-01-01

It is increasingly recognized that studying drug taking in laboratory animals does not equate to studying genuine addiction, characterized by loss of control over drug use. This has inspired recent work aimed at capturing genuine addiction-like behavior in animals. In this work, we summarize empirical evidence for the occurrence of several DSM-IV-like symptoms of addiction in animals after extended drug use. These symptoms include escalation of drug use, neurocognitive deficits, resistance to extinction, increased motivation for drugs, preference for drugs over nondrug rewards, and resistance to punishment. The fact that addiction-like behavior can occur and be studied in animals gives us the exciting opportunity to investigate the neural and genetic background of drug addiction, which we hope will ultimately lead to the development of more effective treatments for this devastating disorder. PMID:23249442

Idiopathic paraproteinaemia. I. Studies in an animal model--the ageing C57BL/KaLwRij mouse.

PubMed Central

Radl, J; Hollander, C F; van den Berg, P; de Glopper, E

1978-01-01

A search for a suitable animal model for studies on idiopathic paraproteinaemia showed that an age-dependent increase in the appearance of homogeneous immunoglobulins in serum was common to all of the seven mouse strains investigated to date. The highest frequency was found in C57Bl/KaLwRij mice. Further investigations in this strain demonstrated that, except for some quantitative differences, most of the features of human and C57BL Mouse idiopathic paraproteinaemia were essentially the same. No clear-cut correlation was found between the idiopathic paraproteinaemia and, in the old C57B1 mice, a rather frequently occurring reticulum cell sarcoma B and amyloidosis. The mouse idiopathic paraproteinaemia can be regarded as an analogue of the human idiopathic paraproteinaemia and therefore as a suitable model for further experimental studies. PMID:367647

Lipoprotein lipase gene-deficient mice with hypertriglyceridaemia associated with acute pancreatitis.

PubMed

Tang, Maochun; Zong, Pengfei; Zhang, Ting; Wang, Dongyan; Wang, Yuhui; Zhao, Yan

2016-10-01

To investigate the severity of pancreatitis in lipoprotein lipase (LPL)-deficient hypertriglyceridaemic (HTG) heterozygous mice and to establish an experimental animal model for HTG pancreatitis study. LPL-deficient HTG heterozygous mice were rescued by somatic gene transfer and mated with wild-type mice. The plasma amylase, triglyceride, and pathologic changes in the pancreas of the LPL-deficient HTG heterozygous mice were compared with those of wild-type mice to assess the severity of pancreatitis. In addition, acute pancreatitis (AP) was induced by caerulein (50 µg/kg) for further assessment. The levels of plasma amylase and triglyceride were significantly higher in the LPL-deficient HTG heterozygous mice. According to the pancreatic histopathologic scores, the LPL-deficient HTG heterozygous mice showed more severe pathologic damage than the wild-type mice. Lipoprotein lipase deficient heterozygous mice developed severe caerulein-induced pancreatitis. In addition, their high triglyceride levels were stable. Therefore, LPL-deficient HTG heterozygous mice are a useful experimental model for studying HTG pancreatitis.

The Possibility of Using the ICR Mouse as an Animal Model to Assess Antimonkeypox Drug Efficacy.

PubMed

Sergeev, Al A; Kabanov, A S; Bulychev, L E; Sergeev, Ar A; Pyankov, O V; Bodnev, S A; Galahova, D O; Zamedyanskaya, A S; Titova, K A; Glotov, A G; Taranov, O S; Omigov, V V; Shishkina, L N; Agafonov, A P; Sergeev, A N

2016-10-01

As a result of the conducted experimental studies on intranasal challenge of ICR mice, rabbits and miniature pigs (even in the maximum variant) with the doses of 4.0-5.5 lg PFU of monkeypox virus (MPXV), some clinical signs such as purulent conjunctivitis, blepharitis and ruffled fur were found only in mice. The 50% infective dose (C ID50 ) of MPXV for these animals estimated by the presence of external clinical signs was 4.8 lg PFU, and L ID50 estimated by the virus presence in the lungs of mice 7 days post-infection taking into account its 10% application in the animal respiratory tract was 1.4 lg PFU. When studying the dynamics of MPXV propagation in mice challenged intranasally with 25 L ID50 of MPXV, the maximum pathogen accumulation was revealed in nasal cavity, lungs and brain: 5.7 ± 0.1, 5.5 ± 0.1 and 5.3 ± 0.3 lg PFU/ml, respectively. The pathomorphological examination of these animals revealed the presence and replication of the pathogen in the traditional primary target cells for MPXV (mononuclear phagocyte system cells and respiratory tract epitheliocytes) as well as in some other types of cells (endothelial cells, reticular cells, connective tissue cells). Our use of these animals to assess the antiviral efficacy of some drugs demonstrated the agreement of the results (a significant positive effect of NIOCH-14 and ST-246) with those described in scientific literature, which opens up the prospects of using ICR mice as animal models for monkeypox to develop preventive antismallpox drugs. © 2015 Blackwell Verlag GmbH.

[Circadian rhythm in susceptibility of mice to the anti-tumor drug carboplatin].

PubMed

Lu, X H; Yin, L J

1994-12-01

The platinum-containing compounds has become a major chemical agent in the treatment of cancer. A circadian rhythm in the susceptibility of rodents and human being to cisplatin has been demonstrated, the maximal tolerance being found in the animal's active phase. Carboplatin is a second generation analog. Two studies were performed on mice with carboplatin under 12:12 light dark cycle to study its chronotoxicity and chronoeffectiveness. In study I, single intraperitoneal injection of 192mg/kg (LD50) carboplatin was given to four groups of mice at four different circadian stage. It was found that at 50% the overall mortality of mice, there was a mortality difference of 28% for mice receiving the drug at 9 a.m. to 71% for mice receiving drug at 9 p.m. It demonstrated that carboplatin was better tolerated in the animal's early sleep phase. In study II, S180 tumor-bearing mice were treated with 50mg/kg of carboplatin. The longest mean survival time and the lowest marrow toxicity occurred in the group which received the drug at the beginning of the sleep phase. It showed that the susceptibility of mice to carboplatin is circadian stage dependent. These data clearly demonstrate that, by timing the administration of drugs according to body rhythms, such as the host susceptibility-resistance rhythm to a drug, one can gain a therapeutic advantage over an approach which ignores such rhythms.

Micro-CT Based Experimental Liver Imaging Using a Nanoparticulate Contrast Agent: A Longitudinal Study in Mice

PubMed Central

Boll, Hanne; Nittka, Stefanie; Doyon, Fabian; Neumaier, Michael; Marx, Alexander; Kramer, Martin; Groden, Christoph; Brockmann, Marc A.

2011-01-01

Background Micro-CT imaging of liver disease in mice relies on high soft tissue contrast to detect small lesions like liver metastases. Purpose of this study was to characterize the localization and time course of contrast enhancement of a nanoparticular alkaline earth metal-based contrast agent (VISCOVER ExiTron nano) developed for small animal liver CT imaging. Methodology ExiTron nano 6000 and ExiTron nano 12000, formulated for liver/spleen imaging and angiography, respectively, were intravenously injected in C57BL/6J-mice. The distribution and time course of contrast enhancement were analysed by repeated micro-CT up to 6 months. Finally, mice developing liver metastases after intrasplenic injection of colon carcinoma cells underwent longitudinal micro-CT imaging after a single injection of ExiTron nano. Principal Findings After a single injection of ExiTron nano the contrast of liver and spleen peaked after 4–8 hours, lasted up to several months and was tolerated well by all mice. In addition, strong contrast enhancement of abdominal and mediastinal lymph nodes and the adrenal glands was observed. Within the first two hours after injection, particularly ExiTron nano 12000 provided pronounced contrast for imaging of vascular structures. ExiTron nano facilitated detection of liver metastases and provided sufficient contrast for longitudinal observation of tumor development over weeks. Conclusions The nanoparticulate contrast agents ExiTron nano 6000 and 12000 provide strong contrast of the liver, spleen, lymph nodes and adrenal glands up to weeks, hereby allowing longitudinal monitoring of pathological processes of these organs in small animals, with ExiTron nano 12000 being particularly optimized for angiography due to its very high initial vessel contrast. PMID:21984939

Proanthocyanidin-Rich Grape Seed Extract Modulates Intestinal Microbiota in Ovariectomized Mice.

PubMed

Jin, Guangwen; Asou, Yoshinori; Ishiyama, Kirika; Okawa, Atsushi; Kanno, Taro; Niwano, Yoshimi

2018-04-01

Grape-seed extract (GSE) is rich in proanthocyanidins (polymers of flavan-3-ols). GSE is well known to have various beneficial effects to health. The objective of this study was to examine the effect of dietary GSE on the intestinal microbiota in ovariectomized (OVX) mice as a model of menopause. Phylum-level analyses using 16S rRNA-targeted group-specific polymerase-chain reaction primers in fecal samples collected 8 weeks postoperatively from OVX mice revealed that the proportion of Firmicutes and Bacteroidetes populations became imbalanced as compared with that in sham-operated control mice. That is, the ratio of Firmicutes:Bacteroidetes populations in the OVX group were increased significantly. When OVX animals were given dietary GSE, the imbalanced proportion of Firmicutes and Bacteroidetes populations was normalized to that seen in control mice. In addition, the body weight of OVX animals measured at 6 weeks postoperatively was significantly higher than that in sham-operated control animals. Dietary GSE also prevented OVX animals from increasing body weight. Thus, we postulated that GSE can improve imbalanced populations of intestinal microbiota, leading to prevention of obesity under conditions of not only menopause but morbidity. The GSE has a great potential to be a functional food to improve dysbiosis in post-menopausal women. © 2018 Institute of Food Technologists®.

Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity.

PubMed

Itzhak, Y; Gandia, C; Huang, P L; Ali, S F

1998-03-01

Methamphetamine (METH) is a powerful psychostimulant that produces dopaminergic neurotoxicity manifested by a decrease in the levels of dopamine, tyrosine hydroxylase activity and dopamine transporter (DAT) binding sites in the nigrostriatal system. We have recently reported that blockade of the neuronal nitric oxide synthase (nNOS) isoform by 7-nitroindazole provides protection against METH-induced neurotoxicity in Swiss Webster mice. The present study was undertaken to investigate the effect of a neurotoxic dose of METH on mutant mice lacking the nNOS gene [nNOS(-/-)] and wild-type controls. In addition, we sought to investigate the behavioral outcome of exposure to a neurotoxic dose of METH. Homozygote nNOS(-/-), heterozygote nNOS(+/-) and wild-type animals were administered either saline or METH (5 mg/kg x 3). Dopamine, DOPAC and HVA levels, as well as DAT binding site levels, were determined in striatal tissue derived 72 h after the last METH injection. This regimen of METH given to nNOS(-/-) mice affected neither the tissue content of dopamine and its metabolites nor the number of DAT binding sites. Although a moderate reduction in the levels of dopamine (35%) and DAT binding sites (32%) occurred in striatum of heterozygote nNOS(+/-) mice, a more profound depletion of the dopaminergic markers (up to 68%) was observed in the wild-type animals. METH-induced hyperthermia was observed in all animal strains examined except the nNOS(-/-) mice. Investigation of the animals' spontaneous locomotor activity before and after administration of the neurotoxic dose of METH (5 mg/kg x 3) revealed no differences. A low dose of METH (1.0 mg/kg) administered to naive animals (nNOS(-/-) and wild-type) resulted in a similar intensity of locomotor stimulation. However, 68 to 72 h after exposure to the high-dose METH regimen, a marked sensitized responses to a challenge METH injection was observed in the wild-type mice but not in the nNOS(-/-) mice. Taken together, these results

Impaired ventilatory acclimatization to hypoxia in mice lacking the immediate early gene fos B.

PubMed

Malik, Mohammad T; Peng, Ying-Jie; Kline, David D; Adhikary, Gautam; Prabhakar, Nanduri R

2005-01-15

Earlier studies on cell culture models suggested that immediate early genes (IEGs) play an important role in cellular adaptations to hypoxia. Whether IEGs are also necessary for hypoxic adaptations in intact animals is not known. In the present study we examined the potential importance of fos B, an IEG in ventilatory acclimatization to hypoxia. Experiments were performed on wild type and mutant mice lacking the fos B gene. Ventilation was monitored by whole body plethysmography in awake animals. Baseline ventilation under normoxia, and ventilatory response to acute hypoxia and hypercapnia were comparable between wild type and mutant mice. Hypobaric hypoxia (0.4 atm; 3 days) resulted in a significant elevation of baseline ventilation in wild type but not in mutant mice. Wild type mice exposed to hypobaric hypoxia manifested an enhanced hypoxic ventilatory response compared to pre-hypobaric hypoxia. In contrast, hypobaric hypoxia had no effect on the hypoxic ventilatory response in mutant mice. Hypercapnic ventilatory responses, however, were unaffected by hypobaric hypoxia in both groups of mice. These results suggest that the fos B, an immediate early gene, plays an important role in ventilatory acclimatization to hypoxia in mice.

Animal violence demystified.

PubMed

Natarajan, Deepa; Caramaschi, Doretta

2010-01-01

Violence has been observed in humans and animals alike, indicating its evolutionary/biological significance. However, violence in animals has often been confounded with functional forms of aggressive behavior. Currently, violence in animals is identified primarily as either a quantitative behavior (an escalated, pathological and abnormal form of aggression characterized primarily by short attack latencies, and prolonged and frequent harm-oriented conflict behaviors) or a qualitative one (characterized by attack bites aimed at vulnerable parts of the opponent's body and context independent attacks regardless of the environment or the sex and type of the opponent). Identification of an operational definition for violence thus not only helps in understanding its potential differences from adaptive forms of aggression but also in the selection of appropriate animal models for both. We address this issue theoretically by drawing parallels from research on aggression and appeasement in humans and other animals. We also provide empirical evidences for violence in mice selected for high aggression by comparing our findings with other currently available potentially violent rodent models. The following violence-specific features namely (1) Display of low levels of pre-escalatory/ritualistic behaviors. (2) Immediate and escalated offense durations with low withdrawal rates despite the opponent's submissive supine and crouching/defeat postures. (3) Context independent indiscriminate attacks aimed at familiar/unfamiliar females, anaesthetized males and opponents and in neutral environments. (4) Orientation of attack-bites toward vulnerable body parts of the opponent resulting in severe wounding. (5) Low prefrontal serotonin (5-HT) levels upon repeated aggression. (6) Low basal heart rates and hyporesponsive hypothalamus-pituitary-adrenocortical (HPA) axis were identified uniquely in the short attack latency (SAL) mice suggesting a qualitative difference between violence and

Animal Violence Demystified

PubMed Central

Natarajan, Deepa; Caramaschi, Doretta

2009-01-01

Violence has been observed in humans and animals alike, indicating its evolutionary/biological significance. However, violence in animals has often been confounded with functional forms of aggressive behavior. Currently, violence in animals is identified primarily as either a quantitative behavior (an escalated, pathological and abnormal form of aggression characterized primarily by short attack latencies, and prolonged and frequent harm-oriented conflict behaviors) or a qualitative one (characterized by attack bites aimed at vulnerable parts of the opponent's body and context independent attacks regardless of the environment or the sex and type of the opponent). Identification of an operational definition for violence thus not only helps in understanding its potential differences from adaptive forms of aggression but also in the selection of appropriate animal models for both. We address this issue theoretically by drawing parallels from research on aggression and appeasement in humans and other animals. We also provide empirical evidences for violence in mice selected for high aggression by comparing our findings with other currently available potentially violent rodent models. The following violence-specific features namely (1) Display of low levels of pre-escalatory/ritualistic behaviors. (2) Immediate and escalated offense durations with low withdrawal rates despite the opponent's submissive supine and crouching/defeat postures. (3) Context independent indiscriminate attacks aimed at familiar/unfamiliar females, anaesthetized males and opponents and in neutral environments. (4) Orientation of attack-bites toward vulnerable body parts of the opponent resulting in severe wounding. (5) Low prefrontal serotonin (5-HT) levels upon repeated aggression. (6) Low basal heart rates and hyporesponsive hypothalamus–pituitary–adrenocortical (HPA) axis were identified uniquely in the short attack latency (SAL) mice suggesting a qualitative difference between violence

[Effects of diazepam on mixed anxiety/depression state in male mice].

PubMed

Galiamina, A G; Smagin, D A; Kovalenko, I L; Bondar', N P; Kudriavtseva, N N

2013-11-01

Chronic social defeat stress in daily agonistic interactions leads to the development of mixed anxiety/depression state in male mice. This paper aimed to study the effects of chronic diazepam treatment on the psychoemotional state of these animals. Diazepam (0.5 mg/kg, i/p, Polfa Tarchomin S. A.) or saline was chronically injected into male mice for two weeks on the background of continuing agonistic interactions (preventive treatment) or into male mice with mixed anxiety/depression state after stopping of social confrontations (therapeutic treatment). Then, the animals were studied in the partition, plus-maze and Porsolt' tests, estimating the levels of communicativeness, anxiety and depressiveness, respectively. Preventive diazepam treatment had a weak protective anxiolytic and pro-depressive effect. The therapeutic diazepam treatment didn't influence on the anxiety and depression-like state. Chronic diazepam was ineffective for the treatment of the mixed anxiety/depression state in male mice. Different effects ofdiazepam on anxiety and depression-like states under preventive treatment confirmed our conclusion shown earlier about the independent development of these pathologies at least in our experimental paradigm.

Topical Treatment of Dermatophytic Lesion on Mice (Mus musculus) Model.

PubMed

Sharma, Bindu; Kumar, Padma; Joshi, Suresh Chandra

2011-06-01

Antidermatophytic potential of three weed plants viz. Tridax procumbens L., Capparis decidua (forsk) Edgew and Lantana camara L. were explored and experimentally induced dermatophytic lesion was topically treated in mice. Microbroth dilution method was carried out for determination of MIC and MFC of different extracts of selected plants. In animal studies, mice were experimentally inoculated with Trichophyton mentagrophytes and infected animals were topically treated with 5 mg/g terbinafine and two concentrations, i.e., 5 and 10 mg/g of test extract ointment. Complete recovery from the infection was observed on 12th day of treatment for reference drug terbinafine (5 mg/g) and 10 mg/g concentration of test extract ointment whereas 5 mg/g concentration of test extract ointment showed complete cure on 16th day of treatment. Fungal burden was also calculated by culturing skin scrapings from infected animals of different groups. Test extract ointment successfully treated induced dermatophytosis in mice without any disease recurrence incidences, thereby indicating efficacy of test extract as an excellent topical antifungal agent for the cure of dermatophytosis.

Central representation of postingestive chemosensory cues in mice that lack the ability to taste.

PubMed

Stratford, Jennifer M; Finger, Thomas E

2011-06-22

The gustatory nerves of mice lacking P2X2 and P2X3 purinergic receptor subunits (P2X-dblKO) are unresponsive to taste stimulation (Finger et al., 2005). Surprisingly, P2X-dblKO mice show residual behavioral responses to concentrated tastants, presumably via postingestive detection. Therefore, the current study tested whether postingestive signaling is functional in P2X-dblKO mice and if so, whether it activates the primary viscerosensory nucleus of the medulla, the nucleus of the solitary tract (nTS). Like WT animals, P2X-dblKO mice learned to prefer a flavor paired with 150 mm monosodium glutamate (MSG) over a flavor paired with water. This preference shows that, even in the absence of taste sensory input, postingestive cues are detected and associated with a flavor in P2X-dblKO mice. MSG-evoked neuronal activation in the nTS was measured by expression of the immediate early gene c-Fos [c-Fos-like immunoreactivity (Fos-LI)]. In rostral, gustatory nTS, P2X-dblKO animals, unlike WT animals, showed no taste quality-specific labeling of neurons. Furthermore, MSG-evoked Fos-LI was significantly less in P2X-dblKO mice compared with WT animals. In contrast, in more posterior, viscerosensory nTS, MSG-induced Fos-LI was similar in WT and P2X-dblKO mice. Together, these results suggest that P2X-dblKO mice can form preferences based on postingestive cues and that postingestive detection of MSG does not rely on the same purinergic signaling that is crucial for taste.

Animal models on HTLV-1 and related viruses: what did we learn?

PubMed Central

Hajj, Hiba El; Nasr, Rihab; Kfoury, Youmna; Dassouki, Zeina; Nasser, Roudaina; Kchour, Ghada; Hermine, Olivier; de Thé, Hugues; Bazarbachi, Ali

2012-01-01

Retroviruses are associated with a wide variety of diseases, including immunological, neurological disorders, and different forms of cancer. Among retroviruses, Oncovirinae regroup according to their genetic structure and sequence, several related viruses such as human T-cell lymphotropic viruses types 1 and 2 (HTLV-1 and HTLV-2), simian T cell lymphotropic viruses types 1 and 2 (STLV-1 and STLV-2), and bovine leukemia virus (BLV). As in many diseases, animal models provide a useful tool for the studies of pathogenesis, treatment, and prevention. In the current review, an overview on different animal models used in the study of these viruses will be provided. A specific attention will be given to the HTLV-1 virus which is the causative agent of adult T-cell leukemia/lymphoma (ATL) but also of a number of inflammatory diseases regrouping the HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), infective dermatitis and some lung inflammatory diseases. Among these models, rabbits, monkeys but also rats provide an excellent in vivo tool for early HTLV-1 viral infection and transmission as well as the induced host immune response against the virus. But ideally, mice remain the most efficient method of studying human afflictions. Genetically altered mice including both transgenic and knockout mice, offer important models to test the role of specific viral and host genes in the development of HTLV-1-associated leukemia. The development of different strains of immunodeficient mice strains (SCID, NOD, and NOG SCID mice) provide a useful and rapid tool of humanized and xenografted mice models, to test new drugs and targeted therapy against HTLV-1-associated leukemia, to identify leukemia stem cells candidates but also to study the innate immunity mediated by the virus. All together, these animal models have revolutionized the biology of retroviruses, their manipulation of host genes and more importantly the potential ways to either prevent their infection or to

Non-Invasive In Vivo Imaging of Calcium Signaling in Mice

PubMed Central

Rogers, Kelly L.; Picaud, Sandrine; Roncali, Emilie; Boisgard, Raphaël; Colasante, Cesare; Stinnakre, Jacques; Tavitian, Bertrand; Brûlet, Philippe

2007-01-01

Rapid and transient elevations of Ca2+ within cellular microdomains play a critical role in the regulation of many signal transduction pathways. Described here is a genetic approach for non-invasive detection of localized Ca2+ concentration ([Ca2+]) rises in live animals using bioluminescence imaging (BLI). Transgenic mice conditionally expressing the Ca2+-sensitive bioluminescent reporter GFP-aequorin targeted to the mitochondrial matrix were studied in several experimental paradigms. Rapid [Ca2+] rises inside the mitochondrial matrix could be readily detected during single-twitch muscle contractions. Whole body patterns of [Ca2+] were monitored in freely moving mice and during epileptic seizures. Furthermore, variations in mitochondrial [Ca2+] correlated to behavioral components of the sleep/wake cycle were observed during prolonged whole body recordings of newborn mice. This non-invasive imaging technique opens new avenues for the analysis of Ca2+ signaling whenever whole body information in freely moving animals is desired, in particular during behavioral and developmental studies. PMID:17912353

Use of transgenic and mutant animal models in the study of heterocyclic amine-induced mutagenesis and carcinogenesis.

PubMed

Dashwood, Roderick H

2003-01-31

Heterocyclic amines (HCAs) are potent mutagens generated during the cooking of meat and fish, and several of these compounds produce tumors in conventional experimental animals. During the past 5 years or so, HCAs have been tested in a number of novel in vivo murine models, including the following: lacZ, lacI, cII, c-myc/lacZ, rpsL, and gptDelta. transgenics, XPA-/-, XPC-/-, Msh2+/-, Msh2-/- and p53+/- knock-outs, Apc mutant mice (ApcDelta716, Apc1638N, Apcmin), and A33DeltaNbeta-cat knock-in mice. Several of these models have provided insights into the mutation spectra induced in vivo by HCAs in target and non-target organs for tumorigenesis, as well as demonstrating enhanced susceptibility to HCA-induced tumors and preneoplastic lesions. This review describes several of the more recent reports in which novel animal models were used to examine HCA-induced mutagenesis and carcinogenesis in vivo, including a number of studies which assessed the inhibitory activities of chemopreventive agents such as 1,2-dithiole-3-thione, conjugated linoleic acids, tea, curcumin, chlorophyllin-chitosan, and sulindac.

Noise in a Laboratory Animal Facility from the Human and Mouse Perspectives

PubMed Central

Reynolds, Randall P; Kinard, Will L; Degraff, Jesse J; Leverage, Ned; Norton, John N

2010-01-01

The current study was performed to understand the level of sound produced by ventilated racks, animal transfer stations, and construction equipment that mice in ventilated cages hear relative to what humans would hear in the same environment. Although the ventilated rack and animal transfer station both produced sound pressure levels above the ambient level within the human hearing range, the sound pressure levels within the mouse hearing range did not increase above ambient noise from either noise source. When various types of construction equipment were used 3 ft from the ventilated rack, the sound pressure level within the mouse hearing range was increased but to a lesser degree for each implement than were the sound pressure levels within the human hearing range. At more distant locations within the animal facility, sound pressure levels from the large jackhammer within the mouse hearing range decreased much more rapidly than did those in the human hearing range, indicating that less of the sound is perceived by mice than by humans. The relatively high proportion of low-frequency sound produced by the shot blaster, used without the metal shot that it normally uses to clean concrete, increased the sound pressure level above the ambient level for humans but did not increase sound pressure levels above ambient noise for mice at locations greater than 3 ft from inside of the cage, where sound was measured. This study demonstrates that sound clearly audible to humans in the animal facility may be perceived to a lesser degree or not at all by mice, because of the frequency content of the sound. PMID:20858361

Olfactory epithelium changes in germfree mice

PubMed Central

François, Adrien; Grebert, Denise; Rhimi, Moez; Mariadassou, Mahendra; Naudon, Laurent; Rabot, Sylvie; Meunier, Nicolas

2016-01-01

Intestinal epithelium development is dramatically impaired in germfree rodents, but the consequences of the absence of microbiota have been overlooked in other epithelia. In the present study, we present the first description of the bacterial communities associated with the olfactory epithelium and explored differences in olfactory epithelium characteristics between germfree and conventional, specific pathogen-free, mice. While the anatomy of the olfactory epithelium was not significantly different, we observed a thinner olfactory cilia layer along with a decreased cellular turn-over in germfree mice. Using electro-olfactogram, we recorded the responses of olfactory sensitive neuronal populations to various odorant stimulations. We observed a global increase in the amplitude of responses to odorants in germfree mice as well as altered responses kinetics. These changes were associated with a decreased transcription of most olfactory transduction actors and of olfactory xenobiotic metabolising enzymes. Overall, we present here the first evidence that the microbiota modulates the physiology of olfactory epithelium. As olfaction is a major sensory modality for most animal species, the microbiota may have an important impact on animal physiology and behaviour through olfaction alteration. PMID:27089944

Safety and Efficacy of Topical Lime Sulfur in Mice Infested with Myocoptes musculinus

PubMed Central

Wood, Jennifer S; Courtney, Cynthia L; Lieber, Karen A; Lee, Vanessa K

2013-01-01

Current treatment options for murine fur mites have limitations in safety and efficacy. This study evaluated whether topical lime sulfur (LS) is an adjunct or alternative to traditional treatment options for Myocoptes musculinus. To evaluate the safety of topical LS, mice were dipped in a 3% LS solution at 34 and 41 d of age. Mice were observed daily for side effects and mortality, with blood work and necropsy at 42 d of age to evaluate for pathologic changes. To determine the efficacy of topical LS, postweanling mice infested with M. musculinus were treated with LS once weekly for 2 wk and then housed with uninfested sentinel mice for 4 wk. Weekly tape tests and postmortem tape tests and skin scrapings were performed on all mice. Treated postweanling mice had significantly lower Hgb levels and higher BUN levels than did control animals. In mite-infested mice, the number of positive cages at euthanasia was the same between treated and control animals. Although topical LS did not cause gross or microscopic changes to organ systems, it may cause clinicopathologic changes, and topical LS is not effective as a sole treatment for M. musculinus infestation of postweanling mice. PMID:23849408

Acetaminophen-induced acute liver injury in HCV transgenic mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle

2013-01-15

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wildmore » type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.« less

The science and necessity of using animal models in the study of necrotizing enterocolitis.

PubMed

Ares, Guillermo J; McElroy, Steven J; Hunter, Catherine J

2018-02-01

Necrotizing enterocolitis (NEC) remains one of the highest causes of mortality and of acute and long-term morbidity in premature infants. Multiple factors are involved in the pathophysiology of NEC including the immaturity of the immune system and the complex changing composition of the intestinal microbiome. This is compounded by the fact that the premature infant should ideally still be a developing fetus and has an immature intestinal tract. Because these complexities are beyond the scope of studies in single-cell cultures, animal models are absolutely essential to understand the mechanisms involved in the pathophysiology of NEC and the effects of inflammation on the immature intestinal tract. To this end, investigators have utilized many different species (e.g., rats, mice, rabbits, quails, piglets, and non-human primates) and conditions to develop models of NEC. Each animal has distinct advantages and drawbacks related to its preterm viability, body size, genetic variability, and cost. The choice of animal model is strongly influenced by the scientific question being addressed. While no model perfectly mimics human NEC, each has greatly improved our understanding of disease. Examples of recent discoveries in NEC pathogenesis and prevention underscore the importance of continued animal research in NEC. Copyright © 2018 Elsevier Inc. All rights reserved.

Cardiac overexpression of Mammalian enabled (Mena) exacerbates heart failure in mice

PubMed Central

Belmonte, Stephen L.; Ram, Rashmi; Mickelsen, Deanne M.; Gertler, Frank B.

2013-01-01

Mammalian enabled (Mena) is a key regulator of cytoskeletal actin dynamics, which has been implicated in heart failure (HF). We have previously demonstrated that cardiac Mena deletion produced cardiac dysfunction with conduction abnormalities and hypertrophy. Moreover, elevated Mena expression correlates with HF in human and animal models, yet the precise role of Mena in cardiac pathophysiology is unclear. In these studies, we evaluated mice with cardiac myocyte-specific Mena overexpression (TTA/TgTetMena) comparable to that observed in cardiac pathology. We found that the hearts of TTA/TgTetMena mice were functionally and morphologically comparable to wild-type littermates, except for mildly increased heart mass in the transgenic mice. Interestingly, TTA/TgTetMena mice were particularly susceptible to cardiac injury, as these animals experienced pronounced decreases in ejection fraction and fractional shortening as well as heart dilatation and hypertrophy after transverse aortic constriction (TAC). By “turning off” Mena overexpression in TTA/TgTetMena mice either immediately prior to or immediately after TAC surgery, we discovered that normalizing Mena levels eliminated cardiac hypertrophy in TTA/TgTetMena animals but did not preclude post-TAC cardiac functional deterioration. These findings indicate that hearts with increased levels of Mena fare worse when subjected to cardiac injury and suggest that Mena contributes to HF pathophysiology. PMID:23832697

Cardiac overexpression of Mammalian enabled (Mena) exacerbates heart failure in mice.

PubMed

Belmonte, Stephen L; Ram, Rashmi; Mickelsen, Deanne M; Gertler, Frank B; Blaxall, Burns C

2013-09-15

Mammalian enabled (Mena) is a key regulator of cytoskeletal actin dynamics, which has been implicated in heart failure (HF). We have previously demonstrated that cardiac Mena deletion produced cardiac dysfunction with conduction abnormalities and hypertrophy. Moreover, elevated Mena expression correlates with HF in human and animal models, yet the precise role of Mena in cardiac pathophysiology is unclear. In these studies, we evaluated mice with cardiac myocyte-specific Mena overexpression (TTA/TgTetMena) comparable to that observed in cardiac pathology. We found that the hearts of TTA/TgTetMena mice were functionally and morphologically comparable to wild-type littermates, except for mildly increased heart mass in the transgenic mice. Interestingly, TTA/TgTetMena mice were particularly susceptible to cardiac injury, as these animals experienced pronounced decreases in ejection fraction and fractional shortening as well as heart dilatation and hypertrophy after transverse aortic constriction (TAC). By "turning off" Mena overexpression in TTA/TgTetMena mice either immediately prior to or immediately after TAC surgery, we discovered that normalizing Mena levels eliminated cardiac hypertrophy in TTA/TgTetMena animals but did not preclude post-TAC cardiac functional deterioration. These findings indicate that hearts with increased levels of Mena fare worse when subjected to cardiac injury and suggest that Mena contributes to HF pathophysiology.

Comparative study of hematopoietic stem and progenitor cells between sexes in mice under physiological conditions along time.

PubMed

Gasco, Samanta; Rando, Amaya; Zaragoza, Pilar; García-Redondo, Alberto; Calvo, Ana Cristina; Osta, Rosario

2017-12-01

Hematopoietic stem and progenitor cells (HSPCs) are attractive targets in regenerative medicine, although the differences in their homeostatic maintenance between sexes along time are still under debate. We accurately monitored hematopoietic stem cells (HSCs), common lymphoid progenitors (CLPs), and common myeloid progenitors (CMPs) frequencies by flow cytometry, by performing serial peripheral blood extractions from male and female B6SJL wild-type mice and found no significant differences. Only modest differences were found in the gene expression profile of Slamf1 and Gata2. Our findings suggest that both sexes could be used indistinctly to perform descriptive studies in the murine hematopoietic system, especially for flow cytometry studies in peripheral blood. This would allow diminishing the number of animals needed for the experimental procedures. In addition, the use of serial extractions in the same animals drastically decreases the number of animals needed. © 2017 International Federation for Cell Biology.

Acute Toxicity Study of Zerumbone-Loaded Nanostructured Lipid Carrier on BALB/c Mice Model

PubMed Central

Rahman, Heshu Sulaiman; Rasedee, Abdullah; Othman, Hemn Hassan; Chartrand, Max Stanley; Namvar, Farideh; Abdul Samad, Nozlena; Andas, Reena Joys; Ng, Kuan Beng; How, Chee Wun

2014-01-01

Zerumbone- (ZER-) loaded nanostructure lipid carrier (NLC) (ZER-NLC) prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50) of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration. PMID:25276798

Acute toxicity study of zerumbone-loaded nanostructured lipid carrier on BALB/c mice model.

PubMed

Rahman, Heshu Sulaiman; Rasedee, Abdullah; Othman, Hemn Hassan; Chartrand, Max Stanley; Namvar, Farideh; Yeap, Swee Keong; Abdul Samad, Nozlena; Andas, Reena Joys; Muhammad Nadzri, Nabilah; Anasamy, Theebaa; Ng, Kuan Beng; How, Chee Wun

2014-01-01

Zerumbone- (ZER-) loaded nanostructure lipid carrier (NLC) (ZER-NLC) prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50) of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration.

[Multifactorial method for assessing the physical work capacity of mice].

PubMed

Dubovik, B V; Bogomazov, S D

1987-01-01

Based on the swimming test according to Kiplinger, in experiments on (CBA X C57BL)F1 mice there were elaborated criteria for animal performance evaluation in the process of repeated swimming of a standard distance thus measuring power, volume of work and rate of the fatigue development in relative units. From the study of effects of sydnocarb, bemethyl and phenazepam on various parameters of physical performance of mice a conclusion was made that the proposed method provides a more informative evaluation of the pharmacological effect on physical performance of animals as compared to the methods based on the record of time of performing the load.

Evidence for Persistence of Ectromelia Virus in Inbred Mice, Recrudescence Following Immunosuppression and Transmission to Naïve Mice.

PubMed

Sakala, Isaac G; Chaudhri, Geeta; Scalzo, Anthony A; Eldi, Preethi; Newsome, Timothy P; Buller, Robert M; Karupiah, Gunasegaran

2015-12-01

Orthopoxviruses (OPV), including variola, vaccinia, monkeypox, cowpox and ectromelia viruses cause acute infections in their hosts. With the exception of variola virus (VARV), the etiological agent of smallpox, other OPV have been reported to persist in a variety of animal species following natural or experimental infection. Despite the implications and significance for the ecology and epidemiology of diseases these viruses cause, those reports have never been thoroughly investigated. We used the mouse pathogen ectromelia virus (ECTV), the agent of mousepox and a close relative of VARV to investigate virus persistence in inbred mice. We provide evidence that ECTV causes a persistent infection in some susceptible strains of mice in which low levels of virus genomes were detected in various tissues late in infection. The bone marrow (BM) and blood appeared to be key sites of persistence. Contemporaneous with virus persistence, antiviral CD8 T cell responses were demonstrable over the entire 25-week study period, with a change in the immunodominance hierarchy evident during the first 3 weeks. Some virus-encoded host response modifiers were found to modulate virus persistence whereas host genes encoded by the NKC and MHC class I reduced the potential for persistence. When susceptible strains of mice that had apparently recovered from infection were subjected to sustained immunosuppression with cyclophosphamide (CTX), animals succumbed to mousepox with high titers of infectious virus in various organs. CTX treated index mice transmitted virus to, and caused disease in, co-housed naïve mice. The most surprising but significant finding was that immunosuppression of disease-resistant C57BL/6 mice several weeks after recovery from primary infection generated high titers of virus in multiple tissues. Resistant mice showed no evidence of a persistent infection. This is the strongest evidence that ECTV can persist in inbred mice, regardless of their resistance status.

[Premature immunosenescence in catecholamines syntesis deficient mice. Effect of social environment].

PubMed

Garrido, Antonio; Cruces, Julia; Iriarte, Idoia; Hernández-Sánchez, Catalina; de Pablo, Flora; de la Fuente, Mónica

Healthy state depends on the appropriate function of the homeostatic systems (nervous, endocrine and immune systems) and the correct communication between them. The functional and redox state of the immune system is an excellent marker of health, and animals with premature immunosenescence show a shorter lifespan. Since catecholamines modulate the function of immune cells, the alteration in their synthesis could provoke immunosenescence. The social environment could be a strategy for modulating this immunosenescence. To determine if an haploinsufficiency of tyrosine hydroxylase (TH), the limiting enzyme of synthesis of catecholamines, may produce a premature immunosenescence and if this immunosenescence could be modulated by the social environment. Adult (9±1 months) male ICR-CD1 mice with deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase enzyme (TH-HZ) and wild-type (WT) mice were used. Animals were housed in four subgroups: WT>50% (in the cage, the proportion of WT mice was higher than 50% in relation to TH-HZ), WT<50%, TH-HZ<50% and TH-HZ>50%. Peritoneal leukocytes were collected and phagocytosis, chemotaxis and proliferation of lymphocytes in the presence of lipopolysaccharide were analyzed. Glutathione reductase and glutathione peroxidase activities as well as oxidized/reduced glutathione ratio were studied. TH-HZ>50% mice showed a deteriorated function and redox state in leukocytes respect to WT>50% and similar to old mice. However, TH-HZ<50% animals had similar values to those found in WT<50% mice. The haploinsufficiency of TH generates premature immunosenescence, which appears to be compensated by living together with an appropriate number of WT animals. Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

Imaging of bioluminescent LNCaP-luc-M6 tumors: a new animal model for the study of metastatic human prostate cancer.

PubMed

Scatena, Caroline D; Hepner, Mischa A; Oei, Yoko A; Dusich, Joan M; Yu, Shang-Fan; Purchio, Tony; Contag, Pamela R; Jenkins, Darlene E

2004-05-15

Animal experiments examining hormone-sensitive metastatic prostate cancer using the human LNCaP cell line have been limited to endpoint analyses. To permit longitudinal studies, we generated a luciferase-expressing cell line and used bioluminescent imaging (BLI) to non-invasively monitor the in vivo growth of primary LNCaP tumors and metastasis. LNCaP.FGC cells were transfected to constitutively express firefly luciferase. LNCaP-luc-M6 cells were tested for bioluminescent signal intensity and hormone responsiveness in vitro. The cells were implanted in subcutaneous and orthotopic sites in SCID-bg mice and imaged over time. The LNCaP-luc-M6 cells formed subcutaneous and orthotopic tumors in SCID-bg mice, and nearly all tumor-bearing animals developed pulmonary metastases. Early detection and temporal growth of primary tumors and metastatic lesions was successfully monitored by BLI. The LNCaP-luc-M6 cell line is a bioluminescent, hormone-sensitive prostate cancer cell line applicable for BLI studies to non-invasively monitor subcutaneous and orthotopic prostate tumor growth and metastasis in vivo. Copyright 2004 Wiley-Liss, Inc.

Comparison of serological assessments in the diagnosis of liver fibrosis in bile duct ligation mice.

PubMed

Xie, Chengxia; Ma, Bo; Wang, Ning; Wan, Lin

2017-08-01

Liver fibrosis assessment is essential to make a prognosis and to determine the appropriate anti-fibrosis treatment. Non-invasive serum markers are widely studied in patients to assess liver fibrosis due to the limitations of liver biopsy. When using animal models to study the mechanism and intervention of hepatic fibrosis, serum markers might be useful for the continuous assessment of liver fibrosis in individual animals, which could avoid the influence of biological differences between individuals. However, it is unclear whether serum markers can assess hepatic fibrosis in the animal model. In the present study, we evaluated and compared the ability of four serum markers to assess liver fibrosis in bile duct ligation mice. According to the stages of liver fibrosis assessed by pathological changes, mice in this study were divided into five groups (F0, F1, F2, F3, and F4). Subsequently, four serum markers, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4), and Forns Index, were calculated for each group. Furthermore, the correlations between serum markers and pathological stages and the ability of serological markers to evaluate liver fibrosis were analyzed. AAR, APRI, FIB-4, and Forns Index could significantly distinguish F0-2 from F3-4 mice. APRI, FIB-4, and Forns Index could detect F0-3 from F4 mice. Among these four markers, FIB-4 was the best able to distinguish ≥F2 and ≥F3, with area under the curve values of 0.882 and 0.92, respectively. Forns Index was best for diagnosing F4 with area under the curve value of 0.879. These results demonstrated that serum markers could be used for assessing liver fibrosis in bile duct ligation mice, and therefore, these markers might lead to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals. Impact statement The assessment of liver fibrosis is

MDMA modifies active avoidance learning and recall in mice.

PubMed

Trigo, José Manuel; Cabrero-Castel, Araceli; Berrendero, Fernando; Maldonado, Rafael; Robledo, Patricia

2008-04-01

Several studies have suggested the existence of cognitive deficits after repeated or high doses of 3,4-methylenedioxymethamphetamine (MDMA) in humans and experimental animals. However, the extent of the impairments observed in learning or memory tasks remains unclear. The objective of this study was to evaluate the effects of different dosing regimens of MDMA on the ability of mice to learn and recall an active avoidance task. Animals were treated with MDMA (0, 1, 3, 10 and 30 mg/kg) under four different experimental conditions, and active avoidance acquisition and recall were evaluated. In experiments 1 and 2, MDMA was administered 1 h before different active avoidance training sessions. In experiments 3 and 4, mice received a repeated treatment with MDMA before or after active avoidance training, respectively. Changes in presynaptic striatal dopamine transporter (DAT) binding sites were evaluated at two different time points in animals receiving a high dose of MDMA (30 mg/kg) or saline twice a day over 4 days. MDMA administered before the active avoidance sessions interfered with the acquisition and the execution of a previously learned task. A repeated treatment with high doses of MDMA administered before training reduced acquisition of active avoidance in mice, while pre-treatment with both high and low doses of MDMA impaired recall of this task. A reduction in DAT binding was observed 4 days but not 23 days after the last MDMA administration. Acute MDMA modifies the acquisition and execution of active avoidance in mice, while repeated pre-treatment with MDMA impairs acquisition and recall of this task.

Health Evaluation of Experimental Laboratory Mice.

PubMed

Burkholder, Tanya; Foltz, Charmaine; Karlsson, Eleanor; Linton, C Garry; Smith, Joanne M

2012-06-01

Good science and good animal care go hand in hand. A sick or distressed animal does not produce the reliable results that a healthy and unstressed animal produces. This unit describes the essentials of assessing mouse health, colony health surveillance, common conditions, and determination of appropriate endpoints. Understanding the health and well-being of the mice used in research enables the investigator to optimize research results and animal care.

Adaptation and Study of AIDS Viruses in Animal and Cell Culture Systems

DTIC Science & Technology

1989-01-30

When irradiated,mice were exposed to 609+/-15 Roentgens (R) of gamma radiation at the body surface (determined by thermal luminescent dosimetry TLD ...vaccines and therapeutic agents. Therefore, it is imperative that common laboratory animals such as the rabbit and mouse be used as in vivo models for...infected with appropriate manipulation. It is clear that rabbits infected with HIV-1 offer much for HIV in vivo experimentation due to the large volume of

Use of animal models for space flight physiology studies, with special focus on the immune system

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

2005-01-01

Animal models have been used to study the effects of space flight on physiological systems. The animal models have been used because of the limited availability of human subjects for studies to be carried out in space as well as because of the need to carry out experiments requiring samples and experimental conditions that cannot be performed using humans. Experiments have been carried out in space using a variety of species, and included developmental biology studies. These species included rats, mice, non-human primates, fish, invertebrates, amphibians and insects. The species were chosen because they best fit the experimental conditions required for the experiments. Experiments with animals have also been carried out utilizing ground-based models that simulate some of the effects of exposure to space flight conditions. Most of the animal studies have generated results that parallel the effects of space flight on human physiological systems. Systems studied have included the neurovestibular system, the musculoskeletal system, the immune system, the neurological system, the hematological system, and the cardiovascular system. Hindlimb unloading, a ground-based model of some of the effects of space flight on the immune system, has been used to study the effects of space flight conditions on physiological parameters. For the immune system, exposure to hindlimb unloading has been shown to results in alterations of the immune system similar to those observed after space flight. This has permitted the development of experiments that demonstrated compromised resistance to infection in rodents maintained in the hindlimb unloading model as well as the beginning of studies to develop countermeasures to ameliorate or prevent such occurrences. Although there are limitations to the use of animal models for the effects of space flight on physiological systems, the animal models should prove very valuable in designing countermeasures for exploration class missions of the future.

Influence of environmental enrichment on the behavior and physiology of mice infected by Trypanosoma cruzi.

PubMed

Silva, Déborah Maria Moreira da; Pinheiro, Laila; Azevedo, Cristiano Schetini; Costa, Guilherme de Paula; Talvani, André

2017-01-01

Enriched environments normally increase behavioral repertoires and diminish the expression of abnormal behaviors and stress-related physiological problems in animals. Although it has been shown that experimental animals infected with microorganisms can modify their behaviors and physiology, few studies have evaluated how environmental enrichment affects these parameters. This study aimed to evaluate the effects of environmental enrichment on the behavior and physiology of confined mice infected with Trypanosoma cruzi. The behaviors of 20 T. cruzi-infected mice and 20 non-infected mice were recorded during three treatments: baseline, enrichment, and post-enrichment. Behavioral data were collected using scan sampling with instantaneous recording of behavior every 30s, totaling 360h. Plasma TNF, CCL2, and IL-10 levels and parasitemia were also evaluated in infected enriched/non-enriched mice. Behavioral data were evaluated by Friedman's test and physiological data by one-way ANOVA and area under the curve (AUC) analysis. Results showed that environmental enrichment significantly increased exploratory behaviors and diminished inactivity. The use of environmental enrichment did not diminish circulating levels of TNF and IL-10 but diminished circulating levels of CCL2 and parasitemia. Positive behavioral and physiological effects of environmental enrichment were observed in mice living in enriched cages. Thus, environmental enrichment improved the welfare of these animals.

Dead mouse hopping: Tyzzer's disease in spinifex hopping-mice (Notomys alexis).

PubMed

Stannard, Hayley J; Tulk, Melissa L; Old, Julie M

2017-03-01

Tyzzer's disease is caused by Clostridium piliformes and affects a wide range of domestic and wildlife species. Non-descript signs, if any, and a short incubation period make Tyzzer's disease difficult to diagnose and treat before death occurs. Here we describe an unexpected outbreak of Tyzzer's disease in a colony of native Australian spinifex hopping-mice (Notomys alexis). In this study captive hopping-mice were used in a nutrition trial (n=11), and others were housed in close proximity (n=4). During the nutrition trial, two hopping-mice exhibited signs of lethargy and diarrhoea, and were removed from the trial but died soon after. Other hopping-mice exhibited limited clinical signs of ill-health, prior to their death. In total four animals were found dead, and another seven were euthanised, to prevent a potential disease outbreak. Tyzzer's disease was confirmed post-mortem using histopathology silver stain to detect the bacilli-shaped bacteria (C. piliformes) in liver tissue of two hopping-mice. After Tyzzer's disease was confirmed enhanced infection control measures were implemented. Enhanced control measures included the use of metal containers for food and water, sick animals were fed and cleaned last, 5% sodium hypochlorite was used as the cleaning agent, stricter hand washing protocols and a change of gloves between feeding animals, and strict limits on persons entering the facility. Control measures for this disease should include euthanasia of any animals suspected to be infected, complete disinfection of all enclosures and associated equipment using sodium hypochlorite. Molecular methods could be employed to ensure complete removal of bacterial spores prior to new animals being moved into enclosures where affected animals were housed. Tyzzer's disease is a fast spreading disease which can cause detrimental effects to captive colonies and their environment. Captive colonies subjected to stress are at risk of Tyzzer's disease. Appropriate quarantine

A pilot study using laser-based technique for non-invasive diagnostics of hypertensive conditions in mice

NASA Astrophysics Data System (ADS)

Litvinova, Karina S.; Ahmad, Shakil; Wang, Keqing; Rafailov, Ilya E.; Sokolovski, Sergei G.; Zhang, Lin; Rafailov, Edik U.; Ahmed, Asif

2016-02-01

Endothelial dysfunction is directly linked to preeclampsia, a maternal hypertensive condition that is life threating for both the mother and the baby. Epidemiological studies show that women with a history of pre-eclampsia have an elevated risk for cardiovascular disease. Here we report a new non-invasive diagnostic test for preeclampsia in mice that allows us to non-invasively assess the condition of the animals during the experiment and treatment in established models of preeclampsia. A laser-based multifunctional diagnostics system (LAKK-M) was chosen to carry out non-invasive analysis of multiple parameters. The device was used to simultaneously record the microcirculatory blood flow and oxygen saturation, as well as fluorescence levels of endogenous fluorophores. Preliminary experiments were conducted on adenoviral (Ad-)- mediated overexpression of sFlt-1 (Ad-sFlt-1) to mimic preeclampsialike symptoms in mice. The recorded data displayed the ability of the LAKK-M diagnostics device to detect significant differences in perfusion measurements between the control and Ad-sFlt-1 treatment. Preliminary results provide a potential avenue to employ these diagnostics technology to monitor and aid in maintaining control of live animal conditions throughout the experiment and treatment.

Surgery plus anesthesia induces loss of attention in mice

PubMed Central

Ren, Quan; Peng, Mian; Dong, Yuanlin; Zhang, Yiying; Chen, Ming; Yin, Ning; Marcantonio, Edward R.; Xie, Zhongcong

2015-01-01

There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium. PMID:26441522

Surgery plus anesthesia induces loss of attention in mice.

PubMed

Ren, Quan; Peng, Mian; Dong, Yuanlin; Zhang, Yiying; Chen, Ming; Yin, Ning; Marcantonio, Edward R; Xie, Zhongcong

2015-01-01

There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium.

Development and Pre-Clinical Evaluation of Recombinant Human Myelin Basic Protein Nano Therapeutic Vaccine in Experimental Autoimmune Encephalomyelitis Mice Animal Model

NASA Astrophysics Data System (ADS)

Al-Ghobashy, Medhat A.; Elmeshad, Aliaa N.; Abdelsalam, Rania M.; Nooh, Mohammed M.; Al-Shorbagy, Muhammad; Laible, Götz

2017-04-01

Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ɛ-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation. In conclusion: i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.

Development and Pre-Clinical Evaluation of Recombinant Human Myelin Basic Protein Nano Therapeutic Vaccine in Experimental Autoimmune Encephalomyelitis Mice Animal Model.

PubMed

Al-Ghobashy, Medhat A; ElMeshad, Aliaa N; Abdelsalam, Rania M; Nooh, Mohammed M; Al-Shorbagy, Muhammad; Laible, Götz

2017-04-20

Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ε-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation. i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.

Ghrelin treatment prevents development of activity based anorexia in mice.

PubMed

Legrand, Romain; Lucas, Nicolas; Breton, Jonathan; Azhar, Saïda; do Rego, Jean-Claude; Déchelotte, Pierre; Coëffier, Moïse; Fetissov, Sergueï O

2016-06-01

Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin׳s orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1nM) together or not with total IgG (1nM) from obese ob/ob or lean mice before access to food during 8 days of 3h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Motor impulsivity in APP-SWE mice: a model of Alzheimer's disease.

PubMed

Adriani, Walter; Ognibene, Elisa; Heuland, Emilie; Ghirardi, Orlando; Caprioli, Antonio; Laviola, Giovanni

2006-09-01

Among transgenic mouse models of Alzheimer's disease, APP-SWE mice have been shown to develop beta-amyloid plaques and to exhibit progressive impairment of cognitive function. Human Alzheimer's disease, however, also includes secondary clinical manifestations, spanning from hyperactivity to agitation. The aim of this study was a better characterization of motor impulsivity in APP-SWE mice, observed at 12 months of age, when levels of soluble beta-amyloid are elevated and beta-amyloid neuritic plaques start to appear. Mice were tested for spatial learning abilities in the Morris water maze (seven daily sessions, four trials per day). The distance traveled to reach the hidden platform showed a learning curve in both groups. This profile, however, was somewhat delayed in APP-SWE mice, thus confirming slightly impaired spatial capacities. To evaluate motor impulsivity, animals were trained to nose-poke for a food reward, which was delivered after a waiting interval that increased over days (15-60 s). Further nose-poking during this signaled waiting interval resulted in food-reward loss and electric-shock punishment. APP-SWE mice received an increased quantity of punishment and were able to earn fewer food rewards, suggesting inability to wait already at the lowest delay. After the animals were killed, prefrontal cortex samples were assessed for neurochemical parameters. Serotonin turnover was elevated in the prefrontal cortex of APP-SWE mice compared with controls. The results clearly confirm cognitive deficits, and are consistent with the hypothesis of reduced behavioral-inhibition abilities. Together with recent findings, APP-SWE mice emerge as a suitable animal model, characterized by a number of specific behavioral alterations, resembling primary and secondary symptoms of human Alzheimer's disease.

Cancer in Inflammatory Bowel Disease: lessons from animal models

PubMed Central

Sussman, Daniel; Santaolalla, Rebeca; Strobel, Sebastian; Dheer, Rishu; Abreu, Maria T.

2012-01-01

Purpose of the review Human colitis-associated cancers (CAC) represent a heterogeneous group of conditions in which multiple oncogenic pathways are involved. In this manuscript we reviewed the latest studies using genetic, chemically induced, bacterial and innate immunity induced experimental models of colitis-associated cancer. Recent findings Using the azoxymethane-dextran sodium sulfate model wound healing pathways seems to be required in the development of CAC. There is also an emerging understanding that commensal and/or pathogenic bacteria can promote tumorigenesis, through T cell mediated inflammation. Using specific transgenic mice (villin-CD98, T cell SMAD7, villin-TLR4) or specific knock-out mice, investigators have identified that derangements in epithelial or innate and adaptive immune pathways can result in CAC. Subtle perturbations in epithelial repair—both too little or too exuberant, can render mice susceptible to tumorigenesis. Summary With the aid of animal models, we have witnessed a rapid expansion of our knowledge of the molecular and immunologic mechanisms underlying inflammatory cancers. Though animal models have contributed a discrete amount of information to our understanding of tumorigenesis in the setting of intestinal inflammation it is clear that no single animal model will be able to adequately recapitulate the pathogenesis of complex CRCs, but each model gets us one step closer to comprehending the nature of CAC. PMID:22614440

A study of quantification of aortic compliance in mice using radial acquisition phase contrast MRI

NASA Astrophysics Data System (ADS)

Zhao, Xuandong

Spatiotemporal changes in blood flow velocity measured using Phase contrast Magnetic Resonance Imaging (MRI) can be used to quantify Pulse Wave Velocity (PWV) and Wall Shear Stress (WSS), well known indices of vessel compliance. A study was conducted to measure the PWV in the aortic arch in young healthy children using conventional phase contrast MRI and a post processing algorithm that automatically track the peak velocity in phase contrast images. It is shown that the PWV calculated using peak velocity-time data has less variability compared to that using mean velocity and flow. Conventional MR data acquisition techniques lack both the spatial and temporal resolution needed to accurately calculate PWV and WSS in in vivo studies using transgenic animal models of arterial diseases. Radial k-space acquisition can improve both spatial and temporal resolution. A major part of this thesis was devoted to developing technology for Radial Phase Contrast Magnetic Resonance (RPCMR) cine imaging on a 7 Tesla Animal scanner. A pulse sequence with asymmetric radial k-space acquisition was designed and implemented. Software developed to reconstruct the RPCMR images include gridding, density compensation and centering of k-Space that corrects the image ghosting introduced by hardware response time. Image processing software was developed to automatically segment the vessel lumen and correct for phase offset due to eddy currents. Finally, in vivo and ex vivo aortic compliance measurements were conducted in a well-established mouse model for atherosclerosis: Apolipoprotein E-knockout (ApoE-KO). Using RPCMR technique, a significantly higher PWV value as well as a higher average WSS was detected among 9 months old ApoE-KO mice compare to in wild type mice. A follow up ex-vivo test of tissue elasticity confirmed the impaired distensibility of aortic arteries among ApoE-KO mice.

Colitis and Colon Cancer in WASP-Deficient Mice Require Helicobacter Spp.

PubMed Central

Nguyen, Deanna D.; Muthupalani, Suresh; Goettel, Jeremy A.; Eston, Michelle A.; Mobley, Melissa; Taylor, Nancy S.; McCabe, Amanda; Marin, Romela; Snapper, Scott B.; Fox, James G.

2014-01-01

Background Wiskott-Aldrich Syndrome protein (WASP)-deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which, Helicobacter spp. have been implicated in disease pathogenesis. We sought to determine the role of Helicobacter spp. in colitis development in WASP-deficient (WKO) mice. Methods Feces from WKO mice raised under specific pathogen free conditions were evaluated for the presence of Helicobacter spp., after which, a subset of mice were rederived in Helicobacter spp.-free conditions. Helicobacter spp.-free WKO animals were subsequently infected with Helicobacter bilis. Results Helicobacter spp. were detected in feces from WKO mice. After re-derivation in Helicobacter spp.-free conditions, WKO mice did not develop spontaneous colitis but were susceptible to radiation-induced colitis. Moreover, a T-cell transfer model of colitis dependent on WASP-deficient innate immune cells also required Helicobacter spp. colonization. Helicobacter bilis infection of rederived WKO mice led to typhlitis and colitis. Most notably, several H. bilis-infected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls. Conclusions Spontaneous and T-cell transfer, but not radiation-induced, colitis in WKO mice is dependent on the presence of Helicobacter spp. Furthermore, H. bilis infection is sufficient to induce typhlocolitis and colon cancer in Helicobacter spp.-free WKO mice. This animal model of a human immunodeficiency with chronic colitis and increased risk of colon cancer parallels what is seen in human colitis and implicates specific microbial constituents in promoting immune dysregulation in the intestinal mucosa. PMID:23820270

Intramuscular Immunization of Mice with a Live-Attenuated Triple Mutant of Yersinia pestis CO92 Induces Robust Humoral and Cell-Mediated Immunity To Completely Protect Animals against Pneumonic Plague.

PubMed

Tiner, Bethany L; Sha, Jian; Ponnusamy, Duraisamy; Baze, Wallace B; Fitts, Eric C; Popov, Vsevolod L; van Lier, Christina J; Erova, Tatiana E; Chopra, Ashok K

2015-12-01

Earlier, we showed that the Δlpp ΔmsbB Δail triple mutant of Yersinia pestis CO92 with deleted genes encoding Braun lipoprotein (Lpp), an acyltransferase (MsbB), and the attachment invasion locus (Ail), respectively, was avirulent in a mouse model of pneumonic plague. In this study, we further evaluated the immunogenic potential of the Δlpp ΔmsbB Δail triple mutant and its derivative by different routes of vaccination. Mice were immunized via the subcutaneous (s.c.) or the intramuscular (i.m.) route with two doses (2 × 10(6) CFU/dose) of the above-mentioned triple mutant with 100% survivability of the animals. Upon subsequent pneumonic challenge with 70 to 92 50% lethal doses (LD(50)) of wild-type (WT) strain CO92, all of the mice survived when immunization occurred by the i.m. route. Since Ail has virulence and immunogenic potential, a mutated version of Ail devoid of its virulence properties was created, and the genetically modified ail replaced the native ail gene on the chromosome of the Δlpp ΔmsbB double mutant, creating a Δlpp ΔmsbB::ailL2 vaccine strain. This newly generated mutant was attenuated similarly to the Δlpp ΔmsbB Δail triple mutant when administered by the i.m. route and provided 100% protection to animals against subsequent pneumonic challenge. Not only were the two above-mentioned mutants cleared rapidly from the initial i.m. site of injection in animals with no histopathological lesions, the immunized mice did not exhibit any disease symptoms during immunization or after subsequent exposure to WT CO92. These two mutants triggered balanced Th1- and Th2-based antibody responses and cell-mediated immunity. A substantial increase in interleukin-17 (IL-17) from the T cells of vaccinated mice, a cytokine of the Th17 cells, further augmented their vaccine potential. Thus, the Δlpp ΔmsbB Δail and Δlpp ΔmsbB::ailL2 mutants represent excellent vaccine candidates for plague, with the latter mutant still retaining Ail immunogenicity but

PGE from Octopus aegina Induces Apoptosis in Ehrlich's Ascites Carcinoma of Mice.

PubMed

Karthigayan, S; Balasubashini, M Sri; Balasubramanian, T; Somasundaram, S T

2007-01-01

ABSTRACT The present study was carried out to assess the antitumor effect of venomous peptide from the cephalopod Octopus aegina on Ehrlich's ascites carcinoma (EAC). Male albino Swiss mice were used in the present study. Four groups of animals were treated with three doses of the sublethal dose of venom, 15, 75, and 150 mug/kg body weight (intraperitoneal injection), along with the standard drug 5-fluorouracil (20 mg/kg b.w.). After 10 days of treatment, six animals from each group were sacrificed for the biochemical analysis and the rest were left to calculate the mean survival time. In EAC-bearing mice, mean lifespan, tumor volume, hemoglobin, red blood cells, and lymphocytes were significantly decreased when compared to the normal animals. While body weight, neutrophils, and viable tumor cell count were increased in the EAC-bearing mice, these changes were brought back to near normal levels in different treatment groups. The macromolecule concentration of peritoneal cells, such as DNA, RNA, and protein, were altered in the EAC-bearing mice and observed to be near normal in the treatment groups. The caspase-3 activity was significantly increased in the peritoneal cells of the treatment groups when compared to the EAC-bearing mice. The role of apoptotic cascade in EAC cell death was confirmed by the DNA fragmentation on agarose gel. Apart from the antitumor effect, octopus venom reduced the tumor burden on the liver and altered the changes in the activities of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Therefore, the venom from O. aegina has a potential antitumor effect on the EAC-bearing mice.

Tinnitus-provoking salicylate treatment triggers social impairments in mice.

PubMed

Guitton, Matthieu J

2009-09-01

Tinnitus (perception of sound in silence) strongly affects the quality of life of sufferers. Tinnitus sufferers and their relatives frequently complain about major social impairments. However, it is not known whether this impairment directly results from the occurrence of tinnitus or is the indirect expression of a preexisting psychological vulnerability. Using the well-characterized animal model of salicylate-induced tinnitus, we investigate in mice whether the occurrence of tinnitus can trigger social impairments. Experiments were performed on 32 male Balb/C mice. Tinnitus was induced in mice using salicylate treatment. Social behavior was assessed in experimental and control animals using social interaction paradigm. Interaction time, number of social events, and number of nonsocial events were assessed in all animals. We demonstrate for the first time that treatment known to induce tinnitus triggers complex social impairments in mice. While salicylate-treated animals present a massive decrease in their overall social interactions compared to control untreated animals, they also display a paradoxal increase in the number of conspecific followings. Tinnitus can thus trigger a complex set of modifications of behavior, which will not only find their expression at the individual level, but also at the social level. Our results suggest that tinnitus can directly be a cause of psychosocial impairment in human and have strong implications for the clinical management of tinnitus sufferers.

EPHRIN-A5 REGULATES INTER-MALE AGGRESSION IN MICE

PubMed Central

Sheleg, Michal; Yochum, Carrie L.; Richardson, Jason R.; Wagner, George C.; Zhou, Renping

2015-01-01

The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5−/−) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5−/− mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5−/− mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice. PMID:25746458

Age-Dependent Ocular Dominance Plasticity in Adult Mice

PubMed Central

Lehmann, Konrad; Löwel, Siegrid

2008-01-01

Background Short monocular deprivation (4 days) induces a shift in the ocular dominance of binocular neurons in the juvenile mouse visual cortex but is ineffective in adults. Recently, it has been shown that an ocular dominance shift can still be elicited in young adults (around 90 days of age) by longer periods of deprivation (7 days). Whether the same is true also for fully mature animals is not yet known. Methodology/Principal Findings We therefore studied the effects of different periods of monocular deprivation (4, 7, 14 days) on ocular dominance in C57Bl/6 mice of different ages (25 days, 90–100 days, 109–158 days, 208–230 days) using optical imaging of intrinsic signals. In addition, we used a virtual optomotor system to monitor visual acuity of the open eye in the same animals during deprivation. We observed that ocular dominance plasticity after 7 days of monocular deprivation was pronounced in young adult mice (90–100 days) but significantly weaker already in the next age group (109–158 days). In animals older than 208 days, ocular dominance plasticity was absent even after 14 days of monocular deprivation. Visual acuity of the open eye increased in all age groups, but this interocular plasticity also declined with age, although to a much lesser degree than the optically detected ocular dominance shift. Conclusions/Significance These data indicate that there is an age-dependence of both ocular dominance plasticity and the enhancement of vision after monocular deprivation in mice: ocular dominance plasticity in binocular visual cortex is most pronounced in young animals, reduced but present in adolescence and absent in fully mature animals older than 110 days of age. Mice are thus not basically different in ocular dominance plasticity from cats and monkeys which is an absolutely essential prerequisite for their use as valid model systems of human visual disorders. PMID:18769674

A study on toxicity of gasoline and GM-10 on liver of mice and it's amelioration by black tea extract.

PubMed

Verma, Ramtej Jayram; Dave, Manjeet; Mathuria, Neeta

2008-01-01

The aim of present study is to investigate the ameliorative effect of black tea extract on gasoline and GM-10 induced toxicity in liver of mice. Eighty healthy male mice weighing 38-40 g approximately were divided into eight groups which included untreated control and various treated groups. Mice were treated with Gasoline 462 mg/kg/day and GM-10 low dose (206 mg/kg/day) and high dose (412 mg/kg/day) subcutaneously for 30 days. Black tea extract was given as 2 g/100 mL drinking water (2% w/v) instead of pure drinking water. All the animals were sacrificed on 31st day by cervical dislocation and livers were isolated and weighed. Parameters such as lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase, glutathione and total ascorbic acid were studied. The results revealed dose-dependent toxicity of gasoline and GM-10 on liver. Administration of black tea extract ameliorates this toxicity of gasoline and GM-10 in liver of mice. This proves the effective ameliorative effect of black tea extract.

Animals In Synchrotrons: Overcoming Challenges For High-Resolution, Live, Small-Animal Imaging

NASA Astrophysics Data System (ADS)

Donnelley, Martin; Parsons, David; Morgan, Kaye; Siu, Karen

2010-07-01

Physiological studies in small animals can be complicated, but the complexity is increased dramatically when performing live-animal synchrotron X-ray imaging studies. Our group has extensive experience in high-resolution live-animal imaging at the Japanese SPring-8 synchrotron, primarily examining airways in two-dimensions. These experiments normally image an area of 1.8 mm×1.2 mm at a pixel resolution of 0.45 μm and are performed with live, intact, anaesthetized mice. There are unique challenges in this experimental setting. Importantly, experiments must be performed in an isolated imaging hutch not specifically designed for small-animal imaging. This requires equipment adapted to remotely monitor animals, maintain their anesthesia, and deliver test substances while collecting images. The horizontal synchrotron X-ray beam has a fixed location and orientation that limits experimental flexibility. The extremely high resolution makes locating anatomical regions-of-interest slow and can result in a high radiation dose, and at this level of magnification small animal movements produce motion-artifacts that can render acquired images unusable. Here we describe our experimental techniques and how we have overcome several challenges involved in performing live mouse synchrotron imaging. Experiments have tested different mouse strains, with hairless strains minimizing overlying skin and hair artifacts. Different anesthetics have also be trialed due to the limited choices available at SPring-8. Tracheal-intubation methods have been refined and controlled-ventilation is now possible using a specialized small-animal ventilator. With appropriate animal restraint and respiratory-gating, motion-artifacts have been minimized. The animal orientation (supine vs. head-high) also appears to affect animal physiology, and can alter image quality. Our techniques and image quality at SPring-8 have dramatically improved and in the near future we plan to translate this experience to the

Animals In Synchrotrons: Overcoming Challenges For High-Resolution, Live, Small-Animal Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donnelley, Martin; Parsons, David; Women's and Children's Health Research Institute, Adelaide, South Australia

Physiological studies in small animals can be complicated, but the complexity is increased dramatically when performing live-animal synchrotron X-ray imaging studies. Our group has extensive experience in high-resolution live-animal imaging at the Japanese SPring-8 synchrotron, primarily examining airways in two-dimensions. These experiments normally image an area of 1.8 mmx1.2 mm at a pixel resolution of 0.45 {mu}m and are performed with live, intact, anaesthetized mice.There are unique challenges in this experimental setting. Importantly, experiments must be performed in an isolated imaging hutch not specifically designed for small-animal imaging. This requires equipment adapted to remotely monitor animals, maintain their anesthesia, andmore » deliver test substances while collecting images. The horizontal synchrotron X-ray beam has a fixed location and orientation that limits experimental flexibility. The extremely high resolution makes locating anatomical regions-of-interest slow and can result in a high radiation dose, and at this level of magnification small animal movements produce motion-artifacts that can render acquired images unusable. Here we describe our experimental techniques and how we have overcome several challenges involved in performing live mouse synchrotron imaging.Experiments have tested different mouse strains, with hairless strains minimizing overlying skin and hair artifacts. Different anesthetics have also be trialed due to the limited choices available at SPring-8. Tracheal-intubation methods have been refined and controlled-ventilation is now possible using a specialized small-animal ventilator. With appropriate animal restraint and respiratory-gating, motion-artifacts have been minimized. The animal orientation (supine vs. head-high) also appears to affect animal physiology, and can alter image quality. Our techniques and image quality at SPring-8 have dramatically improved and in the near future we plan to translate this experience

Association of Diet With Skin Histological Features in UV-B-Exposed Mice.

PubMed

Bhattacharyya, Tapan K; Hsia, Yvonne; Weeks, David M; Dixon, Tatiana K; Lepe, Jessica; Thomas, J Regan

2017-09-01

Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging. To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation. In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control (C) with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016. Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted. Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie restriction, epidermal thickness was increased, but other variables were unaffected. Animals

Cecal ligation and puncture followed by MRSA pneumonia increases mortality in mice and blunts production of local and systemic cytokines

PubMed Central

Jung, Enjae; Perrone, Erin E.; Liang, Zhe; Breed, Elise R.; Dominguez, Jessica A.; Clark, Andrew T.; Fox, Amy C.; Dunne, W. Michael; Burd, Eileen M.; Farris, Alton B.; Hotchkiss, Richard S.; Coopersmith, Craig M.

2011-01-01

Mortality in the ICU frequently results from the synergistic effect of two temporally-distinct infections. This study examined the pathophysiology of a new model of intraabdominal sepsis followed by methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Mice underwent cecal ligation and puncture (CLP) or sham laparotomy followed three days later by an intratracheal injection of MRSA or saline. Both CLP/saline and sham/MRSA mice had 100% survival while animals with CLP followed by MRSA pneumonia had 67% seven-day survival. Animals subjected to CLP/MRSA had increased bronchoalveolar lavage (BAL) concentrations of MRSA compared to sham/MRSA animals. Animals subjected to sham/MRSA pneumonia had increased BAL levels of IL-6, TNF-α, and G-CSF compared to those given intratracheal saline while CLP/MRSA mice had a blunted local inflammatory response with markedly decreased cytokine levels. Similarly, animals subjected to CLP/saline had increased peritoneal lavage levels of IL-6 and IL-1β compared to those subjected to sham laparotomy while this response was blunted in CLP/MRSA mice. Systemic cytokines were upregulated in both CLP/saline and sham/MRSA mice, and this was blunted by the combination of CLP/MRSA. In contrast, no synergistic effect on pneumonia severity, white blood cell count or lymphocyte apoptosis was identified in CLP/MRSA mice compared to animals with either insult in isolation. These results indicate that a clinically relevant model of CLP followed by MRSA pneumonia causes higher mortality than could have been predicted from studying either infection in isolation, and this was associated with a blunted local (pulmonary and peritoneal) and systemic inflammatory response and decreased ability to clear infection. PMID:21937950

Specific genetic modifications of domestic animals by gene targeting and animal cloning

PubMed Central

Wang, Bin; Zhou, Jiangfeng

2003-01-01

The technology of gene targeting through homologous recombination has been extremely useful for elucidating gene functions in mice. The application of this technology was thought impossible in the large livestock species until the successful creation of the first mammalian clone "Dolly" the sheep. The combination of the technologies for gene targeting of somatic cells with those of animal cloning made it possible to introduce specific genetic mutations into domestic animals. In this review, the principles of gene targeting in somatic cells and the challenges of nuclear transfer using gene-targeted cells are discussed. The relevance of gene targeting in domestic animals for applications in bio-medicine and agriculture are also examined. PMID:14614774

Basic mechanisms of MCD in animal models.

PubMed

Battaglia, Giorgio; Becker, Albert J; LoTurco, Joseph; Represa, Alfonso; Baraban, Scott C; Roper, Steven N; Vezzani, Annamaria

2009-09-01

Epilepsy-associated glioneuronal malformations (malformations of cortical development [MCD]) include focal cortical dysplasias (FCD) and highly differentiated glioneuronal tumors, most frequently gangliogliomas. The neuropathological findings are variable but suggest aberrant proliferation, migration, and differentiation of neural precursor cells as essential pathogenetic elements. Recent advances in animal models for MCDs allow new insights in the molecular pathogenesis of these epilepsy-associated lesions. Novel approaches, presented here, comprise RNA interference strategies to generate and study experimental models of subcortical band heterotopia and study functional aspects of aberrantly shaped and positioned neurons. Exciting analyses address impaired NMDA receptor expression in FCD animal models compared to human FCDs and excitatory imbalances in MCD animal models such as lissencephaly gene ablated mice as well as in utero irradiated rats. An improved understanding of relevant pathomechanisms will advance the development of targeted treatment strategies for epilepsy-associated malformations.

Bypass of lethality with mosaic mice generated by Cre-loxP-mediated recombination.

PubMed

Betz, U A; Vosshenrich, C A; Rajewsky, K; Müller, W

1996-10-01

The analysis of gene function based on the generation of mutant mice by homologous recombination in embryonic stem cells is limited if gene disruption results in embryonic lethality. Mosaic mice, which contain a certain proportion of mutant cells in all organs, allow lethality to be circumvented and the potential of mutant cells to contribute to different cell lineages to be analyzed. To generate mosaic animals, we used the bacteriophage P1-derived Cre-loxP recombination system, which allows gene alteration by Cre-mediated deletion of loxP-flanked gene segments. We generated nestin-cre transgenic mouse lines, which expressed the Cre recombinase under the control of the rat nestin promoter and its second intron enhancer. In crosses to animals carrying a loxP-flanked target gene, partial deletion of the loxP-flanked allele occurred before day 10.5 post coitum and was detectable in all adult organs examined, including germ-line cells. Using this approach, we generated mosaic mice containing cells deficient in the gamma-chain of the interleukin-2 receptor (IL-2R gamma); in these animals, the IL-2R gamma-deficient cells were underrepresented in the thymus and spleen. Because mice deficient in DNA polymerase beta die perinatally, we studied the effects of DNA polymerase beta deficiency in mosaic animals. We found that some of the mosaic polymerase beta-deficient animals were viable, but were often reduced in size and weight. The fraction of DNA polymerase beta-deficient cells in mosaic embryos decreased during embryonic development, presumably because wild-type cells had a competitive advantage. The nestin-cre transgenic mice can be used to generate mosaic animals in which target genes are mutated by Cre-mediated recombination of loxP-flanked target genes. By using mosaic animals, embryonic lethality can be bypassed and cell lineages for whose development a given target gene is critical can be identified. In the case of DNA polymerase beta, deficient cells are already

NanoLuc reporter for dual luciferase imaging in living animals.

PubMed

Stacer, Amanda C; Nyati, Shyam; Moudgil, Pranav; Iyengar, Rahul; Luker, Kathryn E; Rehemtulla, Alnawaz; Luker, Gary D

2013-10-01

Bioluminescence imaging is widely used for cell-based assays and animal imaging studies in biomedical research and drug development, capitalizing on the high signal to background of this technique. A relatively small number of luciferases are available for imaging studies, substantially limiting the ability to image multiple molecular and cellular events, as done commonly with fluorescence imaging. To advance dual reporter bioluminescence molecular imaging, we tested a recently developed, adenosine triphosphate–independent luciferase enzyme from Oplophorus gracilirostris (NanoLuc [NL]) as a reporter for animal imaging. We demonstrated that NL could be imaged in superficial and deep tissues in living mice, although the detection of NL in deep tissues was limited by emission of predominantly blue light by this enzyme. Changes in bioluminescence from NL over time could be used to quantify tumor growth, and secreted NL was detectable in small volumes of serum. We combined NL and firefly luciferase reporters to quantify two key steps in transforming growth factor β signaling in intact cells and living mice, establishing a novel dual luciferase imaging strategy for quantifying signal transduction and drug targeting. Our results establish NL as a new reporter for bioluminescence imaging studies in intact cells and living mice that will expand imaging of signal transduction in normal physiology, disease, and drug development.

NanoLuc Reporter for Dual Luciferase Imaging in Living Animals

PubMed Central

Stacer, Amanda C.; Nyati, Shyam; Moudgil, Pranav; Iyengar, Rahul; Luker, Kathryn E.; Rehemtulla, Alnawaz; Luker, Gary D.

2014-01-01

Bioluminescence imaging is utilized widely for cell-based assays and animal imaging studies in biomedical research and drug development, capitalizing on high signal-to-background of this technique. A relatively small number of luciferases are available for imaging studies, substantially limiting the ability to image multiple molecular and cellular events as done commonly with fluorescence imaging. To advance dual reporter bioluminescence molecular imaging, we tested a recently developed, ATP-independent luciferase enzyme from Oplophorus gracilirostris (NanoLuc, NL) as a reporter for animal imaging. We demonstrated that NL could be imaged in superficial and deep tissues in living mice, although detection of NL in deep tissues was limited by emission of predominantly blue light by this enzyme. Changes in bioluminescence from NL over time could be used to quantify tumor growth, and secreted NL was detectable in small volumes of serum. We combined NL and firefly luciferase reporters to quantify two key steps in TGF-β signaling in intact cells and living mice, establishing a novel dual luciferase imaging strategy for quantifying signal transduction and drug targeting. Our results establish NL as new reporter for bioluminescence imaging studies in intact cells and living mice that will expand imaging of signal transduction in normal physiology, disease, and drug development. PMID:24371848

Social transfer of pain in mice

PubMed Central

Smith, Monique L.; Hostetler, Caroline M.; Heinricher, Mary M.; Ryabinin, Andrey E.

2016-01-01

A complex relationship exists between the psychosocial environment and the perception and experience of pain, and the mechanisms of the social communication of pain have yet to be elucidated. The present study examined the social communication of pain and demonstrates that “bystander” mice housed and tested in the same room as mice subjected to inflammatory pain or withdrawal from morphine or alcohol develop corresponding hyperalgesia. Olfactory cues mediate the transfer of hyperalgesia to the bystander mice, which can be measured using mechanical, thermal, and chemical tests. Hyperalgesia in bystanders does not co-occur with anxiety or changes in corticosterone and cannot be explained by visually dependent emotional contagion or stress-induced hyperalgesia. These experiments reveal the multifaceted relationship between the social environment and pain behavior and support the use of mice as a model system for investigating these factors. In addition, these experiments highlight the need for proper consideration of how experimental animals are housed and tested. PMID:27774512

Efficacy of SCH27899 in an Animal Model of Legionnaires' Disease Using Immunocompromised A/J Mice

PubMed Central

Brieland, Joan K.; Loebenberg, David; Menzel, Fred; Hare, Roberta S.

2000-01-01

The efficacy of SCH27899, a new everninomicin antibiotic, against replicative Legionella pneumophila lung infections in an immunocompromised host was evaluated using a murine model of Legionnaires' disease. A/J mice were immunocompromised with cortisone acetate and inoculated intratracheally with L. pneumophila serogroup 1 (105 CFU per mouse). At 24 h postinoculation, mice were administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo once daily for 5 days, and mortality and intrapulmonary growth of L. pneumophila were assessed. In the absence of SCH27899, there was 100% mortality in L. pneumophila-infected mice, with exponential intrapulmonary growth of the bacteria. In contrast, administration of SCH27899 at a dose of ≥30 MPK resulted in ≥90% survival of infected mice, which was associated with inhibition of intrapulmonary growth of L. pneumophila. In subsequent studies, the efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI). Administration of SCH27899, OFX, or AZI at a dose of ≥30 MPK once daily for 5 days resulted in ≥85% survival of infected mice and inhibition of intrapulmonary growth of the bacteria. However, L. pneumophila CFU were recovered in lung homogenates following cessation of therapy with all three antibiotics. These studies demonstrate that SCH27899 effectively prevents fatal replicative L. pneumophila lung infection in immunocompromised A/J mice by inhibition of intrapulmonary growth of the bacteria. However, in this murine model of pulmonary legionellosis, SCH27899, like OFX and AZI, was bacteriostatic. PMID:10770771

Animal Models of Ebolavirus Infection

PubMed Central

Claire, Marisa C St; Ragland, Dan R; Bollinger, Laura; Jahrling, Peter B

2017-01-01

Ebola virus is a highly pathogenic member of the family Filoviridae that causes a severe hemorrhagic disease in humans and NHP. The 2013–2016 West African outbreak has increased interest in the development and refinement of animal models of Ebola virus disease. These models are used to test countermeasures and vaccines, gain scientific insights into the mechanisms of disease progression and transmission, and study key correlates of immunology. Ebola virus is classified as a BSL4 pathogen and Category A agent, for which the United States government requires preparedness in case of bioterrorism. Rodents, such as Syrian golden hamsters (Mesocricetus auratus), mice (Mus musculus), and guinea pigs (Cavia porcellus), are the most common research species. However, NHP, especially macaques, are favored for Ebola virus disease research due to similarities with humans regarding the pathogenesis, clinical presentation, laboratory findings, and causes of fatality. To satisfy the regulatory requirements for approval of countermeasures against high-consequence pathogens, the FDA instituted the Animal Rule, which permits efficacy studies in animal models in place of human clinical data when such studies are not feasible or ethical. This review provides a comprehensive summary of various animal models and their use in Ebola virus disease research. PMID:28662754

[Depressive-like state and sleep in laboratory mice].

PubMed

Strekalova, T V; Cespuglio, R; Koval'zon, V M

2008-01-01

In order to induce the state of anhedonia, a key symptom of depression, mice were subjected to a one-month stress procedure comprised of various stressors. Anhedonic state was defined by a reduction of preference for sucrose solution over tap water. Conventional cortical and neck-muscle electrodes were implanted to control and stressed animals under chloral-hydrate anesthesia. After a two-week recovery and habituation period, mice from chronically stressed group were re-subjected to five-day stress, and the anhedonic state was verified. As not all the stressed mice displayed a decrease in sucrose preference, animals were divided in two groups: stressed-non-anhedonic and stressed-anhedonic animals. Seven-day continuous polygraphic recording was carried out in animals from both stressed groups and the control group in recording chambers under conditions of 12/12-hour light/dark schedule. The anhedonic mice demonstrated a significant advanced shift in circadian distribution of paradoxical sleep and increased amount of paradoxical sleep during the light period. In the course of the dark period, the anhedonic group showed a slight but significant decrease in total amount of slow-wave sleep as compared to the non-anhedonic and control groups. The results suggest that the changes in sleep structure documented in the model of anhedonia are similar to those described for human depression.

Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

PubMed Central

Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

2011-01-01

Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

Characterization of Train-Induced Vibration and its Effect on Fecal Corticosterone Metabolites in Mice.

PubMed

Atanasov, Nicholas A; Sargent, Jennifer L; Parmigiani, John P; Palme, Rupert; Diggs, Helen E

2015-11-01

Excessive environmental vibrations can have deleterious effects on animal health and experimental results, but they remain poorly understood in the animal laboratory setting. The aims of this study were to characterize train-associated vibration in a rodent vivarium and to assess the effects of this vibration on the reproductive success and fecal corticosterone metabolite levels of mice. An instrumented cage, featuring a high-sensitivity microphone and accelerometer, was used to characterize the vibrations and sound in a vivarium that is near an active railroad. The vibrations caused by the passing trains are 3 times larger in amplitude than are the ambient facility vibrations, whereas most of the associated sound was below the audible range for mice. Mice housed in the room closest to the railroad tracks had pregnancy rates that were 50% to 60% lower than those of mice of the same strains but bred in other parts of the facility. To verify the effect of the train vibrations, we used a custom-built electromagnetic shaker to simulate the train-induced vibrations in a controlled environment. Fecal pellets were collected from male and female mice that were exposed to the simulated vibrations and from unexposed control animals. Analysis of the fecal samples revealed that vibrations similar to those produced by a passing train can increase the levels of fecal corticosterone metabolites in female mice. These increases warrant attention to the effects of vibration on mice and, consequently, on reproduction and experimental outcomes.

Characterization of Train-Induced Vibration and its Effect on Fecal Corticosterone Metabolites in Mice

PubMed Central

Atanasov, Nicholas A; Sargent, Jennifer L; Parmigiani, John P; Palme, Rupert; Diggs, Helen E

2015-01-01

Excessive environmental vibrations can have deleterious effects on animal health and experimental results, but they remain poorly understood in the animal laboratory setting. The aims of this study were to characterize train-associated vibration in a rodent vivarium and to assess the effects of this vibration on the reproductive success and fecal corticosterone metabolite levels of mice. An instrumented cage, featuring a high-sensitivity microphone and accelerometer, was used to characterize the vibrations and sound in a vivarium that is near an active railroad. The vibrations caused by the passing trains are 3 times larger in amplitude than are the ambient facility vibrations, whereas most of the associated sound was below the audible range for mice. Mice housed in the room closest to the railroad tracks had pregnancy rates that were 50% to 60% lower than those of mice of the same strains but bred in other parts of the facility. To verify the effect of the train vibrations, we used a custom-built electromagnetic shaker to simulate the train-induced vibrations in a controlled environment. Fecal pellets were collected from male and female mice that were exposed to the simulated vibrations and from unexposed control animals. Analysis of the fecal samples revealed that vibrations similar to those produced by a passing train can increase the levels of fecal corticosterone metabolites in female mice. These increases warrant attention to the effects of vibration on mice and, consequently, on reproduction and experimental outcomes. PMID:26632783

[Development of poliovirus infection in laboratory animals of different species].

PubMed

Koroleva, G A; Lashkevich, V A; Voroshilova, M K

1975-01-01

The capacity of vaccine and virulent strains of poliomyelitis virus to multiply in laboratory animals of different species was studied. Virus reproduction was judged by formation of photoresistant virus progeny in response to inoculation of the animals with photosensitized virus. Multiplication of virulent poliomyelitis virus strains observed in the majority of animal species examined (monkeys, newborn and adult cotton rats, newborn and adult white mice, chickens, chick embryos) resulted in active formation of photoresistant virus population and in some cases was accompanied by clinical symptoms of the disease. Multiplication of vaccine strains was observed in a smaller number of animal species and was limited, as a rule. Among non-primate animals, newborn cotton rats were most susceptible to poliovirus infection. Newborn guinea pigs were the only species of laboratory animals in which no multiplication of any of the six strains under study could be detected.

Chronic Co-species Housing Mice and Rats Increased the Competitiveness of Male Mice.

PubMed

Liu, Ying-Juan; Li, Lai-Fu; Zhang, Yao-Hua; Guo, Hui-Fen; Xia, Min; Zhang, Meng-Wei; Jing, Xiao-Yuan; Zhang, Jing-Hua; Zhang, Jian-Xu

2017-03-01

Rats are predators of mice in nature. Nevertheless, it is a common practice to house mice and rats in a same room in some laboratories. In this study, we investigated the behavioral and physiological responsively of mice in long-term co-species housing conditions. Twenty-four male mice were randomly assigned to their original raising room (control) or a rat room (co-species-housed) for more than 6 weeks. In the open-field and light-dark box tests, the behaviors of the co-species-housed mice and controls were not different. In a 2-choice test of paired urine odors [rabbit urine (as a novel odor) vs. rat urine, cat urine (as a natural predator-scent) vs. rabbit urine, and cat urine vs. rat urine], the co-species-housed mice were more ready to investigate the rat urine odor compared with the controls and may have adapted to it. In an encounter test, the rat-room-exposed mice exhibited increased aggression levels, and their urines were more attractive to females. Correspondingly, the levels of major urinary proteins were increased in the co-species-housed mouse urine, along with some volatile pheromones. The serum testosterone levels were also enhanced in the co-species-housed mice, whereas the corticosterone levels were not different. The norepinephrine, dopamine, and 5-HT levels in the right hippocampus and striatum were not different between the 2. Our findings indicate that chronic co-species housing results in adaptation in male mice; furthermore, it appears that long-term rat-odor stimuli enhance the competitiveness of mice, which suggests that appropriate predator-odor stimuli may be important to the fitness of prey animals. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Life cycle biological efficiency of mice divergently selected for heat loss.

PubMed

Bhatnagar, A S; Nielsen, M K

2014-08-01

Divergent selection in mice for heat loss was conducted in 3 independent replicates creating a high maintenance, high heat loss (MH) and low maintenance, low heat loss (ML) line and unselected control (MC). Improvement in feed efficiency was observed in ML mice due to a reduced maintenance energy requirement but there was also a slight decline in reproductive performance, survivability, and lean content, particularly when compared to MC animals. The objective of this study was to model a life cycle scenario similar to a livestock production system and calculate total inputs and outputs to estimate overall biological efficiency of these lines and determine if reduced feed intake resulted in improved life cycle efficiency. Feed intake, reproductive performance, growth, and body composition were recorded on 21 mating pairs from each line × replicate combination, cohabitated at 7 wk of age and maintained for up to 1 yr unless culled. Proportion of animals at each parity was calculated from survival rates estimated from previous research when enforcing a maximum of 4, 8, or 12 allowed parities. This parity distribution was then combined with values from previous studies to calculate inputs and outputs of mating pairs and offspring produced in a single cycle at equilibrium. Offspring output was defined as kilograms of lean output of offspring at 49 d. Offspring input was defined as megacalories of energy intake for growing offspring from 21 to 49 d. Parent output was defined as kilograms of lean output of culled parents. Parent input was defined as megacalories of energy intake for mating pairs from weaning of one parity to weaning of the next. Offspring output was greatest in MC mice due to superior BW and numbers weaned, while output was lowest in ML mice due to smaller litter sizes and lean content. Parent output did not differ substantially between lines but was greatest in MH mice due to poorer survival rates resulting in more culled animals. Input was greatest in

Differences in Susceptibility of Inbred Mice to Bacillus anthracis

DTIC Science & Technology

1985-04-26

dilutions of the mixture were prepared and injected into A/J and CBA/J mice via the tail vein, as described by Ezzell et al. (9). Five mice per strain were...xylazine (Rompun, Miles Laboratories, Shawnee, Kansas) in 50 pl, and were dissected iwnmediately. Gross pathological changes were noted, heart blood and...anthracis; a histopathological study of skin lesions produced by B. anthracis in susceptible and resistant animal species. J. Infect. Dis. 80:1-13. 9. Ezzell

Animal model of alcoholic pancreatitis: role of viral infections.

PubMed

Jerrells, Thomas R; Chapman, Nora; Clemens, Dahn L

2003-11-01

Pancreatitis is clearly associated with alcohol abuse, but only a relatively small percentage of people who abuse alcohol develops obvious pancreatitis. These observations have led to the concept that the development of alcoholic pancreatitis requires cofactors. Although diet and smoking have been studied, a clear cofactor has not been identified. The study results presented in this paper were obtained to determine whether viral infection of the pancreas would be a cofactor for alcoholic pancreatitis similar to the role of hepatitis virus infections in the development of alcoholic liver disease. To test this hypothesis, mice were fed ethanol with a liquid diet protocol and infected with coxsackievirus B3 (CVB3). It was found that consumption of alcohol alone did not result in pancreatitis as determined by serum levels of amylase or histologic changes in the pancreas. Two strains of CVB3 that are tropic for the pancreas were used; a virulent and an avirulent strain. Infection of alcohol-fed animals with the virulent CVB3 strain 28 resulted in a more severe pancreatitis than the pancreatitis noted in control animals. Alcohol-fed mice infected with the avirulent strain (GA) showed severe pancreatitis, whereas the infection of control mice did not result in obvious pathologic effects in the pancreas. This model allows mechanistic studies to define the role of viral infection as a cofactor for alcoholic pancreatitis.

Long-term toxicity and carcinogenicity studies of cake made from chlorinated flour. 2. Studies in mice.

PubMed

Ginocchio, A V; Fisher, N; Hutchinson, J B; Berry, R; Hardy, J

1983-08-01

Male and female Theiller's Original strain mice were fed for 16 and 17 months respectively on diets in which cake, prepared from flours treated with 0, 1250 or 2500 ppm chlorine, formed 79% by weight on a 12.6% moisture basis. Body weights and food intakes were unaffected by flour treatment but all of the animals on cake diets showed significant increases in body weight compared with controls on a standard diet and became obese. Mortalities in the males were not related to treatment, but in the females there was excess mortality in the treated groups compared with the cake control group, after 13 months in the 1250 group and after 15 months in the 2500 group. No consistent treatment-related effects were observed in the haematological, biochemical and renal-function studies. Dose-related increases in heart and kidney weights and a dose-related decrease in ovary weight were seen in females. No evidence of carcinogenicity resulting from flour treatment was obtained but the early ending of the study, necessitated by high mortalities, greatly diminished the value of this finding. Concentrations of covalently bound chlorine in the perirenal fat were positively correlated with treatment level, but were considerably below those present in the lipid content of the diets on which the mice were fed.

Increased anxiety-related behaviour in Hint1 knockout mice.

PubMed

Varadarajulu, Jeeva; Lebar, Maria; Krishnamoorthy, Gurumoorthy; Habelt, Sonja; Lu, Jia; Bernard Weinstein, I; Li, Haiyang; Holsboer, Florian; Turck, Christoph W; Touma, Chadi

2011-07-07

Several reports have implicated a role for the histidine triad nucleotide-binding protein-1 (Hint1) in psychiatric disorders. We have studied the emotional behaviour of male Hint1 knockout (Hint1 KO) mice in a battery of tests and performed biochemical analyses on brain tissue. The behavioural analysis revealed that Hint1 KO mice exhibit an increased emotionality phenotype compared to wildtype (WT) mice, while no significant differences in locomotion or general exploratory activity were noted. In the elevated plus-maze (EPM) test, the Hint1 KO animals entered the open arms of the apparatus less often than WT littermates. Similarly, in the dark-light box test, Hint1 KO mice spent less time in the lit compartment and the number of entries were reduced, which further confirmed an increased anxiety-related behaviour. Moreover, the Hint1 KO animals showed significantly more struggling and less floating behaviour in the forced swim test (FST), indicating an increased emotional arousal in aversive situations. Hint1 is known as a protein kinase C (PKC) interacting protein. Western blot analysis showed that PKCγ expression was elevated in Hint1 KO compared to WT mice. Interestingly, PKCγ mRNA levels of the two groups did not show a significant difference, implying a post-transcriptional PKCγ regulation. In addition, PKC enzymatic activity was increased in Hint1 KO compared to WT mice. In summary, our results indicate a role for Hint1 and PKCγ in modulating anxiety-related and stress-coping behaviour in mice. Copyright © 2011 Elsevier B.V. All rights reserved.

The individuality of mice.

PubMed

Lathe, R

2004-12-01

Mutant mice simulating human CNS disorders are used as models for therapeutic drug development. Drug evaluation requires a coherent correlation between behavioral phenotype and drug status. Variations in behavioral responses could mask such correlations, a problem highlighted by the three-site studies of Crabbe et al. (1999) and Wahlsten et al. (2003a). Factors contributing to variation are considered, focusing on differences between individual animals. Genetic differences due to minisatellite variation suggest that each mouse is genetically distinct. Effects during gestation, including maternal stress, influence later life behavior; while endocrine exchanges between fetus and parent, and between male and female fetuses dependent on intrauterine position, also contribute. Pre and perinatal nutrition and maternal attention also play a role. In adults, endocrine cyclicity in females is a recognized source of behavioral diversity. Notably, there is increasing recognition that groups of wild and laboratory mice have complex social structures, illustrated through consideration of Crowcroft (1966). Dominance status can markedly modify behavior in test paradigms addressing anxiety, locomotion and aggressiveness, to an extent comparable to mutation or drug status. Understanding how such effects amplify the behavioral spectrum displayed by otherwise identical animals will improve testing.

Studying Biotechnological Methods Using Animations: The Teacher's Role

NASA Astrophysics Data System (ADS)

Yarden, Hagit; Yarden, Anat

2011-12-01

Animation has great potential for improving the way people learn. A number of studies in different scientific disciplines have shown that instruction involving computer animations can facilitate the understanding of processes at the molecular level. However, using animation alone does not ensure learning. Students sometimes miss essential features when they watch only animations, mainly due to the cognitive load involved. Moreover, students seem to attribute a great deal of authority to the computer and may develop misconceptions by taking animations of abstract concepts too literally. In this study, we attempted to explore teachers' perceptions concerning the use of animations in the classroom while studying biotechnological methods, as well as the teachers' contribution to the enactment of animations in class. Thirty high-school biotechnology teachers participated in a professional development workshop, aimed at investigating how teachers plan for and support learning with animation while studying biotechnological methods in class. From that sample, two teachers agreed to participate in two case studies aimed at characterizing teachers' contribution to the enactment of animations in class while studying biotechnological methods. Our findings reveal marked teacher contribution in the following three aspects: establishing the "hands-on" point of view, helping students deal with the cognitive load that accompanies the use of animation, and implementing constructivist aspects of knowledge construction while studying using animations.

Social isolation induces deficit of latent learning performance in mice: a putative animal model of attention deficit/hyperactivity disorder.

PubMed

Ouchi, Hirofumi; Ono, Kazuya; Murakami, Yukihisa; Matsumoto, Kinzo

2013-02-01

Social isolation of rodents (SI) elicits a variety of stress responses such as increased aggressiveness, hyper-locomotion, and reduced susceptibility to pentobarbital. To obtain a better understanding of the relevance of SI-induced behavioral abnormalities to psychiatric disorders, we examined the effect of SI on latent learning as an index of spatial attention, and discussed the availability of SI as an epigenetic model of attention deficit hyperactivity disorder (ADHD). Except in specially stated cases, 4-week-old male mice were housed in a group or socially isolated for 3-70 days before experiments. The animals socially isolated for 1 week or more exhibited spatial attention deficit in the water-finding test. Re-socialized rearing for 5 weeks after 1-week SI failed to attenuate the spatial attention deficit. The effect of SI on spatial attention showed no gender difference or correlation with increased aggressive behavior. Moreover, SI had no effect on cognitive performance elucidated in a modified Y-maze or an object recognition test, but it significantly impaired contextual and conditional fear memory elucidated in the fear-conditioning test. Drugs used for ADHD therapy, methylphenidate (1-10 mg/kg, i.p.) and caffeine (0.5-1 mg/kg, i.p.), improved SI-induced latent learning deficit in a manner reversible with cholinergic but not dopaminergic antagonists. Considering the behavioral features of SI mice together with their susceptibility to ADHD drugs, the present findings suggest that SI provides an epigenetic animal model of ADHD and that central cholinergic systems play a role in the effect of methylphenidate on SI-induced spatial attention deficit. Copyright © 2012 Elsevier B.V. All rights reserved.

Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality.

PubMed

Fox, Amy C; Breed, Elise R; Liang, Zhe; Clark, Andrew T; Zee-Cheng, Brendan R; Chang, Katherine C; Dominguez, Jessica A; Jung, Enjae; Dunne, W Michael; Burd, Eileen M; Farris, Alton B; Linehan, David C; Coopersmith, Craig M

2011-08-15

Lymphocyte apoptosis is thought to have a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, because the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with preexisting cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later, after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced T and B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared with WT mice following P. aeruginosa pneumonia (85 versus 44% 7-d mortality; p = 0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify that the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim(-/-) mice. Septic Bim(-/-) mice with cancer also had increased mortality compared with septic WT mice with cancer. These data demonstrate that, despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia.

Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality

PubMed Central

Fox, Amy C.; Breed, Elise R; Liang, Zhe; Clark, Andrew T.; Zee-Cheng, Brendan R.; Chang, Katherine C.; Dominguez, Jessica A.; Jung, Enjae; Dunne, W. Michael; Burd, Eileen M.; Farris, Alton B.; Linehan, David C.; Coopersmith, Craig M.

2011-01-01

Lymphocyte apoptosis is thought to play a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, since the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with pre-existing cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced T and B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared to WT mice following Pseudomonas aeruginosa pneumonia (85% vs. 44% seven-day mortality, p=0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim-/- mice. Septic Bim-/- mice with cancer also had increased mortality compared to septic WT mice with cancer. These data demonstrate that despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia. PMID:21734077

Status of Animal Experiments on International Space Station, and Animal Care Activities in Japan

NASA Astrophysics Data System (ADS)

Izumi, Ryutaro; Ishioka, Noriaki; Yumoto, Akane; Ito, Isao; Shirakawa, Masaki

We would like to introduce animal experiments status on International Space Station (ISS) of Japan. Aquatic Habitat (AQH) was launched at 2012 July, by H-II Transfer Vehicle (HTV, ‘Kounotori’) from Tanegashima island in Japan, which could house small fish (Medaka, or Zebrafish) at most three months. First experiment using AQH was carried out for two months from Oct. 26, 2012, and second experiment would start from February, 2014. Mice housing hardware is now under development. For animal care activities, current topic in Japan is self-estimation for animal experiment status by each institute, and to open the result for public. JAXA conducted self-estimation of fiscal year 2011 (from 2011 April until 2012 March) for the first time, and would continue every fiscal year. JAXA already have its own animal care regulation, under animal care law and policy in Japan, and also referred COSPAR animal care guideline. And this year, JAXA made handbook for animal experiments in space (only Japanese).

Pre-treatment with antibiotics and Escherichia coli to equalize the gut microbiota in conventional mice.

PubMed

Linninge, Caroline; Ahrné, Siv; Molin, Göran

2015-01-01

The composition of the gut microbiota can vary widely between individual mice of the same batch and thereby affect the resulting outcome in experimental studies. Therefore, an efficient method is needed to equalize the gut microbiota prior to the start of critical experiments. In order to minimize variations in gut microbiota between animals and provide the animals with a Gram-negative flora exposing lipopolysaccharides in the cell-walls, C57BL/6 mice were given a mixture of ampicillin, metronidazole and clindamycin in the drinking water for 3 days and then Escherichia coli for two additional days. Treatment with antibiotics alone or with antibiotics in combination with E. coli was well tolerated by all animals. Body weight and liver weight were not affected, although higher hepatic fat content was found in treated animals (p < 0.05). The diversity of the gut microbiota was strongly reduced in animals treated with antibiotics and antibiotics in combination with E. coli (p < 0.01), without affecting the total amount of bacteria. Cloned and sequenced 16S rRNA genes showed high presence of Enterobacteriaceae and Porphymonadaceae in the treated animals. Analysis with Principal Component Analysis gave a clear separation of the composition in microbiota between different treatment groups. The described treatment efficiently equalized the gut microbiota and provided the animals with a strong abundance of Enterobacteriaceae without changing the total load of bacteria. This is a straightforward, lenient and efficient method of pre-treatment to equalize the gut microbiota of mice as a starting procedure of animal studies.

The effects of enhanced zinc on spatial memory and plaque formation in transgenic mice

USGS Publications Warehouse

Linkous, D.H.; Adlard, P.A.; Wanschura, P.B.; Conko, K.M.; Flinn, J.M.

2009-01-01

There is considerable evidence suggesting that metals play a central role in the pathogenesis of Alzheimer's disease. Reports suggest that elevated dietary metals may both precipitate and potentiate an Alzheimer's disease phenotype. Despite this, there remain few studies that have examined the behavioral consequences of elevated dietary metals in wild type and Alzheimer's disease animals. To further investigate this in the current study, two separate transgenic models of AD (Tg2576 and TgCRND8), together with wild type littermates were administered 10 ppm (0.153 mM) Zn. Tg2576 animals were maintained on a zinc-enriched diet both pre- and postnatally until 11 months of age, while TgCRND8 animals were treated for five months following weaning. Behavioral testing, consisting of "Atlantis" and "moving" platform versions of the Morris water maze, were conducted at the end of the study, and tissues were collected for immunohistochemical analysis of amyloid-β burden. Our data demonstrate that the provision of a zinc-enriched diet potentiated Alzheimer-like spatial memory impairments in the transgenic animals and was associated with reduced hippocampal amyloid-β plaque deposits. Zinc-related behavioral deficits were also demonstrated in wild type mice, which were sometimes as great as those present in the transgenic animals. However, zinc-related cognitive impairments in transgenic mice were greater than the summation of zinc effects in the wild type mice and the transgene effects.

Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice.

PubMed

Seibenhener, Michael L; Wooten, Michael C

2015-02-06

Animal models have proven to be invaluable to researchers trying to answer questions regarding the mechanisms of behavior. The Open Field Maze is one of the most commonly used platforms to measure behaviors in animal models. It is a fast and relatively easy test that provides a variety of behavioral information ranging from general ambulatory ability to data regarding the emotionality of the subject animal. As it relates to rodent models, the procedure allows the study of different strains of mice or rats both laboratory bred and wild-captured. The technique also readily lends itself to the investigation of different pharmacological compounds for anxiolytic or anxiogenic effects. Here, a protocol for use of the open field maze to describe mouse behaviors is detailed and a simple analysis of general locomotor ability and anxiety-related emotional behaviors between two strains of C57BL/6 mice is performed. Briefly, using the described protocol we show Wild Type mice exhibited significantly less anxiety related behaviors than did age-matched Knock Out mice while both strains exhibited similar ambulatory ability.

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | Poster

Cancer.gov

A new breed of lab animals, dubbed “glowing head mice,” may do a better job than conventional mice in predicting the success of experimental cancer drugs—while also helping to meet an urgent need for more realistic preclinical animal models. The mice were developed to tolerate often-used light-emitting molecules, such as luciferase from fireflies and green fluorescent protein

The effect of aging on efferent nerve fibers regeneration in mice.

PubMed

Verdú, E; Butí, M; Navarro, X

1995-10-23

This study evaluates the influence of aging on nerve regeneration and reinnervation of target organs in mice aged 2, 6, 9, 12, 18 and 24 months. In animals of each age group the sciatic nerve was subjected to crush, section or section and suture. Reinnervation of plantar muscles and sweat glands (SG) was evaluated over three months after operation by functional methods. Reappearance of SG secretion and motor responses occurred slightly earlier in young than older mice. The degree of motor and sudomotor reinnervation, with respect to preoperative control values, was also significantly higher in young than old animals. The differences were more pronounced after 12 months of age. The degree of recovery progressively decreased with the severity of the lesion, differences being more marked in older mice. Neurorraphy improved recovery, comparatively more in older than in young mice. These results indicate that, after injuries of peripheral nerves, axonal regeneration and reinnervation are maintained throughout life, but tend to be more delayed and slightly less effective with aging.

Impaired fear extinction learning in adult heterozygous BDNF knock-out mice.

PubMed

Psotta, Laura; Lessmann, Volkmar; Endres, Thomas

2013-07-01

Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuroplasticity, which underlies learning and memory processes in different brain areas. To investigate the role of BDNF in the extinction of amygdala-dependent cued fear memories, we analyzed fear extinction learning in heterozygous BDNF knock-out mice, which possess a reduction of endogenous BDNF protein levels to ~50% of wild-type animals. Since BDNF expression has been shown to decline with aging of animals, we tested the performance in extinction learning of these mice at 2 months (young adults) and 7 months (older adults) of age. The present study shows that older adult heterozygous BDNF knock-out mice, which have a chronic 50% lack of BDNF, also possess a deficit in the acquisition of extinction memory, while extinction learning remains unaffected in young adult heterozygous BDNF knock-out mice. This deficit in extinction learning is accompanied by a reduction of BDNF protein in the hippocampus, amygdala and the prefrontal cortex. Copyright © 2013 Elsevier Inc. All rights reserved.

Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice.

PubMed

Bozdagi, Ozlem; Sakurai, Takeshi; Dorr, Nathan; Pilorge, Marion; Takahashi, Nagahide; Buxbaum, Joseph D

2012-01-01

Copy number variation (CNV) at the 15q11.2 region, which includes a gene that codes for CYFIP1 (cytoplasmic FMR1 interacting protein 1), has been implicated in autism, intellectual disability and additional neuropsychiatric phenotypes. In the current study we studied the function of Cyfip1 in synaptic physiology and behavior, using mice with a disruption of the Cyfip1 gene. We observed that in Cyfip1 heterozygous mice metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) induced by paired-pulse low frequency stimulation (PP-LFS) was significantly increased in comparison to wildtype mice. In addition, mGluR-LTD was not affected in the presence of protein synthesis inhibitor in the Cyfip1 heterozygous mice, while the same treatment inhibited LTD in wildtype littermate controls. mGluR-agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD was also significantly increased in hippocampal slices from Cyfip1 heterozygous mice and again showed independence from protein synthesis only in the heterozygous animals. Furthermore, we observed that the mammalian Target of Rapamycin (mTOR) inhibitor rapamycin was only effective at reducing mGluR-LTD in wildtype animals. Behaviorally, Cyfip1 heterozygous mice showed enhanced extinction of inhibitory avoidance. Application of both mGluR5 and mGluR1 antagonist to slices from Cyfip1 heterozygous mice reversed the increase in DHPG-induced LTD in these mice. These results demonstrate that haploinsufficiency of Cyfip1 mimics key aspects of the phenotype of Fmr1 knockout mice and are consistent with the hypothesis that these effects are mediated by interaction of Cyfip1 and Fmrp in regulating activity-dependent translation. The data provide support for a model where CYFIP1 haploinsufficiency in patients results in intermediate phenotypes increasing risk for neuropsychiatric disorders.

Susceptibility of a potential animal model for pathological anxiety to chronic mild stress.

PubMed

Salomons, Amber R; Kortleve, Tessa; Reinders, Niels R; Kirchhoff, Susanne; Arndt, Saskia S; Ohl, Frauke

2010-06-19

When anxiety-related behaviour in animals appears to lack adaptive value, it might be defined as pathological. Adaptive behaviour can be assessed for example by changes in behavioural responses over time, i.e. habituation. Thus, non-adaptive anxiety would be reflected by a lack of habituation. Recently, we found that 129P3/J mice are characterised by non-adaptive avoidance behaviour after repeated test exposure. The present study was aimed at investigating the sensitivity of the behavioural profile of these animals to exposure to a chronic mild stress (CMS) paradigm followed by repeated exposure to the modified hole board test. If the behavioural profile of 129P3/J mice mirrors pathological anxiety, their behavioural habituation under repeated test exposure conditions should be affected by CMS treatment. The results confirm the profound lack of habituation with respect to anxiety-related behaviour in both control and CMS treated mice. Additionally, CMS treated animals revealed a lower exploratory behaviour, reduced locomotor activity and increased arousal-related behaviour over time when compared to control individuals, proving an extension of their impaired habituation behaviour. Although no effects of CMS treatment on plasma corticosterone levels were found, higher immediate early gene expression in the bed nucleus of the stria terminalis and the ventrolateral periaqueductal grey in CMS treated mice indicated that 129P3/J mice are susceptible to the negative effects of CMS treatment at both the behavioural and the functional level. These results support the hypothesis that 129P3/J mice might be an interesting model for pathological anxiety. Copyright 2010 Elsevier B.V. All rights reserved.

Dysregulation of Aldosterone Secretion in Mast Cell-Deficient Mice.

PubMed

Boyer, Hadrien-Gaël; Wils, Julien; Renouf, Sylvie; Arabo, Arnaud; Duparc, Céline; Boutelet, Isabelle; Lefebvre, Hervé; Louiset, Estelle

2017-12-01

Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice. We have also investigated the regulation of aldosterone secretion in mast cell-deficient C57BL/6 Kit W-sh/W-sh mice in comparison with wild-type C57BL/6 mice. Kit W-sh/W-sh mice submitted to normal sodium diet had basal plasma aldosterone levels similar to those observed in wild-type animals. Conversely, low-sodium diet unexpectedly induced an exaggerated aldosterone response, which seemed to result from an increase in adrenal renin and angiotensin type 1 receptor expression. Severe hyperaldosteronism was associated with an increase in systolic blood pressure and marked hypokalemia, which favored polyuria. Adrenal renin and angiotensin type 1 receptor overexpression may represent a compensatory mechanism aimed at activating aldosterone production in the absence of mast cells. Finally, C57BL/6 Kit W-sh/W-sh mice represent an unexpected animal model of primary aldosteronism, which has the particularity to be triggered by sodium restriction. © 2017 American Heart Association, Inc.

Preventing Drug-Induced Liver Injury: How Useful Are Animal Models?

PubMed

Ballet, François

2015-01-01

Drug-induced liver injury (DILI) is the most common organ toxicity encountered in regulatory animal toxicology studies required prior to the clinical development of new drug candidates. Very few reports have evaluated the value of these studies for predicting DILI in humans. Indeed, compounds inducing liver toxicity in regulatory toxicology studies are not always correlated with a risk of DILI in humans. Conversely, compounds associated with the occurrence of DILI in phase 3 studies or after market release are often tested negative in regulatory toxicology studies. Idiosyncratic DILI is a rare event that is precipitated in an individual by the simultaneous occurrence of several critical factors. These factors may relate to the host (e.g. human leukocyte antigen polymorphism, inflammation), the drug (e.g. reactive metabolites) or the environment (e.g. diet/microbiota). This type of toxicity therefore cannot be detected in conventional animal toxicology studies. Several animal models have recently been proposed for the identification of drugs with the potential to cause idiosyncratic DILI: rats treated with lipopolysaccharide, Sod2(+/-) mice, panels of inbred mouse strains or chimeric mice with humanized livers. These models are not suitable for use in the prospective screening of new drug candidates. Humans therefore constitute the best model for predicting and assessing idiopathic DILI. © 2015 S. Karger AG, Basel.

Photopic visual input is necessary for emmetropization in mice

PubMed Central

Tkatchenko, Tatiana V.; Shen, Yimin; Braun, Rod D.; Bawa, Gurinder; Kumar, Pradeep; Avrutsky, Ivan; Tkatchenko, Andrei V.

2013-01-01

It was recently demonstrated that refractive errors in mice stabilize around emmetropic values during early postnatal development, and that they develop experimental myopia in response to both visual form deprivation and imposed optical defocus similar to other vertebrate species. Animal studies also suggest that photopic vision plays critical role in emmetropization in diurnal species; however, it is unknown whether refractive eye development is guided by photopic vision in the mouse, which is a nocturnal species. We used an infrared mouse photorefractor and a high-resolution MRI to clarify the role of photopic visual input in refractive eye development in the mouse. Refractive eye development and form-deprivation myopia in P21-P89 C57BL/6J mice were analyzed under 12:12 h light-dark cycle, constant light and constant darkness regimens. Animals in all experimental groups were myopic at P21 (-13.2 ± 1.6 D, light-dark cycle; -12.5 ± 0.9 D, constant light; -12.5 ± 2.0 D, constant dark). The mean refractive error in the light-dark-cycle-reared animals was -0.5 ± 1.3 D at P32 and, and did not change significantly until P40 (+0.3 ± 0.6 D, P40). Animals in this group became progressively hyperopic between P40 and P89 (+2.2 ± 0.6, P67; +3.7 ± 2.0, P89). The mean refractive error in the constant-light-reared mice was -1.0 ± 0.7 D at P32 and remained stable until P89 (+0.1 ± 0.6, P40; +0.3 ± 0.6, P67; 0.0 ± 0.4, P89). Dark-reared animals exhibited highly hyperopic refractive errors at P32 (+5.2 ± 1.8) and became progressively more hyperopic with age (+8.7 ± 1.9, P40; +11.2 ± 1.4, P67). MRI analysis revealed that emmetropization in the P40-P89 constant-light-reared animals was associated with larger eyes, a longer axial length and a larger vitreous chamber compared to the light-dark-cycle-reared mice. Constant-light-reared mice also developed 4 times higher degrees of form-deprivation myopia on average compared to light-dark-cycle-reared animals (-12.0 ± 1

Effect of verapamil on bronchial goblet cells of asthma: an experimental study on sensitized animals.

PubMed

Khakzad, Mohammad Reza; Mirsadraee, Majid; Mohammadpour, Amirhooshang; Ghafarzadegan, Kamram; Hadi, Raziye; Saghari, Mahdiye; Meshkat, Mojtaba

2012-04-01

Goblet cell hyperplasia (GCH) and mucus hypersecretion in the airway is recognized as an important contributor to morbidity and mortality in asthma and COPD. Verapamil is a calcium channel blocker that binds to the alpha-subunit of L-type calcium channels and inhibits the mucin gene via the calmodulin and CaM kinase pathway. The objective of this study was to determine the in vivo effect of verapamil on GCH and eosinophilic inflammation in sensitized mice. Male BALB/c mice were sensitized to ovalbumin using the standard method. Two groups of animals were received verapamil via an intramuscular injection: 1-low dose (0.5 mg/kg/day for two weeks), 2-high dose (1.5 mg/kg/day for two weeks). Serum and bronchoalveolar lavage fluid (BALF) was collected and analyzed for inflammatory cells, interferon-γ and IL-4. The left lung was sent for histopathological evaluation, especially for periodic acid-Schiff (PAS), to identify goblet cells in the epithelium. The degree of inflammatory cell infiltration, including eosinophils, mucus plugging, and smooth muscle thickness of the airways were classified on a semi quantitative scale. Inflammatory cell infiltration in peribronchial and perivascular areas was observed in all sensitized groups. Eosinophils percentage in the BALF significantly decreased in verapamil-treated mice compared with sensitized mice (from 19.8% in asthmatic to 5.4% for low dose and 4.4% for high dose). The ratio of airway goblet cells per epithelial cells were significantly lower in verapamil-treated mice versus sensitized mice (1.57±1.30% for low dose; 1.50±0.93% for high dose versus 12.93±7.55%, P<0.05, respectively). Mucus production of goblet cells decreased significantly in verapamil-treated mice versus sensitized mice (mean score was 1.45±0.30 for low dose; 0.81±1.00 for high dose versus 2.85±0.86 in the sensitized control group, P<0.05, respectively). The concentration of serum and BALF-IFN-γ in verapamil-treated mice markedly increased by the

Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy

PubMed Central

McGreevy, Joe W.; Hakim, Chady H.; McIntosh, Mark A.; Duan, Dongsheng

2015-01-01

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder. It is caused by loss-of-function mutations in the dystrophin gene. Currently, there is no cure. A highly promising therapeutic strategy is to replace or repair the defective dystrophin gene by gene therapy. Numerous animal models of DMD have been developed over the last 30 years, ranging from invertebrate to large mammalian models. mdx mice are the most commonly employed models in DMD research and have been used to lay the groundwork for DMD gene therapy. After ~30 years of development, the field has reached the stage at which the results in mdx mice can be validated and scaled-up in symptomatic large animals. The canine DMD (cDMD) model will be excellent for these studies. In this article, we review the animal models for DMD, the pros and cons of each model system, and the history and progress of preclinical DMD gene therapy research in the animal models. We also discuss the current and emerging challenges in this field and ways to address these challenges using animal models, in particular cDMD dogs. PMID:25740330

Immunological effects of the orally administered neuraminidase inhibitor oseltamivir in influenza virus-infected and uninfected mice.

PubMed

Burger, R A; Billingsley, J L; Huffman, J H; Bailey, K W; Kim, C U; Sidwell, R W

2000-04-01

Oseltamivir (GS4104), the ethyl ester prodrug of the carbocyclic transition state sialic acid analog GS4071, has been reported to be a striking inhibitor of influenza A and B virus infections in mice and ferrets. Multiple studies indicate this material to also be active against the disease in humans, and it has recently been approved for human use. The effect of oral gavage (p.o.) therapy of oseltamivir on various immune factors considered to be of importance in primary influenza virus infection was studied in mice. Both uninfected animals and those infected with influenza A/NWS/33 (H1N1) virus were used. Doses of 100 mg kg(-1) day(-1) were administered twice daily for 5 days beginning 16 h pre-virus exposure. Two hours after end of treatment, the mice were killed and their spleens assayed for cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity. Subpopulations of splenic T, T-helper, T-cytotoxic and B lymphocytes as well as macrophages were determined using flow cytometry. Similar significant (P<0.01) increases in CTL activity were seen at effector:target cell ratios of 60:1 and 30:1 in the infected mice treated with oseltamivir or with placebo. NK cell activity was greater in the infected mice than in uninfected mice; the levels in all animals were not significantly affected by treatment with oseltamivir. Macrophage, T, T-helper, T-cytotoxic and B lymphocyte populations were similar in both treated and untreated animals. These data indicate treatment with oseltamivir does not adversely affect the primary in vivo cellular immune responses to influenza virus infection assayed in this study. The experiment was repeated to show that treatment with this compound significantly prevented the development of the infection and inhibited virus titers in the lung. Surviving treated mice on day 21 had mean neutralizing antibody titers of 1:208, and withstood rechallenge with the virus at this time, indicating the initial virus-inhibitory effect also did not

New animal models of cystic fibrosis: what are they teaching us?

PubMed Central

Keiser, Nicholas W.; Engelhardt, John F.

2013-01-01

Purpose of review Cystic fibrosis is the first human genetic disease to benefit from the directed engineering of three different species of animal models (mice, pigs, and ferrets). Recent studies on the cystic fibrosis pig and ferret models are providing new information about the pathophysiology of cystic fibrosis in various organ systems. Additionally, new conditional cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice are teaching unexpected lessons about CFTR function in surprising cellular locations. Comparisons between these animal models and the human condition are key to dissecting the complexities of disease pathophysiology in cystic fibrosis. Recent findings Cystic fibrosis pigs and ferrets have provided new models to study the spontaneous development of disease in the lung and pancreas, two organs that are largely spared overt spontaneous disease in cystic fibrosis mice. New cystic fibrosis mouse models are now interrogating CFTR functions involved in growth and inflammation at an organ-based level using conditional knockout technology. Together, these models are providing new insights on the human condition. Summary Basic and clinical cystic fibrosis research will benefit greatly from the comparative pathophysiology of cystic fibrosis mice, pigs, and ferrets. Both similarities and differences between these three cystic fibrosis models will inform pathophysiologically important mechanisms of CFTR function in humans and aid in the development of both organ-specific and general therapies for cystic fibrosis. PMID:21857224

Does vitamin E prevent tubal damage caused by smoking? A light microscopy and animal study.

PubMed

Duran, Muzeyyen; Ustunyurt, Emin; Kosus, Aydin; Kosus, Nermin; Turhan, Nilgun; Hızlı, Deniz; Sarac, Gulce Naz; Erdogan, Deniz

2014-04-01

To assess the histomorphological effects of smoking on the cilia of fallopian tubes in mice and the effect of vitamin E on the negative effects of smoke. Eighteen 12-14 week-old Swiss albino type female mice were randomly divided into three groups, each consisting of six mice: Group A: control group; Group B: mice exposed to cigarette smoke; Group C: mice exposed to cigarette smoke together with vitamin E. Groups B and C were exposed to cigarette smoke for 10 weeks. After 10 weeks, tubal excision was performed in all animals. Histopathologic examination of excised tubal tissue was conducted under light microscopy. The number of cilia was significantly lower in Group B. Although not statistically significant, the median number of cilia in Group C was measured to be higher than in Group B but lower than in Group A. Based on the results, it can be concluded that smoking decreases tubal cilia numbers. Supplementation by vitamin E may treat or at least help to slow down the decrease in number of cilia caused by smoking; therefore it could be used therapeutically in the treatment of smoking-related tubal damage. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

Chronobiology of alcohol: studies in C57BL/6J and DBA/2J inbred mice.

PubMed

Rosenwasser, Alan M; Fixaris, Michael C

2013-02-17

Human alcoholics display dramatic disruptions of circadian rhythms that may contribute to the maintenance of excessive drinking, thus creating a vicious cycle. While clinical studies cannot establish direct causal mechanisms, recent animal experiments have revealed bidirectional interactions between circadian rhythms and ethanol intake, suggesting that the chronobiological disruptions seen in human alcoholics are mediated in part by alterations in circadian pacemaker function. The present study was designed to further explore these interactions using C57BL/6J (B6) and DBA/2J (D2) inbred mice, two widely employed strains differing in both circadian and alcohol-related phenotypes. Mice were maintained in running-wheel cages with or without free-choice access to ethanol and exposed to a variety of lighting regimens, including standard light-dark cycles, constant darkness, constant light, and a "shift-lag" schedule consisting of repeated light-dark phase shifts. Relative to the standard light-dark cycle, B6 mice showed reduced ethanol intake in both constant darkness and constant light, while D2 mice showed reduced ethanol intake only in constant darkness. In contrast, shift-lag lighting failed to affect ethanol intake in either strain. Access to ethanol altered daily activity patterns in both B6 and D2 mice, and increased activity levels in D2 mice, but had no effects on other circadian parameters. Thus, the overall pattern of results was broadly similar in both strains, and consistent with previous observations that chronic ethanol intake alters circadian activity patterns while environmental perturbation of circadian rhythms modulates voluntary ethanol intake. These results suggest that circadian-based interventions may prove useful in the management of alcohol use disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6.

PubMed

Ladenheim, B; Krasnova, I N; Deng, X; Oyler, J M; Polettini, A; Moran, T H; Huestis, M A; Cadet, J L

2000-12-01

Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6-/-) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [(125)I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6-/- animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6-/- animals. Moreover, METH induced decreases in [(125)I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6-/- mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [(3)H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6-/- animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6-/- mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.

Effect of helicopter transport on neurological outcomes in a mouse model of embolic stroke with reperfusion: AIR-MICE pilot study.

PubMed

Leira, Enrique C; Zaheer, Asgar; Schnell, Thomas; Torner, James C; Olalde, Heena M; Pieper, Andrew A; Ortega-Gutierrez, Santiago; Nagaraja, Nandakumar; Marks, Nancy L; Adams, Harold P

2015-10-01

Patients often suffer a stroke at a significant distance from a center capable of delivering endovascular therapy, thus requiring rapid transport by helicopter emergency medical services while receiving a recombinant tissue plasminogen activator infusion that was initiated locally. But little is known about how a helicopter flight may impact the safety and efficacy of recombinant tissue plasminogen activator-induced reperfusion and patient outcomes. To establish a new animal method to address with fidelity the safety and overall effect of helicopter emergency medical services during thrombolysis. Prospective randomized open blinded end-point study of an actual helicopter flight exposure. Adult C57BL/6 male mice were treated with a 10 mg/kg recombinant tissue plasminogen activator infusion two-hours after an embolic middle cerebral artery occlusion. Mice were randomized in pairs to simultaneously receive the infusion during a local helicopter flight or in a ground hangar. Eighteen mice (nine pairs) were analyzed. The paired t-test analysis showed nonsignificant smaller infarction volumes in the helicopter-assigned animals (mean pair difference 33 mm(3) , P = 0·33). The amount of hemorrhagic transformation between the helicopter and ground groups was 4·08 vs. 4·56 μl, respectively (paired t-test, P = 0·45). This study shows that helicopter emergency medical services do not have an inherent adverse effect on outcome in a mouse model of ischemic stroke with reperfusion. These results endorse the safety of the practice of using helicopter emergency medical services in stroke patients. The observed potential synergistic effect of helicopter-induced factors, such as vibration and changes in altitude, with reperfusion merits further exploration in animal experimental models and in stroke patients. © 2015 World Stroke Organization.

Cadmium Increases the Sensitivity of Adolescent Female Mice to Nicotine-Related Behavioral Deficits

PubMed Central

Adeniyi, Philip Adeyemi; Olatunji, Babawale Peter; Ishola, Azeez Olakunle; Ajonijebu, Duyilemi Chris; Ogundele, Olalekan Michael

2014-01-01

This study investigates spatial and nonspatial working memory, anxiety related behavior, and motor activities in cadmium and/or nicotine exposed female adolescent mice. P28 female adolescent mice (albino strain) were divided into four groups of five (n = 5) mice each. A set of mice (Nic) received subcutaneous nicotine (2.0 mg/kg) while a separate set (Cd) was treated with 2.0 mg/kg cadmium (subcutaneous). For the combined treatments of cadmium and nicotine, we administered 2.0 mg/kg Nicotine and 2.0 mg/kg of Cd. Subsequently, a separate group of animals (n = 5; control) received normal saline. The total duration of treatment for all groups was 28 days (P28–P56). At P56, the treatment was discontinued, after which the animals were examined in behavioural tests. Nicotine and cadmium increased the metabolism and food intake in the female adolescent mice. This also corresponded to an increase in weight when compared with the control. However, a combined nicotine-cadmium treatment induced a decline in weight of the animals versus the control. Also, nicotine administration increased the motor function, while cadmium and nicotine-cadmium treatment caused a decline in motor activity. Both nicotine and cadmium induced a reduction in memory index; however, nicotine-cadmium treatment induced the most significant decrease in nonspatial working memory. PMID:25477708

Olfaction variation in mouse husbandry and its implications for refinement and standardization: UK survey of animal scents.

PubMed

López-Salesansky, Noelia; Mazlan, Nur H; Whitfield, Lucy E; Wells, Dominic J; Burn, Charlotte C

2016-10-01

Olfaction plays a crucial role in mouse communication, providing information about genetic identity, physiological status of conspecifics and alerting mice to potential predators. Scents of animal origin can trigger physiological and behavioural responses that could affect experimental responses and impact positively or negatively on mouse welfare. Additionally, differing olfactory profiles could help explain variation in results between laboratories. A survey was sent to animal research units in the UK to investigate potential transfer of scents of animal origin during routine husbandry procedures, and responses were obtained from animal care workers and researchers using mice in 51 institutions. The results reveal great diversity between animal units regarding the relevant husbandry routines covered. Most [71%] reported housing non-breeding male and female mice in the same room, with 76% reporting that hands were not washed and gloves not changed between handling male and female mice. The most commonly reported species housed in the same facility as mice was the rat (91%), and 41% of respondents were aware that scents from rats could affect mice. Changing of gloves between handling mice and other species was reported by 79% of respondents. Depending on the aspect considered, between 18 and 33% of respondents believed human and non-human animal odours would strongly affect mouse physiology, behaviour or standardization, while approximately 32-54% believed these effects would be weak. This indicates uncertainty regarding the significance of these factors. Understanding and controlling these practices could reduce unwanted variability in experimental results and maximize welfare. © The Author(s) 2015.

Of Fighting Flies, Mice, and Men: Are Some of the Molecular and Neuronal Mechanisms of Aggression Universal in the Animal Kingdom?

PubMed

Thomas, Amanda L; Davis, Shaun M; Dierick, Herman A

2015-08-01

Aggressive behavior is widespread in the animal kingdom, but the degree of molecular conservation between distantly related species is still unclear. Recent reports suggest that at least some of the molecular mechanisms underlying this complex behavior in flies show remarkable similarities with such mechanisms in mice and even humans. Surprisingly, some aspects of neuronal control of aggression also show remarkable similarity between these distantly related species. We will review these recent findings, address the evolutionary implications, and discuss the potential impact for our understanding of human diseases characterized by excessive aggression.

Of Fighting Flies, Mice, and Men: Are Some of the Molecular and Neuronal Mechanisms of Aggression Universal in the Animal Kingdom?

PubMed Central

Dierick, Herman A.

2015-01-01

Aggressive behavior is widespread in the animal kingdom, but the degree of molecular conservation between distantly related species is still unclear. Recent reports suggest that at least some of the molecular mechanisms underlying this complex behavior in flies show remarkable similarities with such mechanisms in mice and even humans. Surprisingly, some aspects of neuronal control of aggression also show remarkable similarity between these distantly related species. We will review these recent findings, address the evolutionary implications, and discuss the potential impact for our understanding of human diseases characterized by excessive aggression. PMID:26312756

SOD2 deficiency in hematopoietic cells in mice results in reduced red blood cell deformability and increased heme degradation

PubMed Central

Mohanty, Joy G.; Nagababu, Enika; Friedman, Jeffrey S.; Rifkind, Joseph M.

2013-01-01

Among the three types of super oxide dismutases (SODs) known, SOD2 deficiency is lethal in neonatal mice owing to cardiomyopathy caused by severe oxidative damage. SOD2 is found in red blood cell (RBC) precursors, but not in mature RBCs. To investigate the potential damage to mature RBCs resulting from SOD2 deficiency in precursor cells, we studied RBCs from mice in which fetal liver stem cells deficient in SOD2 were capable of efficiently rescuing lethally irradiated host animals. These transplanted animals lack SOD2 only in hematopoietically generated cells and live longer than SOD2 knockouts. In these mice, approximately 2.8% of their total RBCs in circulation are iron-laden reticulocytes, with numerous siderocytic granules and increased protein oxidation similar to that seen in sideroblastic anemia. We have studied the RBC deformability and oxidative stress in these animals and the control group by measuring them with a microfluidic ektacytometer and assaying fluorescent heme degradation products with a fluorimeter, respectively. In addition, the rate of hemoglobin oxidation in RBCs from these mice and the control group were measured spectrophotometrically. The results show that RBCs from these SOD2-deficient mice have reduced deformability, increased heme degradation products, and an increased rate of hemoglobin oxidation compared with control animals, indicative of increased RBC oxidative stress. PMID:23142655

Absolute quantification of regional cerebral glucose utilization in mice by 18F-FDG small animal PET scanning and 2-14C-DG autoradiography.

PubMed

Toyama, Hiroshi; Ichise, Masanori; Liow, Jeih-San; Modell, Kendra J; Vines, Douglass C; Esaki, Takanori; Cook, Michelle; Seidel, Jurgen; Sokoloff, Louis; Green, Michael V; Innis, Robert B

2004-08-01

The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR(glc)) in mice by use of (18)F-FDG and a small animal PET scanner. rCMR(glc) determined with (18)F-FDG PET was compared with values determined simultaneously by the autoradiographic 2-(14)C-DG method. In addition, we compared the rCMR(glc) values under isoflurane, ketamine and xylazine anesthesia, and awake states. Immediately after injection of (18)F-FDG and 2-(14)C-DG into mice, timed arterial samples were drawn over 45 min to determine the time courses of (18)F-FDG and 2-(14)C-DG. Animals were euthanized at 45 min and their brain was imaged with the PET scanner. The brains were then processed for 2-(14)C-DG autoradiography. Regions of interest were manually placed over cortical regions on corresponding coronal (18)F-FDG PET and 2-(14)C-DG autoradiographic images. rCMR(glc) values were calculated for both tracers by the autoradiographic 2-(14)C-DG method with modifications for the different rate and lumped constants for the 2 tracers. Average rCMR(glc) values in cerebral cortex with (18)F-FDG PET under normoglycemic conditions (isoflurane and awake) were generally lower (by 8.3%) but strongly correlated with those of 2-(14)C-DG (r(2) = 0.95). On the other hand, under hyperglycemic conditions (ketamine/xylazine) average cortical rCMR(glc) values with (18)F-FDG PET were higher (by 17.3%) than those with 2-(14)C-DG. Values for rCMR(glc) and uptake (percentage injected dose per gram [%ID/g]) with (18)F-FDG PET were significantly lower under both isoflurane and ketamine/xylazine anesthesia than in the awake mice. However, the reductions of rCMR(glc) were markedly greater under isoflurane (by 57%) than under ketamine and xylazine (by 19%), whereas more marked reductions of %ID/g were observed with ketamine/xylazine (by 54%) than with isoflurane (by 37%). These reverse differences between isoflurane and ketamine/xylazine may be due to

Small animal radiotherapy research platforms

NASA Astrophysics Data System (ADS)

Verhaegen, Frank; Granton, Patrick; Tryggestad, Erik

2011-06-01

Advances in conformal radiation therapy and advancements in pre-clinical radiotherapy research have recently stimulated the development of precise micro-irradiators for small animals such as mice and rats. These devices are often kilovolt x-ray radiation sources combined with high-resolution CT imaging equipment for image guidance, as the latter allows precise and accurate beam positioning. This is similar to modern human radiotherapy practice. These devices are considered a major step forward compared to the current standard of animal experimentation in cancer radiobiology research. The availability of this novel equipment enables a wide variety of pre-clinical experiments on the synergy of radiation with other therapies, complex radiation schemes, sub-target boost studies, hypofractionated radiotherapy, contrast-enhanced radiotherapy and studies of relative biological effectiveness, to name just a few examples. In this review we discuss the required irradiation and imaging capabilities of small animal radiation research platforms. We describe the need for improved small animal radiotherapy research and highlight pioneering efforts, some of which led recently to commercially available prototypes. From this, it will be clear that much further development is still needed, on both the irradiation side and imaging side. We discuss at length the need for improved treatment planning tools for small animal platforms, and the current lack of a standard therein. Finally, we mention some recent experimental work using the early animal radiation research platforms, and the potential they offer for advancing radiobiology research.

LASP-06: Drug Efficacy in a Three-Arm Survival Study in Kras/p53 Pancreatic Ductal Adenocarcinoma (PDAC) Mice | Frederick National Laboratory for Cancer Research

Cancer.gov

The Laboratory Animal Sciences Program will induce breed 50 KPC animals with the intent of generating a cohort of 40 animals with confirmed tumor-load matching the following enrollment criteria:female mice are considered eligible for enrollment

Dioxin pollution disrupts reproduction in male Japanese field mice.

PubMed

Ishiniwa, Hiroko; Sakai, Mizuki; Tohma, Shimon; Matsuki, Hidenori; Takahashi, Yukio; Kajiwara, Hideo; Sekijima, Tsuneo

2013-11-01

Dioxins cause various adverse effects in animals including teratogenesis, induction of drug metabolizing enzymes, tumor promotion, and endocrine disruption. Above all, endocrine disruption is known to disturb reproduction in adult animals and may, also seriously impact their offspring. However, most previous studies have quantified the species-specific accumulation of dioxins, whereas few studies have addressed the physiological impacts of dioxins on wildlife, such as reduced reproductive function. Here we clarify an effect of endocrine disruption caused by dioxins on the Japanese field mouse, Apodemus speciosus. Japanese field mice collected from various sites polluted with dioxins accumulated high concentrations of dioxins in their livers. Some dioxin congeners, especially, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, 3,3',4,4',5-pentachloro biphenyl, 1,2,3,4,6,7,8-heptachlorodibenzofuran, and octachlorodibenzo-p-dioxin, which showed high biota-soil accumulation factors, contributed to concentration of dioxins in mouse livers with an increase of accumulation of total dioxins. As for physiological effects on the Japanese field mouse, high levels of cytochrome P450 1A1 (CYP1A1) mRNA, a drug metabolizing enzyme induced by dioxins, were found in the livers of mice captured at polluted sites. Furthermore, at such sites polluted with dioxins, increased CYP1A1 expression coincided with reduced numbers of active spermatozoa in mice. Thus, disruption in gametogenesis observed in these mice suggests that dioxins not only negatively impact reproduction among Japanese field mice, but might also act as a kind of selection pressure in a chemically polluted environment.

Attitudes toward the use of animals in chronic versus acute pain research: results of a web-based forum.

PubMed

Ormandy, Elisabeth H; Griffin, Gilly

2016-09-01

When asked about the use of animals in biomedical research, people often state that the research is only acceptable if pain and distress are minimised. However, pain is caused when the aim is to study pain itself, resulting in unalleviated pain for many of the animals involved. Consequently, the use of animals in pain research is often considered contentious. To date, no research has explored people's views toward different types of animal-based pain research (e.g. chronic or acute pain). This study used a web-based survey to explore people's willingness to support the use of mice in chronic versus acute pain research. The majority of the participants opposed the use of mice for either chronic (68.3%) or acute (63.1%) pain research. There was no difference in the levels of support or opposition for chronic versus acute pain research. Unsupportive participants justified their opposition by focusing on the perceived lack of scientific merit, or the existence of non-animal alternatives. Supporters emphasised the potential benefits that could arise, with some stating that the benefits outweigh the costs. The majority of the participants were opposed to pain research involving mice, regardless of the nature and duration of the pain inflicted, or the perceived benefit of the research. A better understanding of public views toward animal use in pain research may provide a stronger foundation for the development of policy governing the use of animals in research where animals are likely to experience unalleviated pain. 2016 FRAME.

A standardized protocol for repeated social defeat stress in mice

PubMed Central

Golden, Sam A; Covington, Herbert E; Berton, Olivier; Russo, Scott J

2011-01-01

A major impediment to novel drug development has been the paucity of animal models that accurately reflect symptoms of affective disorders. In animal models, prolonged social stress has proven to be useful in understanding the molecular mechanisms underlying affective-like disorders. When considering experimental approaches for studying depression, social defeat stress, in particular, has been shown to have excellent etiological, predictive, discriminative and face validity. Described here is a protocol whereby C57BL/6J mice that are repeatedly subjected to bouts of social defeat by a larger and aggressive CD-1 mouse results in the development of a clear depressive-like syndrome, characterized by enduring deficits in social interactions. Specifically, the protocol consists of three important stages, beginning with the selection of aggressive CD-1 mice, followed by agonistic social confrontations between the CD-1 and C57BL/6J mice, and concluding with the confirmation of social avoidance in subordinate C57BL/6J mice. The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3–4 weeks for completion. PMID:21799487

Sarcocystis neurona infection in gamma interferon gene knockout (KO) mice: comparative infectivity of sporocysts in two strains of KO mice, effect of trypsin digestion on merozoite viability, and infectivity of bradyzoites to KO mice and cell culture.

PubMed

Dubey, J P; Sundar, N; Kwok, O C H; Saville, W J A

2013-09-01

The protozoan Sarcocystis neurona is the primary cause of Equine Protozoal Myeloencephalitis (EPM). EPM or EPM-like illness has been reported in horses, sea otters, and several other mammals. The gamma interferon gene knockout (KO) mouse is often used as a model to study biology and discovery of new therapies against S. neurona because it is difficult to induce clinical EPM in other hosts, including horses. In the present study, infectivity of three life cycle stages (merozoites, bradyzoites, sporozoites) to KO mice and cell culture was studied. Two strains of KO mice (C57-black, and BALB/c-derived, referred here as black or white) were inoculated orally graded doses of S. neurona sporocysts; 12 sporocysts were infective to both strains of mice and all infected mice died or became ill within 70 days post-inoculation. Although there was no difference in infectivity of sporocysts to the two strains of KO mice, the disease was more severe in black mice. S. neurona bradyzoites were not infectious to KO mice and cell culture. S. neurona merozoites survived 120 min incubation in 0.25% trypsin, indicating that trypsin digestion can be used to recover S. neurona from tissues of acutely infected animals. Published by Elsevier B.V.

Molecular Determinants of Influenza Virus Pathogenesis in Mice

PubMed Central

Katz, Jaqueline M.; York, Ian A.

2015-01-01

Mice are widely used for studying influenza virus pathogenesis and immunology because of their low cost, the wide availability of mouse-specific reagents, and the large number of mouse strains available, including knockout and transgenic strains. However, mice do not fully recapitulate the signs of influenza infection of humans: transmission of influenza between mice is much less efficient than in humans, and influenza viruses often require adaptation before they are able to efficiently replicate in mice. In the process of mouse adaptation, influenza viruses acquire mutations that enhance their ability to attach to mouse cells, replicate within the cells, and suppress immunity, among other functions. Many such mouse-adaptive mutations have been identified, covering all 8 genomic segments of the virus. Identification and analysis of these mutations have provided insight into the molecular determinants of influenza virulence and pathogenesis, not only in mice but also in humans and other species. In particular, several mouse-adaptive mutations of avian influenza viruses have proved to be general mammalian-adaptive changes that are potential markers of pre-pandemic viruses. As well as evaluating influenza pathogenesis, mice have also been used as models for evaluation of novel vaccines and anti-viral therapies. Mice can be a useful animal model for studying influenza biology as long as differences between human and mice infections are taken into account. PMID:25038937

Protective role of p53 in skin cancer: Carcinogenesis studies in mice lacking epidermal p53.

PubMed

Page, Angustias; Navarro, Manuel; Suarez-Cabrera, Cristian; Alameda, Josefa P; Casanova, M Llanos; Paramio, Jesús M; Bravo, Ana; Ramirez, Angel

2016-04-12

p53 is a protein that causes cell cycle arrest, apoptosis or senescence, being crucial in the process of tumor suppression in several cell types. Different in vitro and animal models have been designed for the study of p53 role in skin cancer. These models have revealed opposing results, as in some experimental settings it appears that p53 protects against skin cancer, but in others, the opposite conclusion emerges. We have generated cohorts of mice with efficient p53 deletion restricted to stratified epithelia and control littermates expressing wild type p53 and studied their sensitivity to both chemically-induced and spontaneous tumoral transformation, as well as the tumor types originated in each experimental group. Our results indicate that the absence of p53 in stratified epithelia leads to the appearance, in two-stage skin carcinogenesis experiments, of a higher number of tumors that grow faster and become malignant more frequently than tumors arisen in mice with wild type p53 genotype. In addition, the histological diversity of the tumor type is greater in mice with epidermal p53 loss, indicating the tumor suppressive role of p53 in different epidermal cell types. Aging mice with p53 inactivation in stratified epithelia developed spontaneous carcinomas in skin and other epithelia. Overall, these results highlight the truly protective nature of p53 functions in the development of cancer in skin and in other stratified epithelia.

Attenuation of Cocaine-Induced Locomotor Activity in Male and Female Mice by Active Immunization

PubMed Central

Kosten, Therese A.; Shen, Xiaoyun Y.; Kinsey, Berma M.; Kosten, Thomas R.; Orson, Frank M.

2014-01-01

Background and objectives Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Methods Male and female BALB/c mice were vaccinated (n=44) or served as non-vaccinated controls (n=34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7-wk and plasma obtained at 8-wk to assess antibody levels. Results High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. Discussion and conclusions The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Scientific significance Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction. PMID:25251469

Attenuation of cocaine-induced locomotor activity in male and female mice by active immunization.

PubMed

Kosten, Therese A; Shen, Xiaoyun Y; Kinsey, Berma M; Kosten, Thomas R; Orson, Frank M

2014-01-01

Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Male and female BALB/c mice were vaccinated (n = 44) or served as non-vaccinated controls (n = 34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7 weeks and plasma obtained at 8 weeks to assess antibody levels. High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction. © American Academy of Addiction Psychiatry.

The Mice Drawer System Tissue Sharing Program (MDS-TSP)

NASA Astrophysics Data System (ADS)

Biticchi, Roberta; Cancedda, Ranieri; Cilli, Michele; Cotronei, Vittorio; Costa, Delfina; Liu, Yi; Piccardi, Federica; Pignataro, Salvatore; Ruggiu, Alessandra; Tasso, Roberta; Tavella, Sara

Several organs and apparatus are affected by weightless conditions and in particular by the weightless experienced during space flights. Therefore space missions are good opportunities to investigate in a whole organism the controlling cellular and molecular mechanisms. For this type of studies mice represent an excellent animal model for several reasons: reduced body size, relatively short time needed to reach adulthood, availability of strains with different genetic background and of different transgenic lines, etc. In line with the International Space Station (ISS) development, the Italian Space Agency (ASI) contracted Thales Alenia Space Italia, the largest Italian aerospace industry, to design and build a spaceflight payload for rodent research on ISS, the Mouse Drawer System (MDS -see abstract P. Cipparelli et al.). This payload meets NIH guideline for several physical parameters to maintain 6 animals in good health conditions in a space environment. Given the interest of our laboratory in the microgravity induced skeleton alterations, we focused our attention on transgenic mice over-expressing pleiotrophin (PTN) under the control of the human bone specific osteocalcin promoter. This protein is a heparin-binding cytokine with different functions. PTN is expressed by the cells in an early differentiation stage and is upregulated in tissue injury and wound repair. PTN is specifically involved in bone formation, neurite outgrowth and angiogenesis. As PTN-transgenic mice show an increased bone mass and mineralization, we decided to use this mouse model in the flight experiment and to study its potential role in counteracting bone loss in microgravity. Not all mouse strains are equally suitable for flight. After preliminary tests in the MDS breadboard at our animal facility on the behavior of different mouse strains, PTN-transgenic mice originally obtained in the BDF strain were backcrossed in the C57Bl/J10 strain before being used in this study. In order to

Mortality of atomic bomb survivors predicted from laboratory animals

NASA Technical Reports Server (NTRS)

Carnes, Bruce A.; Grahn, Douglas; Hoel, David

2003-01-01

Exposure, pathology and mortality data for mice, dogs and humans were examined to determine whether accurate interspecies predictions of radiation-induced mortality could be achieved. The analyses revealed that (1) days of life lost per unit dose can be estimated for a species even without information on radiation effects in that species, and (2) accurate predictions of age-specific radiation-induced mortality in beagles and the atomic bomb survivors can be obtained from a dose-response model for comparably exposed mice. These findings illustrate the value of comparative mortality analyses and the relevance of animal data to the study of human health effects.

Mibefradil reduces blood glucose concentration in db/db mice

PubMed Central

Lu, Yujie; Long, Min; Zhou, Shiwen; Xu, Zihui; Hu, Fuquan; Li, Ming

2014-01-01

OBJECTIVE: Numerous recent studies suggest that abnormal intracellular calcium concentration ([Ca2+]i) is a common defect in diabetic animal models and patients. Abnormal calcium handling is an important mechanism in the defective pancreatic β-cell function in type 2 diabetes. T-type Ca2+ channel antagonists lower blood glucose in type 2 diabetes, but the mechanism remains unknown. METHODS: We examined the effect of the Ca2+ channel antagonist mibefradil on blood glucose in male db/db mice and phenotypically normal heterozygous mice by intraperitoneal injection. RESULTS: Mibefradil (15 mg/kg, i.p., b.i.d.) caused a profound reduction of fasting blood glucose from 430.92±20.46 mg/dl to 285.20±5.74 mg/dl in three days. The hypoglycemic effect of mibefradil was reproduced by NNC 55-0396, a compound structurally similar to mibefradil but more selective for T-type Ca2+ channels, but not by the specific L-type Ca2+ channel blocker nicardipine. Mibefradil did not show such hypoglycemic effects in heterozygous animals. In addition, triglycerides, basal insulin and food intake were significantly decreased by mibefradil treatment in the db/db mice but not in the controls. Western blot analysis, immunohistochemistry and immunofluorescence staining showed a significantly increased expression of T-type Ca2+ channel α-subunits Cav3.1 and Cav3.2 in liver and brain tissues from db/db mice compared to those from heterozygous animals. CONCLUSIONS: Collectively, these results suggest that T-type Ca2+ channels are potential therapeutic targets for antidiabetic drugs. PMID:24473561

Endothelial Arginine Resynthesis Contributes to the Maintenance of Vasomotor Function in Male Diabetic Mice

PubMed Central

Chennupati, Ramesh; Meens, Merlijn J. P. M. T.; Marion, Vincent; Janssen, Ben J.; Lamers, Wouter H.; De Mey, Jo G. R.; Köhler, S. Eleonore

2014-01-01

Aim Argininosuccinate synthetase (ASS) is essential for recycling L-citrulline, the by-product of NO synthase (NOS), to the NOS substrate L-arginine. Here, we assessed whether disturbed arginine resynthesis modulates endothelium-dependent vasodilatation in normal and diabetic male mice. Methods and Results Endothelium-selective Ass-deficient mice (Assfl/fl/Tie2Cretg/− = Ass-KOTie2) were generated by crossing Assfl/fl mice ( = control) with Tie2Cre mice. Gene ablation in endothelial cells was confirmed by immunohistochemistry. Blood pressure (MAP) was recorded in 34-week-old male mice. Vasomotor responses were studied in isolated saphenous arteries of 12- and 34-week-old Ass-KOTie2 and control animals. At the age of 10 weeks, diabetes was induced in control and Ass-KOTie2 mice by streptozotocin injections. Vasomotor responses of diabetic animals were studied 10 weeks later. MAP was similar in control and Ass-KOTie2 mice. Depletion of circulating L-arginine by arginase 1 infusion or inhibition of NOS activity with L-NAME resulted in an increased MAP (10 and 30 mmHg, respectively) in control and Ass-KOTie2 mice. Optimal arterial diameter, contractile responses to phenylephrine, and relaxing responses to acetylcholine and sodium nitroprusside were similar in healthy control and Ass-KOTie2 mice. However, in diabetic Ass-KOTie2 mice, relaxation responses to acetylcholine and endothelium-derived NO (EDNO) were significantly reduced when compared to diabetic control mice. Conclusions Absence of endothelial citrulline recycling to arginine did not affect blood pressure and systemic arterial vasomotor responses in healthy mice. EDNO-mediated vasodilatation was significantly more impaired in diabetic Ass-KOTie2 than in control mice demonstrating that endothelial arginine recycling becomes a limiting endothelial function in diabetes. PMID:25033204

Men and mice: Relating their ages.

PubMed

Dutta, Sulagna; Sengupta, Pallav

2016-05-01

Since the late 18th century, the murine model has been widely used in biomedical research (about 59% of total animals used) as it is compact, cost-effective, and easily available, conserving almost 99% of human genes and physiologically resembling humans. Despite the similarities, mice have a diminutive lifespan compared to humans. In this study, we found that one human year is equivalent to nine mice days, although this is not the case when comparing the lifespan of mice versus humans taking the entire life at the same time without considering each phase separately. Therefore, the precise correlation of age at every point in their lifespan must be determined. Determining the age relation between mice and humans is necessary for setting up experimental murine models more analogous in age to humans. Thus, more accuracy can be obtained in the research outcome for humans of a specific age group, although current outcomes are based on mice of an approximate age. To fill this gap between approximation and accuracy, this review article is the first to establish a precise relation between mice age and human age, following our previous article, which explained the relation in ages of laboratory rats with humans in detail. Copyright © 2015 Elsevier Inc. All rights reserved.

Corticosterone levels and behavioral changes induced by simultaneous exposure to chronic social stress and enriched environments in NMRI male mice.

PubMed

Mesa-Gresa, Patricia; Ramos-Campos, Marta; Redolat, Rosa

2016-05-01

Environmental enrichment (EE) is an experimental model which is believed to counteract some of the effects induced by stressors, although few studies have exposed rodents simultaneously to EE and stress. Our aim was to compare the short- and long-term effects of different housing conditions in mice submitted to chronic stress. 128 NMRI male mice arrived at our laboratory on postnatal day (PND) 21. During Phase I (PND 28), animals were randomly assigned to four experimental conditions: 1) EE+STRESS: mice housed in EE and submitted to social stress (n=32); 2) EE+NO STRESS: mice housed in EE without stress (n=32); 3) SE+STRESS: mice maintained in standard conditions (SE) and submitted to social stress (n=32); and 4) SE+NO STRESS (n=32). At the end of Phase I (PND 77), one cohort of 32 animals was used for behavioral assessment whereas another cohort of 32 was sacrificed for corticosterone analysis. Results indicated that EE animals showed less body weight, higher water and food intake, diminished anxiety response and decreased motor and exploratory behavior than SE mice. Mice exposed to stress gained less body weight, showed higher food and fluid intake and displayed decreased exploratory behavior than non-stressed mice. Furthermore, EE+STRESS group displayed significantly higher corticosterone levels than EE+NO STRESS group whereas EE+NO STRESS group showed lower levels than SE+NO STRESS. On PND 83, Phase II of the study began. Animals (n=96) were assigned to two different housing conditions: EE (n=48) and SE (n=48). On PND 112, corticosterone analysis (n=32) and behavioral study (n=64) were done. The factor "Housing Phase II" reached statistical significance. Results indicated that EE animals showed lower body weight and higher fluid intake than SE group, as well as decreased anxiety. No clear effects on motor and exploratory behavior or learning were observed. When long-term effects were analyzed, results indicated that "Initial Housing" condition was significant

Orthotopic tumorgrafts in nude mice: A new method to study human prostate cancer.

PubMed

Saar, Matthias; Körbel, Christina; Linxweiler, Johannes; Jung, Volker; Kamradt, Jörn; Hasenfus, Andrea; Stöckle, Michael; Unteregger, Gerhard; Menger, Michael D

2015-10-01

In vivo model systems in prostate cancer research that authentically reproduce tumor growth are still sparse. While orthotopic implantation is technically difficult, particularly in the mouse, most models favor subcutaneous tumor growth. This however provides little information about natural tumor growth behavior and tumor stroma interaction. Furthermore, established prostate cancer cell lines grown as in vivo xenografts are not able to reflect the variety of tumor specific growth patterns and growth behavior in men. Primary cell cultures are difficult to handle and an induction of orthotopic tumors has not been successful yet. Therefore, a tumorgraft model using tumor tissue from prostatectomy specimens was developed. Balb/c nude mice were used to graft fresh prostate tumor tissue by renal subcapsular and orthotopic implantation. Testosterone propionate was supplemented. Animals were tracked by means of 30 MHz ultrasound to monitor tumor engraftment and growth. Autopsy, histology, PSA measurements as well as immunostaining and PCR for human tissue were performed to confirm orthotopic tumor growth. Renal subcapsular engraftment was seen in 2 of 3 mice. Orthotopic engraftment was observed in 7 of 11 animals (63.6%) with an overall engraftment of 5 out of 9 patient specimens (55.6%). Ultrasound confirmed the tumor growth over time. Of interest, the tumorgrafts not only retained essential features of the parental tumors, but also stained positive for tumor specific markers such as AR, PSA, and AMACR. Tumor positive animals showed highly elevated serum PSA levels with confirmation of a human specific PCR sequence and a human endothelial cell lining in the tumor vessels. Standardized implantation of fresh tumor tissue in nude mice prostates generates tumorgrafts with histological properties of organ-confined prostate cancer. These tumorgrafts display a new approach for an optimized in vivo model of prostate cancer and will allow further investigations on specific

Engineering Large Animal Species to Model Human Diseases.

PubMed

Rogers, Christopher S

2016-07-01

Animal models are an important resource for studying human diseases. Genetically engineered mice are the most commonly used species and have made significant contributions to our understanding of basic biology, disease mechanisms, and drug development. However, they often fail to recreate important aspects of human diseases and thus can have limited utility as translational research tools. Developing disease models in species more similar to humans may provide a better setting in which to study disease pathogenesis and test new treatments. This unit provides an overview of the history of genetically engineered large animals and the techniques that have made their development possible. Factors to consider when planning a large animal model, including choice of species, type of modification and methodology, characterization, production methods, and regulatory compliance, are also covered. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Evaluation of rodent spaceflight in the NASA animal enclosure module for an extended operational period (up to 35 days).

PubMed

Moyer, Eric L; Dumars, Paula M; Sun, Gwo-Shing; Martin, Kara J; Heathcote, David G; Boyle, Richard D; Skidmore, Mike G

2016-01-01

The National Aeronautics and Space Administration Animal Enclosure Module (AEM) was developed as a self-contained rodent habitat for shuttle flight missions that provides inhabitants with living space, food, water, ventilation, and lighting, and this study reports whether, after minimal hardware modification, the AEM could support an extended term up to 35 days for Sprague-Dawley rats and C57BL/6 female mice for use on the International Space Station. Success was evaluated based on comparison of AEM housed animals to that of vivarium housed and to normal biological ranges through various measures of animal health and well-being, including animal health evaluations, animal growth and body masses, organ masses, rodent food bar consumption, water consumption, and analysis of blood contents. The results of this study confirmed that the AEMs could support 12 adult female C57BL/6 mice for up to 35 days with self-contained RFB and water, and the AEMs could also support 5 adult male Sprague-Dawley rats for 35 days with external replenishment of diet and water. This study has demonstrated the capability and flexibility of the AEM to operate for up to 35 days with minor hardware modification. Therefore, with modifications, it is possible to utilize this hardware on the International Space Station or other operational platforms to extend the space life science research use of mice and rats.

Evaluation of rodent spaceflight in the NASA animal enclosure module for an extended operational period (up to 35 days)

PubMed Central

Moyer, Eric L; Dumars, Paula M; Sun, Gwo-Shing; Martin, Kara J; Heathcote, David G; Boyle, Richard D; Skidmore, Mike G

2016-01-01

The National Aeronautics and Space Administration Animal Enclosure Module (AEM) was developed as a self-contained rodent habitat for shuttle flight missions that provides inhabitants with living space, food, water, ventilation, and lighting, and this study reports whether, after minimal hardware modification, the AEM could support an extended term up to 35 days for Sprague-Dawley rats and C57BL/6 female mice for use on the International Space Station. Success was evaluated based on comparison of AEM housed animals to that of vivarium housed and to normal biological ranges through various measures of animal health and well-being, including animal health evaluations, animal growth and body masses, organ masses, rodent food bar consumption, water consumption, and analysis of blood contents. The results of this study confirmed that the AEMs could support 12 adult female C57BL/6 mice for up to 35 days with self-contained RFB and water, and the AEMs could also support 5 adult male Sprague-Dawley rats for 35 days with external replenishment of diet and water. This study has demonstrated the capability and flexibility of the AEM to operate for up to 35 days with minor hardware modification. Therefore, with modifications, it is possible to utilize this hardware on the International Space Station or other operational platforms to extend the space life science research use of mice and rats. PMID:28725722

Maporal Hantavirus Causes Mild Pathology in Deer Mice (Peromyscus maniculatus).

PubMed

McGuire, Amanda; Miedema, Kaitlyn; Fauver, Joseph R; Rico, Amber; Aboellail, Tawfik; Quackenbush, Sandra L; Hawkinson, Ann; Schountz, Tony

2016-10-18

Rodent-borne hantaviruses can cause two human diseases with many pathological similarities: hantavirus cardiopulmonary syndrome (HCPS) in the western hemisphere and hemorrhagic fever with renal syndrome in the eastern hemisphere. Each virus is hosted by specific reservoir species without conspicuous disease. HCPS-causing hantaviruses require animal biosafety level-4 (ABSL-4) containment, which substantially limits experimental research of interactions between the viruses and their reservoir hosts. Maporal virus (MAPV) is a South American hantavirus not known to cause disease in humans, thus it can be manipulated under ABSL-3 conditions. The aim of this study was to develop an ABSL-3 hantavirus infection model using the deer mouse ( Peromyscus maniculatus ), the natural reservoir host of Sin Nombre virus (SNV), and a virus that is pathogenic in another animal model to examine immune response of a reservoir host species. Deer mice were inoculated with MAPV, and viral RNA was detected in several organs of all deer mice during the 56 day experiment. Infected animals generated both nucleocapsid-specific and neutralizing antibodies. Histopathological lesions were minimal to mild with the peak of the lesions detected at 7-14 days postinfection, mainly in the lungs, heart, and liver. Low to modest levels of cytokine gene expression were detected in spleens and lungs of infected deer mice, and deer mouse primary pulmonary cells generated with endothelial cell growth factors were susceptible to MAPV with viral RNA accumulating in the cellular fraction compared to infected Vero cells. Most features resembled that of SNV infection of deer mice, suggesting this model may be an ABSL-3 surrogate for studying the host response of a New World hantavirus reservoir.

Lessons with Living Harvest Mice: An empirical study of their effects on intrinsic motivation and knowledge acquisition

NASA Astrophysics Data System (ADS)

Wilde, Matthias; Hußmann, Jona Samuel; Lorenzen, Simone; Meyer, Annika; Randler, Christoph

2012-12-01

The aim of this study was to evaluate the effects of living animals on pupils' intrinsic motivation and knowledge. Various studies from the late 1970s and 1980s stress the high effectiveness of authentic learning experiences in pupils' knowledge acquisition. However, there are only few current empirical studies on this topic. The research question of our study is to assess whether the use of living animals in the biology classroom supports intrinsic motivation and knowledge acquisition. In a pre-/post-test design, 185 fifth graders received two different treatments: the experimental group (N = 74) was taught with living harvest mice (Micromys minutus) and the control group (N = 111) received lessons with the same content which was presented in short film clips on laptop computers. Knowledge acquisition was assessed with open-ended and closed questions, while intrinsic motivation was tested with an adapted version of the Intrinsic Motivation Inventory (IMI). There were no differences in knowledge acquisition between the treatments. However, the results of the IMI showed significant differences in favour of the experimental group in interest/enjoyment, perceived competence, and perceived autonomy. Thus, living animals exert a positive influence on motivation.

Gene expression profiles of immune mediators and histopathological findings in animal models of leptospirosis: comparison between susceptible hamsters and resistant mice.

PubMed

Matsui, Mariko; Rouleau, Vincent; Bruyère-Ostells, Lilian; Goarant, Cyrille

2011-11-01

Leptospirosis is a widespread zoonosis characterized by multiple organ failure and variable host susceptibility toward pathogenic Leptospira strains. In this study, we put the role of inflammatory mediators in parallel with bacterial burdens and organ lesions by comparing a susceptible animal model, the hamster, and a resistant one, the Oncins France 1 (OF1) mouse, both infected with virulent Leptospira interrogans serovar Icterohaemorrhagiae strain Verdun. Histological observations evidenced edema, congestion, hemorrhage, and inflammatory infiltration in the organs of hamsters, in contrast to limited changes in mice. Using reverse transcription-quantitative PCR techniques, we showed that the relative Leptospira burden progressively increased in hamster tissues, while a rapid clearance was observed in mouse tissues. The early regulation of the proinflammatory mediators interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha, and cyclo-oxygenase-2 and the chemokines gamma interferon-inducible protein 10 kDa/CXCL10 and macrophage inflammatory protein-1α/CCL3 in mouse tissues contrasted with their delayed and massive overexpression in hamster tissues. Conversely, the induction of the anti-inflammatory cytokine IL-10 was faster in the resistant than in the susceptible animal model. The role of these cytokines in the pathophysiology of leptospirosis and the implications of their differential regulation in the development of this disease are discussed.

Radiation-induced hematopoietic myelosuppression and genotoxicity get significantly countered by active principles of Podophyllum hexandrum: A study in strain 'A' mice.

PubMed

Verma, Savita; Gupta, Manju Lata

2015-01-01

To investigate the protective role of a novel formulation, prepared by a combination of three active principles isolated from Podophyllum hexandrum (G-002M), against radiation- mediated hematopoietic suppression and cytogenetic aberrations in lethally irradiated mice. G-002M, a combination of podophyllotoxin, podophyllotoxin-β-D glucoside and rutin, was administered intramuscularly in mice (- 1 h) to radiation (9 Gy) exposure. The animals were autopsied at different time intervals for further studies. Loss of bone marrow progenitor cells, altered myeloid/erythroid ratio, serum erythropoietin and pancytopenia in irradiated mice was found significantly (p < 0.001) ameliorated in G-002M pre-administered mice within 30 d. Bcl-2 (B-cell lymphoma 2) and BAX (Bcl-2-associated X) protein expression was also positively (p < 0.001) countered in these mice. Chromosomal aberrations in 30 d were found remarkably (p < 0.001) reduced in marrow of G-002M pretreated mice. Accelerated antioxidants, reduced DNA damage, stimulated lymphocyte proliferation and minimal cellular atrophy in spleen were some of the other key features observed in G-002M administered mice. Reduction in hematopoietic aplasia and chromosomal aberrations, besides, early recovery in bone marrow and spleen of G-002M pretreated mice, could be attributed to its free radical scavenging, DNA protecting and apoptotic proteins modulating ability against radiation.

Measuring normal and pathological anxiety-like behaviour in mice: a review.

PubMed

Belzung, C; Griebel, G

2001-11-01

Measuring anxiety-like behaviour in mice has been mostly undertaken using a few classical animal models of anxiety such as the elevated plus-maze, the light/dark choice or the open-field tests. All these procedures are based upon the exposure of subjects to unfamiliar aversive places. Anxiety can also be elicited by a range of threats such as predator exposure. Furthermore, the concepts of "state" and "trait" anxiety have been proposed to differentiate anxiety that the subject experiences at a particular moment of time and that is increased by the presence of an anxiogenic stimulus, and anxiety that does not vary from moment to moment and is considered to be an "enduring feature of an individual". Thus, when assessing the behaviour of mice, it is necessary to increase the range of behavioural paradigms used, including animal models of "state" and "trait" anxiety. In the last few years, many mice with targeted mutations have been generated. Among them some have been proposed as animal models of pathological anxiety, since they display high level of anxiety-related behaviours in classical tests. However, it is important to emphasise that such mice are animal models of a single gene dysfunction, rather than models of anxiety, per se. Inbred strains of mice, such as the BALB/c line, which exhibits spontaneously elevated anxiety appear to be a more suitable model of pathological anxiety.

Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice.

PubMed

Oliveira, Wilma Helena; Nunes, Ana Karolina; França, Maria Eduarda Rocha; Santos, Laise Aline; Lós, Deniele Bezerra; Rocha, Sura Wanessa; Barbosa, Karla Patrícia; Rodrigues, Gabriel Barros; Peixoto, Christina Alves

2016-08-01

The aim of the present study was to analyze the action of metformin on short-term memory, glial cell activation and neuroinflammation caused by experimental diabetic encephalopathy in C57BL/6 mice. Diabetes was induced by the intraperitoneal injection of a dose of 90mg/kg of streptozotocin on two successive days. Mice with blood glucose levels ≥200dl/ml were considered diabetic and were given metformin hydrochloride at doses of 100mg/kg and 200mg/kg (by gavage, twice daily) for 21 days. On the final day of treatment, the mice underwent a T-maze test. On the 22nd day of treatment all the animals were anesthetized and euthanized. Diabetic animals treated with metformin had a higher spatial memory score. The hippocampus of the diabetic animals presented reactive gliosis, neuronal loss, NF-kB signaling activation, and high levels of IL-1 and VEGF. In addition, the T-maze test scores of these animals were low. Treatment with metformin reduced the expression of GFAP, Iba-1 (astrocyte and microglial markers) and the inflammation markers (p-IKB, IL-1 and VEGF), while enhancing p-AMPK and eNOS levels and increasing neuronal survival (Fox-1 and NeuN). Treatment with metformin also improved the spatial memory scores of diabetic animals. In conclusion, the present study showed that metformin can significantly reduce neuroinflammation and can decrease the loss of neurons in the hippocampus of diabetic animals, which can subsequently promote improvements in spatial memory. Copyright © 2016 Elsevier B.V. All rights reserved.

H2S induces a suspended animation-like state in mice.

PubMed

Blackstone, Eric; Morrison, Mike; Roth, Mark B

2005-04-22

Mammals normally maintain their core body temperature (CBT) despite changes in environmental temperature. Exceptions to this norm include suspended animation-like states such as hibernation, torpor, and estivation. These states are all characterized by marked decreases in metabolic rate, followed by a loss of homeothermic control in which the animal's CBT approaches that of the environment. We report that hydrogen sulfide can induce a suspended animation-like state in a nonhibernating species, the house mouse (Mus musculus). This state is readily reversible and does not appear to harm the animal. This suggests the possibility of inducing suspended animation-like states for medical applications.

Environmental enrichment improves novel object recognition and enhances agonistic behavior in male mice.

PubMed

Mesa-Gresa, Patricia; Pérez-Martinez, Asunción; Redolat, Rosa

2013-01-01

Environmental enrichment (EE) is an experimental paradigm in which rodents are housed in complex environments containing objects that provide stimulation, the effects of which are expected to improve the welfare of these subjects. EE has been shown to considerably improve learning and memory in rodents. However, knowledge about the effects of EE on social interaction is generally limited and rather controversial. Thus, our aim was to evaluate both novel object recognition and agonistic behavior in NMRI mice receiving EE, hypothesizing enhanced cognition and slightly enhanced agonistic interaction upon EE rearing. During a 4-week period half the mice (n = 16) were exposed to EE and the other half (n = 16) remained in a standard environment (SE). On PND 56-57, animals performed the object recognition test, in which recognition memory was measured using a discrimination index. The social interaction test consisted of an encounter between an experimental animal and a standard opponent. Results indicated that EE mice explored the new object for longer periods than SE animals (P < .05). During social encounters, EE mice devoted more time to sociability and agonistic behavior (P < .05) than their non-EE counterparts. In conclusion, EE has been shown to improve object recognition and increase agonistic behavior in adolescent/early adulthood mice. In the future we intend to extend this study on a longitudinal basis in order to assess in more depth the effect of EE and the consistency of the above-mentioned observations in NMRI mice. Copyright © 2013 Wiley Periodicals, Inc.

Papaver Rhoeas L. Hydroalcoholic Extract Exacerbates Forced Swimming Test-Induced Depression in Mice.

PubMed

Osanloo, Naser; Najafi-Abedi, Akram; Jafari, Fatemeh; Javid, Farshid; Pirpiran, Mohsen; Memar Jafari, Mohammad-Reza; Mousavi Khosravi, Seyed Ali; Rahimzadeh Behzadi, Mohammad; Ranjbaran, Mina; Sahraei, Hedayat

2016-07-01

Depression is one of the most frequent psychiatric disorders in the world with occurs with higher incidence in women. In the present study, the effect of water-alcoholic extract of Papaver rhoeas L. on forced swimming test (FST) in Swiss-Webster mice were examined. We used Swiss-Webster mice (20-25 g) to execute FST on them. The plant extract (1, 10, 30, and 100 mg/kg) was injected to the animals 30 minutes before each session. Fluoxetine (20 mg/kg) was used as standard antidepressant drug. In another group of animals, 30 minutes after extract administration, blood samples were taken from retro-orbital sinus for corticosterone assay. Yet in third group, the drugs were injected to the animals and 30 minutes later, their activities were tested in an open field apparatus. Our experiments showed that the extract efficiently reduced FST time both in male and female mice dose-dependently. This effect was comparable with fluoxetine. In addition, corticosterone assay indicated that plasma corticosterone in animals which received extract was higher than those amounts in fluoxetine and saline controls. Moreover, the animals did not show any motor activity deficit in all doses of the extract and fluoxetine compared to saline control. The extract of Papaver rhoeas can reduce immobility time which is comparable to the effect of fluoxetine. Also the effect of the extract is contrary to its effects on plasma corticosterone level and or animals' activity.

Animal Models of Hemophilia and Related Bleeding Disorders

PubMed Central

Lozier, Jay N.; Nichols, Timothy C.

2013-01-01

Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

Association of Diet With Skin Histological Features in UV-B–Exposed Mice

PubMed Central

Hsia, Yvonne; Weeks, David M.; Dixon, Tatiana K.; Lepe, Jessica; Thomas, J. Regan

2017-01-01

Importance Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging. Objectives To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation. Design, Setting, and Participants In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control (C) with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016. Main Outcomes and Measures Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted. Results Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie

Neuropeptide Y-Y2 receptor knockout mice: influence of genetic background on anxiety-related behaviors.

PubMed

Zambello, E; Zanetti, L; Hédou, G F; Angelici, O; Arban, R; Tasan, R O; Sperk, G; Caberlotto, L

2011-03-10

Neuropeptide Y (NPY) has been extensively studied in relation to anxiety and depression but of the seven NPY receptors known to date, it is not yet clear which one is mainly involved in mediating its effects in emotional behavior. Mice lacking the NPY-Y2 receptors were previously shown to be less anxious due to their improved ability to cope with stressful situations. In the present study, the behavioral phenotype including the response to challenges was analyzed in NPY-Y2 knockout (KO) mice backcrossed in to congenic C57BL/6 background. In the elevated plus-maze (EPM) and the forced swim test (FST), the anxiolytic-like or antidepressant-like phenotype of the NPY-Y2 KO mice could not be confirmed, although this study differs from the previous one only with regard to the genetic background of the mice. In addition, no differences in response to acute stress or to the antidepressant desipramine in the FST were detected between wild type (WT) and NPY-Y2 KO animals. These results suggest that the genetic background of the animals appears to have a strong influence on the behavioral phenotype of NPY-Y2 KO mice. Additionally, to further characterize the animals by their biochemical response to a challenge, the neurochemical changes induced by the anxiogenic compound yohimbine were measured in the medial prefrontal cortex (mPFC) of NPY-Y2 KO and compared to WT mice. Dopamine (DA) levels were significantly increased by yohimbine in the WT but unaffected in the KO mice, suggesting that NPY-Y2 receptor exerts a direct control over both the tonic and phasic release of DA and that, although the anxiety-like behavior of these NPY-Y2 KO mice is unaltered, there are clear modifications of DA dynamics. However, yohimbine led to a significant increase in noradrenaline (NA) concentration and a slight reduction in serotonin concentration that were identical for both phenotypes. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma.

PubMed

Liu, Hen-Yu; Huang, Chiung-Fang; Lin, Tzu-Chieh; Tsai, Ching-Yu; Tina Chen, Szu-Yu; Liu, Alice; Chen, Wei-Hong; Wei, Hong-Jian; Wang, Ming-Fu; Williams, David F; Deng, Win-Ping

2014-12-01

Aging is related to loss of functional stem cell accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging. We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice. The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Public perceptions of animal experimentation across Europe.

PubMed

von Roten, Fabienne Crettaz

2013-08-01

The goal of this article is to map out public perceptions of animal experimentation in 28 European countries. Postulating cross-cultural differences, this study mixes country-level variables (from the Eurostat database) and individual-level variables (from Eurobarometer Science and Technology 2010). It is shown that experimentation on animals such as mice is generally accepted in European countries, but perceptions are divided on dogs and monkeys. Between 2005 and 2010, we observe globally a change of approval on dogs and monkeys, with a significant decrease in nine countries. Multilevel analysis results show differences at country level (related to a post-industrialism model) and at individual level (related to gender, age, education, proximity and perceptions of science and the environment). These results may have consequences for public perceptions of science and we call for more cross-cultural research on press coverage of animal research and on the level of public engagement of scientists doing animal research.

Systemic study on the safety of immuno-deficient nude mice treated by atmospheric plasma-activated water

NASA Astrophysics Data System (ADS)

Dehui, XU; Qingjie, CUI; Yujing, XU; Bingchuan, WANG; Miao, TIAN; Qiaosong, LI; Zhijie, LIU; Dingxin, LIU; Hailan, CHEN; Michael, G. KONG

2018-04-01

Cold atmospheric-pressure plasma is a new technology, widely used in many fields of biomedicine, especially in cancer treatment. Cold plasma can selectively kill a variety of tumor cells, and its biological safety in clinical trials is also very important. In many cases, the patient’s immune level is relatively low, so we first studied the safety assessment of plasma treatment in an immuno-compromised animal model. In this study, we examined the safety of immuno-deficient nude mice by oral lavage treatment of plasma-activated water, and studied the growth status, main organs and blood biochemical indexes. Acute toxicity test results showed that the maximum dose of plasma treatment for 15 min had no lethal effect and other acute toxicity. There were no significant changes in body weight and survival status of mice after 2 min and 4 min of plasma-activated water (PAW) treatment for 2 weeks. After treatment, the major organs, including heart, liver, spleen, lung and kidney, were not significantly changed in organ coefficient and tissue structure. Blood biochemical markers showed that blood neutrophils and mononuclear cells were slightly increased, and the others remained unchanged. Liver function, renal function, electrolytes, glucose metabolism and lipid metabolism were not affected by different doses of PAW treatment. The above results indicate that PAW treatment can be used to treat immuno-deficient nude mice without significant safety problems.

Effects of natural enrichment materials on stress, memory and exploratory behavior in mice.

PubMed

Acklin, Casey J; Gault, Ruth A

2015-07-01

Environmental enrichment is an essential component of laboratory animal housing that allows animals to engage in natural behaviors in an otherwise artificial setting. Previous research by the authors suggested that, compared with synthetic enrichment materials, natural materials were associated with lower stress levels in mice. Here, the authors compare the effects of different enrichment materials on stress, memory and exploratory behavior in Swiss Webster mice. Mice that were provided with natural enrichment materials had lower stress levels, better memory and greater exploratory behavior than did mice provided with synthetic enrichment materials or with no enrichment materials. These findings suggest that provision of natural enrichment materials can improve well-being of laboratory mice.

The growth of glioblastoma orthotopic xenografts in nude mice is directly correlated with impaired object recognition memory.

PubMed

Wasilewska-Sampaio, Ana Paula; Santos, Tiago G; Lopes, Marilene Hohmuth; Cammarota, Martin; Martins, Vilma Regina

2014-01-17

Cognitive dysfunction is found in patients with brain tumors and there is a need to determine whether it can be replicated in an experimental model. In the present study, the object recognition (OR) paradigm was used to investigate cognitive performance in nude mice, which represent one of the most important animal models available to study human tumors in vivo. Mice with orthotopic xenografts of the human U87MG glioblastoma cell line were trained at 9, 14, and 18days (D9, D14, and D18, respectively) after implantation of 5×10(5) cells. At D9, the mice showed normal behavior when tested 90min or 24h after training and compared to control nude mice. Animals at D14 were still able to discriminate between familiar and novel objects, but exhibited a lower performance than animals at D9. Total impairment in the OR memory was observed when animals were evaluated on D18. These alterations were detected earlier than any other clinical symptoms, which were observed only 22-24days after tumor implantation. There was a significant correlation between the discrimination index (d2) and time after tumor implantation as well as between d2 and tumor volume. These data indicate that the OR task is a robust test to identify early behavior alterations caused by glioblastoma in nude mice. In addition, these results suggest that OR task can be a reliable tool to test the efficacy of new therapies against these tumors. © 2013 Elsevier Inc. All rights reserved.

Alterations in bladder function associated with urothelial defects in uroplakin II and IIIa knockout mice.

PubMed

Aboushwareb, Tamer; Zhou, Ge; Deng, Fang-Ming; Turner, Chanda; Andersson, Karl-Erik; Tar, Moses; Zhao, Weixin; Melman, Arnold; D'Agostino, Ralph; Sun, Tung-Tien; Christ, George J

2009-01-01

The effects of deleting genes encoding uroplakins II (UPII) and III (UPIIIa) on mouse bladder physiology/dysfunction were studied in male and female wild type and knockout (KO) mice. UPII, UPIIIa, and WT mice were catheterized using previously described techniques. Continuous cystometry was conducted in conscious, freely moving animals. Bladder strips were harvested after animal sacrifice and pharmacological studies and EFS were conducted in an organ chamber. Histological studies were also carried on with H&E staining to identify differences among the three mouse types. These studies have revealed numerous alterations, some of which were apparently gender-specific. Nonvoiding contractions were common in both UPII and UPIIIa KO mice, although more severe in the former. In particular, the increased bladder capacity, micturition pressure and demonstrable nonvoiding contractions observed in the male UPII KO's, were reminiscent of an obstruction-like syndrome accompanied by evidence of emerging bladder decompensation, as reflected by an increased residual volume. Pharmacological studies revealed a modest, gender-specific reduction in sensitivity of isolated detrusor strips from UPII KO female mice to carbachol-induced contractions. A similar reduction was observed in UPIIIa KO female mice. Histological investigation showed urothelial hyperplasia in both UPII KO and UPIIIa KO mice, although again, apparently more severe in the former. These results confirm and extend previous work to indicate that urothelial defects due to uroplakin deficiency are associated with significant alterations in bladder function and further highlight the importance of the urothelium to bladder physiology/dysfunction.

To enrich or not to enrich: providing shelter does not complicate handling of laboratory mice.

PubMed

Moons, Christel P H; Van Wiele, Peggy; Odberg, Frank O

2004-07-01

Environmental enrichment (EE) is used in laboratory animal housing to provide stimuli exceeding those of barren cages and is intended to improve the welfare of captive animals. It is argued that when laboratory mice can routinely retreat in sheltering objects when humans are present, they do not habituate to humans and continue to shy away, thereby increasing the time needed for husbandry and testing procedures. To this date very limited research has been carried out to determine whether providing EE in the form of shelter interferes with the habituation of mice to humans and thus complicates catching and handling them. We housed 20 FVB (inbred) and 20 NMRI (outbred) male mice in standard cages and another 20 FVB and 20 NMRI male mice in cages enriched with two PVC conduits. When the mice were 10 weeks old, measurements of food and water consumption, weight, latency of catching, and a behavior score in response to handling during a sham subcutaneous injection were performed weekly for 4 consecutive weeks. Food and water consumption and weight were influenced by strain, but the presence of EE in the home cage did not affect these parameters as much. Outbred mice ate, drank, and weighed more than did the inbred animals, but they did not significantly gain weight during the course of the 4 testing weeks. Cage enrichment in the form of PVC conduits decreased the time needed to catch outbred animals and did not increase the time needed to catch mice from the inbred strain. Furthermore, no differences in resistance to being held during the sham injection could be detected between animals from the enriched versus non-enriched group. These results indicate that EE in the form of sheltering objects does not complicate catching or handling mice and that allowing access to enrichment in the laboratory cage, which has been shown to have positive effects on welfare, does not interfere with the management or cost of laboratory animals. Copyright 2004 American Association for

Novel transcranial magnetic stimulation coil for mice

NASA Astrophysics Data System (ADS)

March, Stephen; Stark, Spencer; Crowther, Lawrence; Hadimani, Ravi; Jiles, David

2014-03-01

Transcranial magnetic stimulation (TMS) shows potential for non-invasive treatment of various neurological disorders. Significant work has been performed on the design of coils used for TMS on human subjects but few reports have been made on the design of coils for use on the brains of animals such as mice. This work is needed as TMS studies utilizing mice can allow rapid preclinical development of TMS for human disorders but the coil designs developed for use on humans are inadequate for optimal stimulation of the much smaller mouse brain. A novel TMS coil has been developed with the goal of inducing strong and focused electric fields for the stimulation of small animals such as mice. Calculations of induced electric fields were performed utilizing an MRI derived inhomogeneous model of an adult male mouse. Mechanical and thermal analysis of this new TMS helmet-coil design have also been performed at anticipated TMS operating conditions to ensure mechanical stability of the new coil and establish expected linear attraction and rotational force values. Calculated temperature increases for typical stimulation periods indicate the helmet-coil system is capable of operating within established medical standards. A prototype of the coil has been fabricated and characterization results are presented.

Acute toxicity of karlotoxins to mice

PubMed Central

Place, Allen R.; Munday, R.; Munday, J.S.

2015-01-01

Karlotoxins, polyketide derivatives produced by the dinoflagellate Karlodinium veneficum, are associated with fish kills in temperate estuaries world wide. In this study, the acute effects of 3 pure karlotoxin analogs (KmTx 1, KmTx 3 and KmTx 2) have been examined in mice. Transient lethargy and increased respiratory rates were observed soon after dosing with the karlotoxins by intraperitoneal injection, but no deaths were recorded in animals dosed with KmTx 2 at up to 500 μg/kg or with KmTx 1 or KmTx 3 at up to 4000 μg/kg. Animals dosed intraperitoneally with KmTx 1 and KmTx 3 at 4000 μg/kg showed a pronounced decrease in food and water intake, lasting 3–4 days after dosing, accompanied by a significant decrease in body weight. After this time, the lost body weight was regained and the behavior and appearance of the mice remained normal throughout the following 10 day observation period. No effects were seen in mice dosed orally with KmTx 1 or KmTx 3 at a dose of 4000 μg/kg. It is concluded that contamination of seafood if it were to occur with these karlotoxins is unlikely to pose a major risk of acute intoxication in consumers. PMID:25150200

Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice.

PubMed

Gröticke, Ina; Hoffmann, Katrin; Löscher, Wolfgang

2007-10-01

Psychiatric disorders frequently occur in patients with epilepsy, but the relationship between epilepsy and psychopathology is poorly understood. Frequent comorbidities in epilepsy patients comprise major depression, anxiety disorders, psychosis and cognitive dysfunction. Animal models of epilepsy, such as the pilocarpine model of acquired epilepsy, are useful to study the relationship between epilepsy and behavioral dysfunctions. However, despite the advantages of mice in studying the genetic underpinning of behavioral alterations in epilepsy, mice have only rarely been used to characterize behavioral correlates of epilepsy. This prompted us to study the behavioral and cognitive alterations developing in NMRI mice in the pilocarpine model of epilepsy, using an anxiety test battery as well as tests for depression, drug-induced psychosis, spatial memory, and motor functions. In order to ensure the occurrence of status epilepticus (SE) and decrease mortality, individual dosing of pilocarpine was performed by ramping up the dose until onset of SE. This protocol was used for studying the consequences of SE, i.e. hippocampal damage, incidence of epilepsy with spontaneous recurrent seizures, and behavioral alterations. SE was terminated by diazepam after either 60, 90 or 120 min. All mice that survived SE developed epilepsy, but the severity of hippocampal damage varied depending on SE length. In all anxiety tests, except the elevated plus maze test, epileptic mice exhibited significant increases of anxiety-related behavior. Surprisingly, a decrease in depression-like behavior was observed in the forced swimming and tail suspension tests. Furthermore, epileptic mice were less sensitive than controls to most of the behavioral effects induced by MK-801 (dizocilpine). Learning and memory were impaired in epileptic mice irrespective of SE duration. Thus, the pilocarpine-treated mice seem to reflect several of the behavioral and cognitive disturbances that are associated with

Automated measurement of pulmonary emphysema and small airway remodeling in cigarette smoke-exposed mice.

PubMed

Laucho-Contreras, Maria E; Taylor, Katherine L; Mahadeva, Ravi; Boukedes, Steve S; Owen, Caroline A

2015-01-16

COPD is projected to be the third most common cause of mortality world-wide by 2020((1)). Animal models of COPD are used to identify molecules that contribute to the disease process and to test the efficacy of novel therapies for COPD. Researchers use a number of models of COPD employing different species including rodents, guinea-pigs, rabbits, and dogs((2)). However, the most widely-used model is that in which mice are exposed to cigarette smoke. Mice are an especially useful species in which to model COPD because their genome can readily be manipulated to generate animals that are either deficient in, or over-express individual proteins. Studies of gene-targeted mice that have been exposed to cigarette smoke have provided valuable information about the contributions of individual molecules to different lung pathologies in COPD((3-5)). Most studies have focused on pathways involved in emphysema development which contributes to the airflow obstruction that is characteristic of COPD. However, small airway fibrosis also contributes significantly to airflow obstruction in human COPD patients((6)), but much less is known about the pathogenesis of this lesion in smoke-exposed animals. To address this knowledge gap, this protocol quantifies both emphysema development and small airway fibrosis in smoke-exposed mice. This protocol exposes mice to CS using a whole-body exposure technique, then measures respiratory mechanics in the mice, inflates the lungs of mice to a standard pressure, and fixes the lungs in formalin. The researcher then stains the lung sections with either Gill's stain to measure the mean alveolar chord length (as a readout of emphysema severity) or Masson's trichrome stain to measure deposition of extracellular matrix (ECM) proteins around small airways (as a readout of small airway fibrosis). Studies of the effects of molecular pathways on both of these lung pathologies will lead to a better understanding of the pathogenesis of COPD.