WorldWideScience

Sample records for rodent model systems

  1. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology.

    Directory of Open Access Journals (Sweden)

    Wen Liang

    Full Text Available The recently developed histological scoring system for non-alcoholic fatty liver disease (NAFLD by the NASH Clinical Research Network (NASH-CRN has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models. Based upon the features pertaining to mouse NAFLD, we aimed at establishing a modified generic scoring system that is applicable to broad spectrum of rodent models.The histopathology of NAFLD was analyzed in several different mouse models of NAFLD to define generic criteria for histological assessment (preclinical scoring system. For validation of this scoring system, 36 slides of mouse livers, covering the whole spectrum of NAFLD, were blindly analyzed by ten observers. Additionally, the livers were blindly scored by one observer during two separate assessments longer than 3 months apart.The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC = 0.784 and 0.776, all p<0.001, respectively and moderate for the analysis of hypertrophy and inflammation (ICC = 0.685 and 0.650, all p<0.001, respectively. The intra-observer reproducibility between the different observations of one observer was high for the analysis of macrovesicular steatosis, microvesicular steatosis and hypertrophy (ICC = 0.871, 0.871 and 0.896, all p<0.001, respectively and very high for the analysis of inflammation (ICC = 0.931, p

  2. Virtual reality systems for rodents.

    Science.gov (United States)

    Thurley, Kay; Ayaz, Aslı

    2017-02-01

    Over the last decade virtual reality (VR) setups for rodents have been developed and utilized to investigate the neural foundations of behavior. Such VR systems became very popular since they allow the use of state-of-the-art techniques to measure neural activity in behaving rodents that cannot be easily used with classical behavior setups. Here, we provide an overview of rodent VR technologies and review recent results from related research. We discuss commonalities and differences as well as merits and issues of different approaches. A special focus is given to experimental (behavioral) paradigms in use. Finally we comment on possible use cases that may further exploit the potential of VR in rodent research and hence inspire future studies.

  3. Swim stress exaggerates the hyperactive mesocortical dopamine system in a rodent model of autism.

    Science.gov (United States)

    Nakasato, Akane; Nakatani, Yasushi; Seki, Yoshinari; Tsujino, Naohisa; Umino, Masahiro; Arita, Hideho

    2008-02-08

    Several clinical reports have suggested that there is a hyperactivation of the dopaminergic system in people with autism. Using rats exposed prenatally to valproic acid (VPA) as an animal model of autism, we measured dopamine (DA) levels in samples collected from the frontal cortex (FC) using in vivo microdialysis and HPLC. The basal DA level in FC was significantly higher in VPA-exposed rats relative to controls. Since the mesocortical DA system is known to be sensitive to physical and psychological stressors, we measured DA levels in FC before, during, and after a 60-min forced swim test (FST). There were further gradual increases in FC DA levels during the FST in the VPA-exposed rats, but not in the control rats. Behavioral analysis during the last 10 min of the FST revealed a significant decrease in active, escape-oriented behavior and an increase in immobility, which is thought to reflect the development of depressive behavior that disengages the animal from active forms of coping with stressful stimuli. These results suggest that this rodent model of autism exhibits a hyperactive mesocortical DA system, which is exaggerated by swim stress. This abnormality may be responsible for depressive and withdrawal behavior observed in autism.

  4. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology

    NARCIS (Netherlands)

    Liang, W.; Menke, A.L.; Driessen, A.; Koek, G.H.; Lindeman, J.H.; Stoop, R.; Havekes, L.M.; Kleemann., R.; Hoek, A.M. van den

    2014-01-01

    Results: The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient) between the ten observers was high

  5. Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

    Directory of Open Access Journals (Sweden)

    Kathryn M. Buller

    2012-01-01

    Full Text Available Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

  6. Systems biology integration of proteomic data in rodent models of depression reveals involvement of the immune response and glutamatergic signaling.

    Science.gov (United States)

    Carboni, Lucia; Nguyen, Thanh-Phuong; Caberlotto, Laura

    2016-12-01

    The pathophysiological basis of major depression is incompletely understood. Recently, numerous proteomic studies have been performed in rodent models of depression to investigate the molecular underpinnings of depressive-like behaviours with an unbiased approach. The objective of the study is to integrate the results of these proteomic studies in depression models to shed light on the most relevant molecular pathways involved in the disease. Network analysis is performed integrating preexisting proteomic data from rodent models of depression. The IntAct mouse and the HRPD are used as reference protein-protein interaction databases. The functionality analyses of the networks are then performed by testing overrepresented GO biological process terms and pathways. Functional enrichment analyses of the networks revealed an association with molecular processes related to depression in humans, such as those involved in the immune response. Pathways impacted by clinically effective antidepressants are modulated, including glutamatergic signaling and neurotrophic responses. Moreover, dysregulations of proteins regulating energy metabolism and circadian rhythms are implicated. The comparison with protein pathways modulated in depressive patients revealed significant overlapping. This systems biology study supports the notion that animal models can contribute to the research into the biology and therapeutics of depression. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Rodent Models for Metabolic Syndrome Research

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    Sunil K. Panchal

    2011-01-01

    Full Text Available Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet-induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat-fed male rodent.

  8. Identification of early indicators of altered metabolism in normal development using a rodent model system

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    Ashok Daniel Prabakaran

    2018-03-01

    Full Text Available Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as a model to link this with later adult disease. Because embryonic size variation also occurs under normal growth and differentiation, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important. The birth weight of rat pups vary according to the uterine horn positions. Using birth weight as a marker, we compared two groups of rat pups – lower birth weight (LBW, 5th to 25th percentile and average birth weight (ABW, 50th to 75th percentile – using morphological, biochemical and molecular biology, and genetic techniques. Our results show that insulin metabolism, Pi3k/Akt and Pparγ signaling and the genes regulating growth and metabolism are significantly different in these groups. Methylation at the promoter of the InsII (Ins2 gene and DNA methyltransferase 1 in LBW pups are both increased. Additionally, the Dnmt1 repressor complex, which includes Hdac1, Rb (Rb1 and E2f1, was also upregulated in LBW pups. We conclude that the Dnmt1 repressor complex, which regulates the restriction point of the cell cycle, retards the rate at which cells traverse the G1 or G0 phase of the cell cycle in LBW pups, thereby slowing down growth. This regulatory mechanism mediated by Dnmt1 might contribute to the production of small-size pups and altered physiology and pathology in adult life.

  9. A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPD.

    Science.gov (United States)

    Davidsen, Peter K; Herbert, John M; Antczak, Philipp; Clarke, Kim; Ferrer, Elisabet; Peinado, Victor I; Gonzalez, Constancio; Roca, Josep; Egginton, Stuart; Barberá, Joan A; Falciani, Francesco

    2014-01-01

    A relatively large percentage of patients with chronic obstructive pulmonary disease (COPD) develop systemic co-morbidities that affect prognosis, among which muscle wasting is particularly debilitating. Despite significant research effort, the pathophysiology of this important extrapulmonary manifestation is still unclear. A key question that remains unanswered is to what extent systemic inflammatory mediators might play a role in this pathology. Cigarette smoke (CS) is the main risk factor for developing COPD and therefore animal models chronically exposed to CS have been proposed for mechanistic studies and biomarker discovery. Although mice have been successfully used as a pre-clinical in vivo model to study the pulmonary effects of acute and chronic CS exposure, data suggest that they may be inadequate models for studying the effects of CS on peripheral muscle function. In contrast, recent findings indicate that the guinea pig model (Cavia porcellus) may better mimic muscle wasting. We have used a systems biology approach to compare the transcriptional profile of hindlimb skeletal muscles from a Guinea pig rodent model exposed to CS and/or chronic hypoxia to COPD patients with muscle wasting. We show that guinea pigs exposed to long-term CS accurately reflect most of the transcriptional changes observed in dysfunctional limb muscle of severe COPD patients when compared to matched controls. Using network inference, we could then show that the expression profile in whole lung of genes encoding for soluble inflammatory mediators is informative of the molecular state of skeletal muscles in the guinea pig smoking model. Finally, we show that CXCL10 and CXCL9, two of the candidate systemic cytokines identified using this pre-clinical model, are indeed detected at significantly higher levels in serum of COPD patients, and that their serum protein level is inversely correlated with the expression of aerobic energy metabolism genes in skeletal muscle. We conclude that

  10. Evaluation of molecular brain changes associated with environmental stress in rodent models compared to human major depressive disorder: A proteomic systems approach.

    Science.gov (United States)

    Cox, David Alan; Gottschalk, Michael Gerd; Stelzhammer, Viktoria; Wesseling, Hendrik; Cooper, Jason David; Bahn, Sabine

    2016-11-25

    Rodent models of major depressive disorder (MDD) are indispensable when screening for novel treatments, but assessing their translational relevance with human brain pathology has proved difficult. Using a novel systems approach, proteomics data obtained from post-mortem MDD anterior prefrontal cortex tissue (n = 12) and matched controls (n = 23) were compared with equivalent data from three commonly used preclinical models exposed to environmental stressors (chronic mild stress, prenatal stress and social defeat). Functional pathophysiological features associated with depression-like behaviour were identified in these models through enrichment of protein-protein interaction networks. A cross-species comparison evaluated which model(s) represent human MDD pathology most closely. Seven functional domains associated with MDD and represented across at least two models such as "carbohydrate metabolism and cellular respiration" were identified. Through statistical evaluation using kernel-based machine learning techniques, the social defeat model was found to represent MDD brain changes most closely for four of the seven domains. This is the first study to apply a method for directly evaluating the relevance of the molecular pathology of multiple animal models to human MDD on the functional level. The methodology and findings outlined here could help to overcome translational obstacles of preclinical psychiatric research.

  11. A Mathematical Model of the Olfactory Bulb for the Selective Adaptation Mechanism in the Rodent Olfactory System.

    Science.gov (United States)

    Soh, Zu; Nishikawa, Shinya; Kurita, Yuichi; Takiguchi, Noboru; Tsuji, Toshio

    2016-01-01

    To predict the odor quality of an odorant mixture, the interaction between odorants must be taken into account. Previously, an experiment in which mice discriminated between odorant mixtures identified a selective adaptation mechanism in the olfactory system. This paper proposes an olfactory model for odorant mixtures that can account for selective adaptation in terms of neural activity. The proposed model uses the spatial activity pattern of the mitral layer obtained from model simulations to predict the perceptual similarity between odors. Measured glomerular activity patterns are used as input to the model. The neural interaction between mitral cells and granular cells is then simulated, and a dissimilarity index between odors is defined using the activity patterns of the mitral layer. An odor set composed of three odorants is used to test the ability of the model. Simulations are performed based on the odor discrimination experiment on mice. As a result, we observe that part of the neural activity in the glomerular layer is enhanced in the mitral layer, whereas another part is suppressed. We find that the dissimilarity index strongly correlates with the odor discrimination rate of mice: r = 0.88 (p = 0.019). We conclude that our model has the ability to predict the perceptual similarity of odorant mixtures. In addition, the model also accounts for selective adaptation via the odor discrimination rate, and the enhancement and inhibition in the mitral layer may be related to this selective adaptation.

  12. Protective effects of systemic treatment with methylprednisolone in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION).

    Science.gov (United States)

    Huang, Tzu-Lun; Huang, Shun-Ping; Chang, Chung-Hsing; Lin, Kung-Hung; Chang, Shu-Wen; Tsai, Rong-Kung

    2015-02-01

    This study investigated the protective effects of the administration of steroids on optic nerves (ON) and retinal ganglion cells (RGCs) in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION). We induced rAION using rose bengal and argon laser irradiation in a photodynamic procedure on the optic discs of rats. The treated groups received methylprednisolone (MP) via peritoneal injection for 2 weeks. The control group received intraperitoneal injections of phosphate-buffered saline (PBS) post-rAION. At the 4th week post-infarct, MP treatments significantly rescued the RGCs (mm(2)) in the central retinas (1920 ± 210, p < 0.001) and mid-peripheral retinas (950 ± 240, respectively, p = 0.018) compared with those of the PBS-treated rats (central: 900 ± 210 and mid-peripheral: 440 ± 180). Functional assessment with flash visual-evoked potentials demonstrated that P1 latency (ms) was shortened in the MP group compared to the PBS group (108 ± 14 and 147 ± 9, respectively, p < 0.001). In addition, the P1 amplitude (uV) was enhanced in the MP group compared to the PBS group (55 ± 12 and 41 ± 13, respectively, p < 0.05). TUNEL assays showed a decrease in the number of apoptotic cells in the RGC layers of MP-treated retinas compared to the PBS-treated group (p < 0.05). ED1 positive cells (/HPF) were significantly decreased in the ONs of the MP group compared to the PBS group (p < 0.001). In conclusion, systemic administration of MP had neuroprotective effects on RGC survival and ON function in the rAION animal model. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Translational Rodent Models for Research on Parasitic Protozoa-A Review of Confounders and Possibilities.

    Science.gov (United States)

    Ehret, Totta; Torelli, Francesca; Klotz, Christian; Pedersen, Amy B; Seeber, Frank

    2017-01-01

    Rodents, in particular Mus musculus , have a long and invaluable history as models for human diseases in biomedical research, although their translational value has been challenged in a number of cases. We provide some examples in which rodents have been suboptimal as models for human biology and discuss confounders which influence experiments and may explain some of the misleading results. Infections of rodents with protozoan parasites are no exception in requiring close consideration upon model choice. We focus on the significant differences between inbred, outbred and wild animals, and the importance of factors such as microbiota, which are gaining attention as crucial variables in infection experiments. Frequently, mouse or rat models are chosen for convenience, e.g., availability in the institution rather than on an unbiased evaluation of whether they provide the answer to a given question. Apart from a general discussion on translational success or failure, we provide examples where infections with single-celled parasites in a chosen lab rodent gave contradictory or misleading results, and when possible discuss the reason for this. We present emerging alternatives to traditional rodent models, such as humanized mice and organoid primary cell cultures. So-called recombinant inbred strains such as the Collaborative Cross collection are also a potential solution for certain challenges. In addition, we emphasize the advantages of using wild rodents for certain immunological, ecological, and/or behavioral questions. The experimental challenges (e.g., availability of species-specific reagents) that come with the use of such non-model systems are also discussed. Our intention is to foster critical judgment of both traditional and newly available translational rodent models for research on parasitic protozoa that can complement the existing mouse and rat models.

  14. Translational Rodent Models for Research on Parasitic Protozoa—A Review of Confounders and Possibilities

    Directory of Open Access Journals (Sweden)

    Totta Ehret

    2017-06-01

    Full Text Available Rodents, in particular Mus musculus, have a long and invaluable history as models for human diseases in biomedical research, although their translational value has been challenged in a number of cases. We provide some examples in which rodents have been suboptimal as models for human biology and discuss confounders which influence experiments and may explain some of the misleading results. Infections of rodents with protozoan parasites are no exception in requiring close consideration upon model choice. We focus on the significant differences between inbred, outbred and wild animals, and the importance of factors such as microbiota, which are gaining attention as crucial variables in infection experiments. Frequently, mouse or rat models are chosen for convenience, e.g., availability in the institution rather than on an unbiased evaluation of whether they provide the answer to a given question. Apart from a general discussion on translational success or failure, we provide examples where infections with single-celled parasites in a chosen lab rodent gave contradictory or misleading results, and when possible discuss the reason for this. We present emerging alternatives to traditional rodent models, such as humanized mice and organoid primary cell cultures. So-called recombinant inbred strains such as the Collaborative Cross collection are also a potential solution for certain challenges. In addition, we emphasize the advantages of using wild rodents for certain immunological, ecological, and/or behavioral questions. The experimental challenges (e.g., availability of species-specific reagents that come with the use of such non-model systems are also discussed. Our intention is to foster critical judgment of both traditional and newly available translational rodent models for research on parasitic protozoa that can complement the existing mouse and rat models.

  15. Rodent models of adaptive decision making.

    Science.gov (United States)

    Izquierdo, Alicia; Belcher, Annabelle M

    2012-01-01

    Adaptive decision making affords the animal the ability to respond quickly to changes in a dynamic environment: one in which attentional demands, cost or effort to procure the reward, and reward contingencies change frequently. The more flexible the organism is in adapting choice behavior, the more command and success the organism has in navigating its environment. Maladaptive decision making is at the heart of much neuropsychiatric disease, including addiction. Thus, a better understanding of the mechanisms that underlie normal, adaptive decision making helps achieve a better understanding of certain diseases that incorporate maladaptive decision making as a core feature. This chapter presents three general domains of methods that the experimenter can manipulate in animal decision-making tasks: attention, effort, and reward contingency. Here, we present detailed methods of rodent tasks frequently employed within these domains: the Attentional Set-Shift Task, Effortful T-maze Task, and Visual Discrimination Reversal Learning. These tasks all recruit regions within the frontal cortex and the striatum, and performance is heavily modulated by the neurotransmitter dopamine, making these assays highly valid measures in the study of psychostimulant addiction.

  16. A rodent malarial model of Plasmodium berghei for the development ...

    African Journals Online (AJOL)

    A rodent malarial model of Plasmodium berghei for the development of pyrimethamine and sulphadoxine-pyrimethamine resistant malaria in mice. ... course approach with 125/6.25mg/kg S/P. The stability of resistance phenotypes, parasite pathogenic disposition and host leukocyte response were also investigated.

  17. The in vivo rodent test systems for assessment of carcinogenic potential

    DEFF Research Database (Denmark)

    van der Laan, Jan-Willem; Spindler, Per

    2002-01-01

    A Drug Information Association (DIA) workshop was held in May 2001 to discuss the outcome of the International Life Sciences Institute-Health and Environmental Sciences Institute (ILSI-HESI) project on alternative models for carcinogenicity assessment such as the P53(+/-) and XPA(+/-) knockout...... mouse models, the RasH2 and Tg.AC transgenic mouse models, and the neonatal mouse model. The "ICH Guideline S1B on Testing for Carcinogenicity of Pharmaceuticals" advocates that carcinogenicity testing of pharmaceuticals, when needed, might be carried out choosing one 2-year rodent carcinogenicity study...... (rat) plus one other study that supplements the 2-year study and providing additional information that is not readily available from the 2-year study: either (1) a short- or medium-term in vivo rodent test system or (2) a 2-year carcinogenicity study in a second rodent species (mouse). Another topic...

  18. Optimizing Cardiovascular Benefits of Exercise: A Review of Rodent Models

    Science.gov (United States)

    Davis, Brittany; Moriguchi, Takeshi; Sumpio, Bauer

    2013-01-01

    Although research unanimously maintains that exercise can ward off cardiovascular disease (CVD), the optimal type, duration, intensity, and combination of forms are yet not clear. In our review of existing rodent-based studies on exercise and cardiovascular health, we attempt to find the optimal forms, intensities, and durations of exercise. Using Scopus and Medline, a literature review of English language comparative journal studies of cardiovascular benefits and exercise was performed. This review examines the existing literature on rodent models of aerobic, anaerobic, and power exercise and compares the benefits of various training forms, intensities, and durations. The rodent studies reviewed in this article correlate with reports on human subjects that suggest regular aerobic exercise can improve cardiac and vascular structure and function, as well as lipid profiles, and reduce the risk of CVD. Findings demonstrate an abundance of rodent-based aerobic studies, but a lack of anaerobic and power forms of exercise, as well as comparisons of these three components of exercise. Thus, further studies must be conducted to determine a truly optimal regimen for cardiovascular health. PMID:24436579

  19. The valproic acid-induced rodent model of autism.

    Science.gov (United States)

    Nicolini, Chiara; Fahnestock, Margaret

    2018-01-01

    Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Of mice and women: rodent models of placental malaria

    DEFF Research Database (Denmark)

    Hviid, Lars; Marinho, Claudio R F; Staalsoe, Trine

    2010-01-01

    Pregnant women are at increased malaria risk. The infections are characterized by placental accumulation of infected erythrocytes (IEs) with adverse consequences for mother and baby. Placental IE sequestration in the intervillous space is mediated by variant surface antigens (VSAs) selectively...... expressed in placental malaria (PM) and specific for chondroitin sulfate A (CSA). In Plasmodium falciparum, these VSA(PM) appear largely synonymous with the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family variant VAR2CSA. As rodent malaria parasites do not possess PfEMP1 homologs......, the usefulness of experimental mouse PM models remains controversial. However, many features of murine and human PM are similar, including involvement of VSAs analogous to PfEMP1. It thus appears that rodent model studies can further the understanding of VSA-dependent malaria pathogenesis and immunity....

  1. Miniature wireless recording and stimulation system for rodent behavioural testing

    Science.gov (United States)

    Pinnell, R. C.; Dempster, J.; Pratt, J.

    2015-12-01

    Objective. Elucidation of neural activity underpinning rodent behaviour has traditionally been hampered by the use of tethered systems and human involvement. Furthermore the combination of deep-brain stimulation (DBS) and various neural recording modalities can lead to complex and time-consuming laboratory setups. For studies of this type, novel tools are required to drive forward this research. Approach. A miniature wireless system weighing 8.5 g (including battery) was developed for rodent use that combined multichannel DBS and local-field potential (LFP) recordings. Its performance was verified in a working memory task that involved 4-channel fronto-hippocampal LFP recording and bilateral constant-current fimbria-fornix DBS. The system was synchronised with video-tracking for extraction of LFP at discrete task phases, and DBS was activated intermittently at discrete phases of the task. Main results. In addition to having a fast set-up time, the system could reliably transmit continuous LFP at over 8 hours across 3-5 m distances. During the working memory task, LFP pertaining to discrete task phases was extracted and compared with well-known neural correlates of active exploratory behaviour in rodents. DBS could be wirelessly activated/deactivated at any part of the experiment during EEG recording and transmission, allowing for a seamless integration of this modality. Significance. The wireless system combines a small size with a level of robustness and versatility that can greatly simplify rodent behavioural experiments involving EEG recording and DBS. Designed for versatility and simplicity, the small size and low-cost of the system and its receiver allow for enhanced portability, fast experimental setup times, and pave the way for integration with more complex behaviour.

  2. STRESS INDUCED OBESITY: LESSONS FROM RODENT MODELS OF STRESS

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    Zachary Robert Patterson

    2013-07-01

    Full Text Available Stress is defined as the behavioral and physiological responses generated in the face of, or in anticipation of, a perceived threat. The stress response involves activation of the sympathetic nervous system and recruitment of the hypothalamic-pituitary-adrenal (HPA axis. When an organism encounters a stressor (social, physical, etc., these endogenous stress systems are stimulated in order to generate a fight-or-flight response, and manage the stressful situation. As such, an organism is forced to liberate energy resources in attempt to meet the energetic demands posed by the stressor. A change in the energy homeostatic balance is thus required to exploit an appropriate resource and deliver useable energy to the target muscles and tissues involved in the stress response. Acutely, this change in energy homeostasis and the liberation of energy is considered advantageous, as it is required for the survival of the organism. However, when an organism is subjected to a prolonged stressor, as is the case during chronic stress, a continuous irregularity in energy homeostasis is considered detrimental and may lead to the development of metabolic disturbances such as cardiovascular disease, type II diabetes mellitus and obesity. This concept has been studied extensively using animal models, and the neurobiological underpinnings of stress induced metabolic disorders are beginning to surface. However, different animal models of stress continue to produce divergent metabolic phenotypes wherein some animals become anorexic and loose body mass while others increase food intake and body mass and become vulnerable to the development of metabolic disturbances. It remains unclear exactly what factors associated with stress models can be used to predict the metabolic outcome of the organism. This review will explore a variety of rodent stress models and discuss the elements that influence the metabolic outcome in order to further our understanding of stress

  3. Measuring Motivation and Reward-Related Decision Making in the Rodent Operant Touchscreen System.

    Science.gov (United States)

    Heath, Christopher J; Phillips, Benjamin U; Bussey, Timothy J; Saksida, Lisa M

    2016-01-04

    This unit is designed to facilitate implementation of the fixed and progressive ratio paradigms and the effort-related choice task in the rodent touchscreen apparatus to permit direct measurement of motivation and reward-related decision making in this equipment. These protocols have been optimized for use in the mouse and reliably yield stable performance levels that can be enhanced or suppressed by systemic pharmacological manipulation. Instructions are also provided for the adjustment of task parameters to permit use in mouse models of neurodegenerative disease. These tasks expand the utility of the rodent touchscreen apparatus beyond the currently available battery of cognitive assessment paradigms. Copyright © 2016 John Wiley & Sons, Inc.

  4. Two new rodent models for actinide toxicity studies

    International Nuclear Information System (INIS)

    Taylor, G.N.; Jones, C.W.; Gardner, P.A.; Lloyd, R.D.; Mays, C.W.; Charrier, K.E.

    1981-01-01

    Two small rodent species, the grasshopper mouse (Onychomys leucogaster) and the deer mouse (Peromyscus maniculatus), have tenacious and high retention in the liver and skeleton of plutonium and americium following intraperitoneal injection of Pu and Am in citrate solution. Liver retention of Pu and Am in the grasshopper mouse is higher than liver retention in the deer mouse. Both of these rodents are relatively long-lived, breed well in captivity, and adapt suitably to laboratory conditions. It is suggested that these two species of mice, in which plutonium retention is high and prolonged in both the skeleton and liver, as it is in man, may be useful animal models for actinide toxicity studies

  5. Rodent models of congenital and hereditary cataract in man.

    Science.gov (United States)

    Tripathi, B J; Tripathi, R C; Borisuth, N S; Dhaliwal, R; Dhaliwal, D

    1991-01-01

    Because the organogenesis and physiology of the lens are essentially similar in various mammals, an understanding of the etiology and pathogenesis of the formation of cataract in an animal model will enhance our knowledge of cataractogenesis in man. In this review, we summarize the background, etiology, and pathogenesis of cataracts that occur in rodents. The main advantages of using rodent mutants include the well-researched genetics of the animals and the comparative ease of breeding of large litters. Numerous rodent models of congenital and hereditary cataracts have been studied extensively. In mice, the models include the Cts strain, Fraser mouse, lens opacity gene (Lop) strain, Lop-2 and Lop-3 strains, Philly mouse, Nakano mouse, Nop strain, Deer mouse, Emory mouse, Swiss Webster strain, Balb/c-nct/nct mouse, and SAM-R/3 strain. The rat models include BUdR, ICR, Sprague-Dawley, and Wistar rats, the spontaneously hypertensive rat (SHR), the John Rapp inbred strain of Dahl salt-sensitive rat, as well as WBN/Kob, Royal College of Surgeons (RCS), and Brown-Norway rats. Other proposed models for the study of hereditary cataract include the degu and the guinea pig. Because of the ease of making clinical observations in vivo and the subsequent availability of the intact lens for laboratory analyses at different stages of cataract formation, these animals provide excellent models for clinicopathologic correlations, for monitoring of the natural history of the aging process and of metabolic defects, as well as for investigations on the effect of cataract-modulating agents and drugs, including the prospect of gene therapy.

  6. Models and detection of spontaneous recurrent seizures in laboratory rodents

    Directory of Open Access Journals (Sweden)

    Bin Gu

    2017-07-01

    Full Text Available Epilepsy, characterized by spontaneous recurrent seizures (SRS, is a serious and common neurological disorder afflicting an estimated 1% of the population worldwide. Animal experiments, especially those utilizing small laboratory rodents, remain essential to understanding the fundamental mechanisms underlying epilepsy and to prevent, diagnose, and treat this disease. While much attention has been focused on epileptogenesis in animal models of epilepsy, there is little discussion on SRS, the hallmark of epilepsy. This is in part due to the technical difficulties of rigorous SRS detection. In this review, we comprehensively summarize both genetic and acquired models of SRS and discuss the methodology used to monitor and detect SRS in mice and rats.

  7. Studying autism in rodent models: reconciling endophenotypes with comorbidities.

    Directory of Open Access Journals (Sweden)

    Andrew eArgyropoulos

    2013-07-01

    Full Text Available Autism spectrum disorder (ASD patients commonly exhibit a variety of comorbid traits including seizures, anxiety, aggressive behavior, gastrointestinal problems, motor deficits, abnormal sensory processing and sleep disturbances for which the cause is unknown. These features impact negatively on daily life and can exaggerate the effects of the core diagnostic traits (social communication deficits and repetitive behaviors. Studying endophenotypes relevant to both core and comorbid features of ASD in rodent models can provide insight into biological mechanisms underlying these disorders. Here we review the characterization of endophenotypes in a selection of environmental, genetic and behavioural rodent models of ASD. In addition to exhibiting core ASD-like behaviours, each of these animal models display one or more endophenotypes relevant to comorbid features including altered sensory processing, seizure susceptibility, anxiety-like behaviour and disturbed motor functions, suggesting that these traits are indicators of altered biological pathways in ASD. However, the study of behaviours paralleling comorbid traits in animal models of ASD is an emerging field and further research is needed to assess altered gastrointestinal function, aggression and disorders of sleep onset across models. Future studies should include investigation of these endophenotypes in order to advance our understanding of the etiology of this complex disorder.

  8. New Insights from Rodent Models of Fatty Liver Disease

    Science.gov (United States)

    2011-01-01

    Abstract Rodent models of fatty liver disease are essential research tools that provide a window into disease pathogenesis and a testing ground for prevention and treatment. Models come in many varieties involving dietary and genetic manipulations, and sometimes both. High-energy diets that induce obesity do not uniformly cause fatty liver disease; this has prompted close scrutiny of specific macronutrients and nutrient combinations to determine which have the greatest potential for hepatotoxicity. At the same time, diets that do not cause obesity or the metabolic syndrome but do cause severe steatohepatitis have been exploited to study factors important to progressive liver injury, including cell death, oxidative stress, and immune activation. Rodents with a genetic predisposition to overeating offer yet another model in which to explore the evolution of fatty liver disease. In some animals that overeat, steatohepatitis can develop even without resorting to a high-energy diet. Importantly, these models and others have been used to document that aerobic exercise can prevent or reduce fatty liver disease. This review focuses primarily on lessons learned about steatohepatitis from manipulations of diet and eating behavior. Numerous additional insights about hepatic lipid metabolism, which have been gained from genetically engineered mice, are also mentioned. Antioxid. Redox Signal. 15, 535–550. PMID:21126212

  9. Spatial memory tasks in rodents: what do they model?

    Science.gov (United States)

    Morellini, Fabio

    2013-10-01

    The analysis of spatial learning and memory in rodents is commonly used to investigate the mechanisms underlying certain forms of human cognition and to model their dysfunction in neuropsychiatric and neurodegenerative diseases. Proper interpretation of rodent behavior in terms of spatial memory and as a model of human cognitive functions is only possible if various navigation strategies and factors controlling the performance of the animal in a spatial task are taken into consideration. The aim of this review is to describe the experimental approaches that are being used for the study of spatial memory in rats and mice and the way that they can be interpreted in terms of general memory functions. After an introduction to the classification of memory into various categories and respective underlying neuroanatomical substrates, I explain the concept of spatial memory and its measurement in rats and mice by analysis of their navigation strategies. Subsequently, I describe the most common paradigms for spatial memory assessment with specific focus on methodological issues relevant for the correct interpretation of the results in terms of cognitive function. Finally, I present recent advances in the use of spatial memory tasks to investigate episodic-like memory in mice.

  10. Modelling the emergence of rodent filial huddling from physiological huddling

    Science.gov (United States)

    Wilson, Stuart P.

    2017-11-01

    Huddling behaviour in neonatal rodents reduces the metabolic costs of physiological thermoregulation. However, animals continue to huddle into adulthood, at ambient temperatures where they are able to sustain a basal metabolism in isolation from the huddle. This `filial huddling' in older animals is known to be guided by olfactory rather than thermal cues. The present study aimed to test whether thermally rewarding contacts between young mice, experienced when thermogenesis in brown adipose fat tissue (BAT) is highest, could give rise to olfactory preferences that persist as filial huddling interactions in adults. To this end, a simple model was constructed to fit existing data on the development of mouse thermal physiology and behaviour. The form of the model that emerged yields a remarkable explanation for filial huddling; associative learning maintains huddling into adulthood via processes that reduce thermodynamic entropy from BAT metabolism and increase information about social ordering among littermates.

  11. Osseointegration of biochemically modified implants in an osteoporosis rodent model

    Directory of Open Access Journals (Sweden)

    B Stadlinger

    2013-07-01

    Full Text Available The present study examined the impact of implant surface modifications on osseointegration in an osteoporotic rodent model. Sandblasted, acid-etched titanium implants were either used directly (control or were further modified by surface conditioning with NaOH or by coating with one of the following active agents: collagen/chondroitin sulphate, simvastatin, or zoledronic acid. Control and modified implants were inserted into the proximal tibia of aged ovariectomised (OVX osteoporotic rats (n = 32/group. In addition, aged oestrogen competent animals received either control or NaOH conditioned implants. Animals were sacrificed 2 and 4 weeks post-implantation. The excised tibiae were utilised for biomechanical and morphometric readouts (n = 8/group/readout. Biomechanical testing revealed at both time points dramatically reduced osseointegration in the tibia of oestrogen deprived osteoporotic animals compared to intact controls irrespective of NaOH exposure. Consistently, histomorphometric and microCT analyses demonstrated diminished bone-implant contact (BIC, peri-implant bone area (BA, bone volume/tissue volume (BV/TV and bone-mineral density (BMD in OVX animals. Surface coating with collagen/chondroitin sulphate had no detectable impact on osseointegration. Interestingly, statin coating resulted in a transient increase in BIC 2 weeks post-implantation; which, however, did not correspond to improvement of biomechanical readouts. Local exposure to zoledronic acid increased BIC, BA, BV/TV and BMD at 4 weeks. Yet this translated only into a non-significant improvement of biomechanical properties. In conclusion, this study presents a rodent model mimicking severely osteoporotic bone. Contrary to the other bioactive agents, locally released zoledronic acid had a positive impact on osseointegration albeit to a lesser extent than reported in less challenging models.

  12. Odor supported place cell model and goal navigation in rodents

    DEFF Research Database (Denmark)

    Kulvicius, Tomas; Tamosiunaite, Minija; Ainge, James

    2008-01-01

    Experiments with rodents demonstrate that visual cues play an important role in the control of hippocampal place cells and spatial navigation. Nevertheless, rats may also rely on auditory, olfactory and somatosensory stimuli for orientation. It is also known that rats can track odors or self......-generated scent marks to find a food source. Here we model odor supported place cells by using a simple feed-forward network and analyze the impact of olfactory cues on place cell formation and spatial navigation. The obtained place cells are used to solve a goal navigation task by a novel mechanism based on self......-marking by odor patches combined with a Q-learning algorithm. We also analyze the impact of place cell remapping on goal directed behavior when switching between two environments. We emphasize the importance of olfactory cues in place cell formation and show that the utility of environmental and self...

  13. Reliable critical sized defect rodent model for cleft palate research.

    Science.gov (United States)

    Mostafa, Nesrine Z; Doschak, Michael R; Major, Paul W; Talwar, Reena

    2014-12-01

    Suitable animal models are necessary to test the efficacy of new bone grafting therapies in cleft palate surgery. Rodent models of cleft palate are available but have limitations. This study compared and modified mid-palate cleft (MPC) and alveolar cleft (AC) models to determine the most reliable and reproducible model for bone grafting studies. Published MPC model (9 × 5 × 3 mm(3)) lacked sufficient information for tested rats. Our initial studies utilizing AC model (7 × 4 × 3 mm(3)) in 8 and 16 weeks old Sprague Dawley (SD) rats revealed injury to adjacent structures. After comparing anteroposterior and transverse maxillary dimensions in 16 weeks old SD and Wistar rats, virtual planning was performed to modify MPC and AC defects dimensions, taking the adjacent structures into consideration. Modified MPC (7 × 2.5 × 1 mm(3)) and AC (5 × 2.5 × 1 mm(3)) defects were employed in 16 weeks old Wistar rats and healing was monitored by micro-computed tomography and histology. Maxillary dimensions in SD and Wistar rats were not significantly different. Preoperative virtual planning enhanced postoperative surgical outcomes. Bone healing occurred at defect margin leaving central bone void confirming the critical size nature of the modified MPC and AC defects. Presented modifications for MPC and AC models created clinically relevant and reproducible defects. Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  14. Use of rodents as models of human diseases

    Directory of Open Access Journals (Sweden)

    Thierry F Vandamme

    2014-01-01

    Full Text Available Advances in molecular biology have significantly increased the understanding of the biology of different diseases. However, these discoveries have not yet been fully translated into improved treatments for patients with diseases such as cancers. One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. In this brief review, we will discuss the advantages and disadvantages of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM models, we will review some of the current genetic strategies for modeling diseases in the mouse and the preclinical studies that have already been undertaken. We will also discuss how recent improvements in imaging technologies may increase the information derived from using these GEMs during early assessments of potential therapeutic pathways. Furthermore, it is interesting to note that one of the values of using a mouse model is the very rapid turnover rate of the animal, going through the process of birth to death in a very short timeframe relative to that of larger mammalian species.

  15. Fully Implantable Deep Brain Stimulation System with Wireless Power Transmission for Long-term Use in Rodent Models of Parkinson's Disease.

    Science.gov (United States)

    Heo, Man Seung; Moon, Hyun Seok; Kim, Hee Chan; Park, Hyung Woo; Lim, Young Hoon; Paek, Sun Ha

    2015-03-01

    The purpose of this study to develop new deep-brain stimulation system for long-term use in animals, in order to develop a variety of neural prostheses. Our system has two distinguished features, which are the fully implanted system having wearable wireless power transfer and ability to change the parameter of stimulus parameter. It is useful for obtaining a variety of data from a long-term experiment. To validate our system, we performed pre-clinical test in Parkinson's disease-rat models for 4 weeks. Through the in vivo test, we observed the possibility of not only long-term implantation and stability, but also free movement of animals. We confirmed that the electrical stimulation neither caused any side effect nor damaged the electrodes. We proved possibility of our system to conduct the long-term pre-clinical test in variety of parameter, which is available for development of neural prostheses.

  16. Gut microbiome may contribute to insulin resistance and systemic inflammation in obese rodents: a meta-analysis.

    Science.gov (United States)

    Jiao, Na; Baker, Susan S; Nugent, Colleen A; Tsompana, Maria; Cai, Liting; Wang, Yong; Buck, Michael J; Genco, Robert J; Baker, Robert D; Zhu, Ruixin; Zhu, Lixin

    2018-04-01

    A number of studies have associated obesity with altered gut microbiota, although results are discordant regarding compositional changes in the gut microbiota of obese animals. Herein we used a meta-analysis to obtain an unbiased evaluation of structural and functional changes of the gut microbiota in diet-induced obese rodents. The raw sequencing data of nine studies generated from high-fat diet (HFD)-induced obese rodent models were processed with QIIME to obtain gut microbiota compositions. Biological functions were predicted and annotated with KEGG pathways with PICRUSt. No significant difference was observed for alpha diversity and Bacteroidetes-to-Firmicutes ratio between obese and lean rodents. Bacteroidia, Clostridia, Bacilli, and Erysipelotrichi were dominant classes, but gut microbiota compositions varied among studies. Meta-analysis of the nine microbiome data sets identified 15 differential taxa and 57 differential pathways between obese and lean rodents. In obese rodents, increased abundance was observed for Dorea, Oscillospira, and Ruminococcus, known for fermenting polysaccharide into short chain fatty acids (SCFAs). Decreased Turicibacter and increased Lactococcus are consistent with elevated inflammation in the obese status. Differential functional pathways of the gut microbiome in obese rodents included enriched pyruvate metabolism, butanoate metabolism, propanoate metabolism, pentose phosphate pathway, fatty acid biosynthesis, and glycerolipid metabolism pathways. These pathways converge in the function of carbohydrate metabolism, SCFA metabolism, and biosynthesis of lipid. HFD-induced obesity results in structural and functional dysbiosis of gut microbiota. The altered gut microbiome may contribute to obesity development by promoting insulin resistance and systemic inflammation.

  17. Traumatic brain injury–Modeling neuropsychiatric symptoms in rodents

    Directory of Open Access Journals (Sweden)

    Oz eMalkesman

    2013-10-01

    Full Text Available Each year in the United States, approximately 1.5 million people sustain a traumatic brain injury (TBI. Victims of TBI can suffer from chronic post-TBI symptoms, such as sensory and motor deficits, cognitive impairments including problems with memory, learning, and attention, and neuropsychiatric symptoms such as depression, anxiety, irritability, aggression, and suicidal rumination. Although partially associated with the site and severity of injury, the biological mechanisms associated with many of these symptoms—and why some patients experience differing assortments of persistent maladies—are largely unknown. The use of animal models is a promising strategy for elucidation of the mechanisms of impairment and treatment, and learning, memory, sensory and motor tests have widespread utility in rodent models of TBI and psychopharmacology. Comparatively, behavioral tests for the evaluation of neuropsychiatric symptomatology are rarely employed in animal models of TBI and, as determined in this review, the results have been inconsistent. Animal behavioral studies contribute to the understanding of the biological mechanisms by which TBI is associated with neurobehavioral symptoms and offer a powerful means for pre-clinical treatment validation. Therefore, further exploration of the utility of animal behavioral tests for the study of injury mechanisms and therapeutic strategies for the alleviation of emotional symptoms are relevant and essential.

  18. Mathematical modeling of sleep state dynamics in a rodent model of shift work

    Directory of Open Access Journals (Sweden)

    Michael J. Rempe

    2018-06-01

    Full Text Available Millions of people worldwide are required to work when their physiology is tuned for sleep. By forcing wakefulness out of the body’s normal schedule, shift workers face numerous adverse health consequences, including gastrointestinal problems, sleep problems, and higher rates of some diseases, including cancers. Recent studies have developed protocols to simulate shift work in rodents with the intention of assessing the effects of night-shift work on subsequent sleep (Grønli et al., 2017. These studies have already provided important contributions to the understanding of the metabolic consequences of shift work (Arble et al., 2015; Marti et al., 2016; Opperhuizen et al., 2015 and sleep-wake-specific impacts of night-shift work (Grønli et al., 2017. However, our understanding of the causal mechanisms underlying night-shift-related sleep disturbances is limited. In order to advance toward a mechanistic understanding of sleep disruption in shift work, we model these data with two different approaches. First we apply a simple homeostatic model to quantify differences in the rates at which sleep need, as measured by slow wave activity during slow wave sleep (SWS rises and falls. Second, we develop a simple and novel mathematical model of rodent sleep and use it to investigate the timing of sleep in a simulated shift work protocol (Grønli et al., 2017. This mathematical framework includes the circadian and homeostatic processes of the two-process model, but additionally incorporates a stochastic process to model the polyphasic nature of rodent sleep. By changing only the time at which the rodents are forced to be awake, the model reproduces some key experimental results from the previous study, including correct proportions of time spent in each stage of sleep as a function of circadian time and the differences in total wake time and SWS bout durations in the rodents representing night-shift workers and those representing day-shift workers

  19. Vagus nerve stimulation inhibits trigeminal nociception in a rodent model of episodic migraine

    Directory of Open Access Journals (Sweden)

    Jordan L. Hawkins

    2017-12-01

    Conclusion:. Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine.

  20. Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans

    Directory of Open Access Journals (Sweden)

    Elke Winterhager

    2017-11-01

    Full Text Available Although the causes of intrauterine growth restriction (IUGR have been intensively investigated, important information is still lacking about the role of the placenta as a link from adverse maternal environment to adverse pregnancy outcomes of IUGR and preterm birth. IUGR is associated with an increased risk of cardiovascular, metabolic, and neurological diseases later in life. Determination of the most important pathways that regulate transplacental transport systems is necessary for identifying marker genes as diagnostic tools and for developing drugs that target the molecular pathways. Besides oxygen, the main nutrients required for appropriate fetal development and growth are glucose, amino acids, and fatty acids. Dysfunction in transplacental transport is caused by impairments in both placental morphology and blood flow, as well as by factors such as alterations in the expression of insulin-like growth factors and changes in the mTOR signaling pathway leading to a change in nutrient transport. Animal models are important tools for systematically studying such complex events. Debate centers on whether the rodent placenta is an appropriate tool for investigating the alterations in the human placenta that result in IUGR. This review provides an overview of the alterations in expression and activity of nutrient transporters and alterations in signaling associated with IUGR and compares these findings in rodents and humans. In general, the data obtained by studies of the various types of rodent and human nutrient transporters are similar. However, direct comparison is complicated by the fact that the results of such studies are controversial even within the same species, making the interpretation of the results challenging. This difficulty could be due to the absence of guidelines of the experimental design and, especially in humans, the use of trophoblast cell culture studies instead of clinical trials. Nonetheless, developing new therapy

  1. Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans.

    Science.gov (United States)

    Winterhager, Elke; Gellhaus, Alexandra

    2017-01-01

    Although the causes of intrauterine growth restriction (IUGR) have been intensively investigated, important information is still lacking about the role of the placenta as a link from adverse maternal environment to adverse pregnancy outcomes of IUGR and preterm birth. IUGR is associated with an increased risk of cardiovascular, metabolic, and neurological diseases later in life. Determination of the most important pathways that regulate transplacental transport systems is necessary for identifying marker genes as diagnostic tools and for developing drugs that target the molecular pathways. Besides oxygen, the main nutrients required for appropriate fetal development and growth are glucose, amino acids, and fatty acids. Dysfunction in transplacental transport is caused by impairments in both placental morphology and blood flow, as well as by factors such as alterations in the expression of insulin-like growth factors and changes in the mTOR signaling pathway leading to a change in nutrient transport. Animal models are important tools for systematically studying such complex events. Debate centers on whether the rodent placenta is an appropriate tool for investigating the alterations in the human placenta that result in IUGR. This review provides an overview of the alterations in expression and activity of nutrient transporters and alterations in signaling associated with IUGR and compares these findings in rodents and humans. In general, the data obtained by studies of the various types of rodent and human nutrient transporters are similar. However, direct comparison is complicated by the fact that the results of such studies are controversial even within the same species, making the interpretation of the results challenging. This difficulty could be due to the absence of guidelines of the experimental design and, especially in humans, the use of trophoblast cell culture studies instead of clinical trials. Nonetheless, developing new therapy concepts for IUGR will

  2. Large Animal Stroke Models vs. Rodent Stroke Models, Pros and Cons, and Combination?

    Science.gov (United States)

    Cai, Bin; Wang, Ning

    2016-01-01

    Stroke is a leading cause of serious long-term disability worldwide and the second leading cause of death in many countries. Long-time attempts to salvage dying neurons via various neuroprotective agents have failed in stroke translational research, owing in part to the huge gap between animal stroke models and stroke patients, which also suggests that rodent models have limited predictive value and that alternate large animal models are likely to become important in future translational research. The genetic background, physiological characteristics, behavioral characteristics, and brain structure of large animals, especially nonhuman primates, are analogous to humans, and resemble humans in stroke. Moreover, relatively new regional imaging techniques, measurements of regional cerebral blood flow, and sophisticated physiological monitoring can be more easily performed on the same animal at multiple time points. As a result, we can use large animal stroke models to decrease the gap and promote translation of basic science stroke research. At the same time, we should not neglect the disadvantages of the large animal stroke model such as the significant expense and ethical considerations, which can be overcome by rodent models. Rodents should be selected as stroke models for initial testing and primates or cats are desirable as a second species, which was recommended by the Stroke Therapy Academic Industry Roundtable (STAIR) group in 2009.

  3. Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models

    OpenAIRE

    Canet, Mark J.; Hardwick, Rhiannon N.; Lake, April D.; Dzierlenga, Anika L.; Clarke, John D.; Cherrington, Nathan J.

    2014-01-01

    Nonalcoholic fatty liver disease is a prevalent form of chronic liver disease that can progress to the more advanced stage of nonalcoholic steatohepatitis (NASH). NASH has been shown to alter drug transporter regulation and may have implications in the development of adverse drug reactions. Several experimental rodent models have been proposed for the study of NASH, but no single model fully recapitulates all aspects of the human disease. The purpose of the current study was to determine whic...

  4. The trophic responses of two different rodent-vector-plague systems to climate change.

    Science.gov (United States)

    Xu, Lei; Schmid, Boris V; Liu, Jun; Si, Xiaoyan; Stenseth, Nils Chr; Zhang, Zhibin

    2015-02-07

    Plague, the causative agent of three devastating pandemics in history, is currently a re-emerging disease, probably due to climate change and other anthropogenic changes. Without understanding the response of plague systems to anthropogenic or climate changes in their trophic web, it is unfeasible to effectively predict years with high risks of plague outbreak, hampering our ability for effective prevention and control of the disease. Here, by using surveillance data, we apply structural equation modelling to reveal the drivers of plague prevalence in two very different rodent systems: those of the solitary Daurian ground squirrel and the social Mongolian gerbil. We show that plague prevalence in the Daurian ground squirrel is not detectably related to its trophic web, and that therefore surveillance efforts should focus on detecting plague directly in this ecosystem. On the other hand, plague in the Mongolian gerbil is strongly embedded in a complex, yet understandable trophic web of climate, vegetation, and rodent and flea densities, making the ecosystem suitable for more sophisticated low-cost surveillance practices, such as remote sensing. As for the trophic webs of the two rodent species, we find that increased vegetation is positively associated with higher temperatures and precipitation for both ecosystems. We furthermore find a positive association between vegetation and ground squirrel density, yet a negative association between vegetation and gerbil density. Our study thus shows how past surveillance records can be used to design and improve existing plague prevention and control measures, by tailoring them to individual plague foci. Such measures are indeed highly needed under present conditions with prevailing climate change. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  5. Temporal and Spatial Characterization of Gait Pattern in Rodents as an Animal model of Cerebrovascular Lesion

    Directory of Open Access Journals (Sweden)

    Jaison D Cucarián

    2017-09-01

    Full Text Available Animal experimentation is crucial for the advance in the understanding of pathophysiological mechanisms and their application on both clinical diagnosis and neuro-rehabilitation. Particularly, rodent brain lesion is commonly used in the modeling of locomotor, somatosensory and cognitive symptoms. The automated rodent gait analysis has been proposed as a tool for studying locomotor and sensory abilities and its use includes the identification of functional alterations, structural adaptations as well as neuro-rehabilitation mechanisms. From that standpoint, the effectiveness of many therapeutic intervention (i.e. physical exercises has been documented in rodents and humans. The translation from experimental data to clinical conditions requires the continuous collaboration and feedback between researchers and health clinicians looking for the selection of the best rehabilitation protocols obtained from animal research. Here we will show some locomotor alterations, the traditional methods used to assess motor dysfunction and gait abnormalities in rodent models with stroke. The aim of this review is to show some motor deficiencies and some methods used to establish gait disturbances in rodents with cerebrovascular lesion. The review included the search of defined terms (MeSH in PychINFO, Medline and Web of Science, between January 2000 and January 2017. Qualitative and narrative reports, dissertations, end course works and conference resumes were discarded. The review focuses on some clinical signs, their effects on rodent locomotor activity, some methodologies used to create lesion and to study motor function, some assessment methods and some translational aspects.

  6. An improved cost-effective, reproducible method for evaluation of bone loss in a rodent model.

    Science.gov (United States)

    Fine, Daniel H; Schreiner, Helen; Nasri-Heir, Cibele; Greenberg, Barbara; Jiang, Shuying; Markowitz, Kenneth; Furgang, David

    2009-02-01

    This study was designed to investigate the utility of two "new" definitions for assessment of bone loss in a rodent model of periodontitis. Eighteen rats were divided into three groups. Group 1 was infected by Aggregatibacter actinomycetemcomitans (Aa), group 2 was infected with an Aa leukotoxin knock-out, and group 3 received no Aa (controls). Microbial sampling and antibody titres were determined. Initially, two examiners measured the distance from the cemento-enamel-junction to alveolar bone crest using the three following methods; (1) total area of bone loss by radiograph, (2) linear bone loss by radiograph, (3) a direct visual measurement (DVM) of horizontal bone loss. Two "new" definitions were adopted; (1) any site in infected animals showing bone loss >2 standard deviations above the mean seen at that site in control animals was recorded as bone loss, (2) any animal with two or more sites in any quadrant affected by bone loss was considered as diseased. Using the "new" definitions both evaluators independently found that infected animals had significantly more disease than controls (DVM system; p<0.05). The DVM method provides a simple, cost effective, and reproducible method for studying periodontal disease in rodents.

  7. Animal models of polycystic ovary syndrome: a focused review of rodent models in relationship to clinical phenotypes and cardiometabolic risk.

    Science.gov (United States)

    Shi, Danni; Vine, Donna F

    2012-07-01

    To review rodent animal models of polycystic ovary syndrome (PCOS), with a focus on those associated with the metabolic syndrome and cardiovascular disease risk factors. Review. Rodent models of PCOS. Description and comparison of animal models. Comparison of animal models to clinical phenotypes of PCOS. Animals used to study PCOS include rodents, mice, rhesus monkeys, and ewes. Major methods to induce PCOS in these models include subcutaneous injection or implantation of androgens, estrogens, antiprogesterone, letrozole, prenatal exposure to excess androgens, and exposure to constant light. In addition, transgenic mice models and spontaneous PCOS-like rodent models have also been developed. Rodents are the most economical and widely used animals to study PCOS and ovarian dysfunction. The model chosen to study the development of PCOS and other metabolic parameters remains dependent on the specific etiologic hypotheses being investigated. Rodent models have been shown to demonstrate changes in insulin metabolism, with or without induction of hyperandrogenemia, and limited studies have investigated cardiometabolic risk factors for type 2 diabetes and cardiovascular disease. Given the clinical heterogeneity of PCOS, the utilization of different animal models may be the best approach to further our understanding of the pathophysiologic mechanisms associated with the early etiology of PCOS and cardiometabolic risk. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  8. Functional evolution of the feeding system in rodents.

    Directory of Open Access Journals (Sweden)

    Philip G Cox

    Full Text Available The masticatory musculature of rodents has evolved to enable both gnawing at the incisors and chewing at the molars. In particular, the masseter muscle is highly specialised, having extended anteriorly to originate from the rostrum. All living rodents have achieved this masseteric expansion in one of three ways, known as the sciuromorph, hystricomorph and myomorph conditions. Here, we used finite element analysis (FEA to investigate the biomechanical implications of these three morphologies, in a squirrel, guinea pig and rat. In particular, we wished to determine whether each of the three morphologies is better adapted for either gnawing or chewing. Results show that squirrels are more efficient at muscle-bite force transmission during incisor gnawing than guinea pigs, and that guinea pigs are more efficient at molar chewing than squirrels. This matches the known diet of nuts and seeds that squirrels gnaw, and of grasses that guinea pigs grind down with their molars. Surprisingly, results also indicate that rats are more efficient as well as more versatile feeders than both the squirrel and guinea pig. There seems to be no compromise in biting efficiency to accommodate the wider range of foodstuffs and the more general feeding behaviour adopted by rats. Our results show that the morphology of the skull and masticatory muscles have allowed squirrels to specialise as gnawers and guinea pigs as chewers, but that rats are high-performance generalists, which helps explain their overwhelming success as a group.

  9. A cell kinetic model of granulopoiesis under radiation exposure: Extension from rodents to canines and humans

    International Nuclear Information System (INIS)

    Hu, S.; Cucinotta, F. A.

    2011-01-01

    As significant ionising radiation exposure will occur during prolonged space travel in future, it is essential to understand their adverse effects on the radiosensitive organ systems that are important for immediate survival of humans, e.g. the haematopoietic system. In this paper, a bio-mathematical model of granulopoiesis is used to analyse the granulocyte changes seen in the blood of mammalians under acute and continuous radiation exposure. This is one of a set of haematopoietic models that have been successfully utilised to simulate and interpret the experimental data of acute and chronic radiation on rodents. Extension to canine and human systems indicates that the results of the model are consistent with the cumulative experimental and empirical data from various sources, implying the potential to integrate them into one united model system to monitor the haematopoietic response of various species under irradiation. The suppression of granulocytes' level of a space traveller under chronic stress of low-dose irradiation as well as the granulopoietic response when encountering a historically large solar particle event is also discussed. (authors)

  10. Aberrant dopamine D2-like receptor function in a rodent model of schizophrenia.

    Science.gov (United States)

    Perez, Stephanie M; Lodge, Daniel J

    2012-11-01

    Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAM-treated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcription-polymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

  11. Recent advances using rodent models for predicting human allergenicity

    International Nuclear Information System (INIS)

    Knippels, Leon M.J.; Penninks, Andre H.

    2005-01-01

    The potential allergenicity of newly introduced proteins in genetically engineered foods has become an important safety evaluation issue. However, to evaluate the potential allergenicity and the potency of new proteins in our food, there are still no widely accepted and reliable test systems. The best-known allergy assessment proposal for foods derived from genetically engineered plants was the careful stepwise process presented in the so-called ILSI/IFBC decision tree. A revision of this decision tree strategy was proposed by a FAO/WHO expert consultation. As prediction of the sensitizing potential of the novel introduced protein based on animal testing was considered to be very important, animal models were introduced as one of the new test items, despite the fact that non of the currently studied models has been widely accepted and validated yet. In this paper, recent results are summarized of promising models developed in rat and mouse

  12. Rodent model for assessing the long term safety and performance of peripheral nerve recording electrodes

    Science.gov (United States)

    Vasudevan, Srikanth; Patel, Kunal; Welle, Cristin

    2017-02-01

    Objective. In the US alone, there are approximately 185 000 cases of limb amputation annually, which can reduce the quality of life for those individuals. Current prosthesis technology could be improved by access to signals from the nervous system for intuitive prosthesis control. After amputation, residual peripheral nerves continue to convey motor signals and electrical stimulation of these nerves can elicit sensory percepts. However, current technology for extracting information directly from peripheral nerves has limited chronic reliability, and novel approaches must be vetted to ensure safe long-term use. The present study aims to optimize methods to establish a test platform using rodent model to assess the long term safety and performance of electrode interfaces implanted in the peripheral nerves. Approach. Floating Microelectrode Arrays (FMA, Microprobes for Life Sciences) were implanted into the rodent sciatic nerve. Weekly in vivo recordings and impedance measurements were performed in animals to assess performance and physical integrity of electrodes. Motor (walking track analysis) and sensory (Von Frey) function tests were used to assess change in nerve function due to the implant. Following the terminal recording session, the nerve was explanted and the health of axons, myelin and surrounding tissues were assessed using immunohistochemistry (IHC). The explanted electrodes were visualized under high magnification using scanning electrode microscopy (SEM) to observe any physical damage. Main results. Recordings of axonal action potentials demonstrated notable session-to-session variability. Impedance of the electrodes increased upon implantation and displayed relative stability until electrode failure. Initial deficits in motor function recovered by 2 weeks, while sensory deficits persisted through 6 weeks of assessment. The primary cause of failure was identified as lead wire breakage in all of animals. IHC indicated myelinated and unmyelinated axons

  13. Rodent Models of Non-classical Progesterone Action Regulating Ovulation

    Directory of Open Access Journals (Sweden)

    Melinda A. Mittelman-Smith

    2017-07-01

    Full Text Available It is becoming clear that steroid hormones act not only by binding to nuclear receptors that associate with specific response elements in the nucleus but also by binding to receptors on the cell membrane. In this newly discovered manner, steroid hormones can initiate intracellular signaling cascades which elicit rapid effects such as release of internal calcium stores and activation of kinases. We have learned much about the translocation and signaling of steroid hormone receptors from investigations into estrogen receptor α, which can be trafficked to, and signal from, the cell membrane. It is now clear that progesterone (P4 can also elicit effects that cannot be exclusively explained by transcriptional changes. Similar to E2 and its receptors, P4 can initiate signaling at the cell membrane, both through progesterone receptor and via a host of newly discovered membrane receptors (e.g., membrane progesterone receptors, progesterone receptor membrane components. This review discusses the parallels between neurotransmitter-like E2 action and the more recently investigated non-classical P4 signaling, in the context of reproductive behaviors in the rodent.

  14. Genetic Rodent Models of Obesity-Associated Ovarian Dysfunction and Subfertility: Insights into Polycystic Ovary Syndrome

    Science.gov (United States)

    Huang-Doran, Isabel; Franks, Stephen

    2016-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women and a leading cause of female infertility worldwide. Defined clinically by the presence of hyperandrogenemia and oligomenorrhoea, PCOS represents a state of hormonal dysregulation, disrupted ovarian follicle dynamics, and subsequent oligo- or anovulation. The syndrome’s prevalence is attributed, at least partly, to a well-established association with obesity and insulin resistance (IR). Indeed, the presence of severe PCOS in human genetic obesity and IR syndromes supports a causal role for IR in the pathogenesis of PCOS. However, the molecular mechanisms underlying this causality, as well as the important role of hyperandrogenemia, remain poorly elucidated. As such, treatment of PCOS is necessarily empirical, focusing on symptom alleviation. The generation of knockout and transgenic rodent models of obesity and IR offers a promising platform in which to address mechanistic questions about reproductive dysfunction in the context of metabolic disease. Similarly, the impact of primary perturbations in rodent gonadotrophin or androgen signaling has been interrogated. However, the insights gained from such models have been limited by the relatively poor fidelity of rodent models to human PCOS. In this mini review, we evaluate the ovarian phenotypes associated with rodent models of obesity and IR, including the extent of endocrine disturbance, ovarian dysmorphology, and subfertility. We compare them to both human PCOS and other animal models of the syndrome (genetic and hormonal), explore reasons for their discordance, and consider the new opportunities that are emerging to better understand and treat this important condition. PMID:27375552

  15. Functional recovery after facial nerve cable grafting in a rodent model.

    NARCIS (Netherlands)

    Hohman, M.H.; Kleiss, I.J.; Knox, C.J.; Weinberg, J.S.; Heaton, J.T.; Hadlock, T.A.

    2014-01-01

    IMPORTANCE: Cable grafting is widely considered to be the preferred alternative to primary repair of the injured facial nerve; however, quantitative comparison of the 2 techniques has not been previously undertaken in a rodent model. OBJECTIVE: To establish functional recovery parameters after

  16. The relevance of non-human primate and rodent malaria models for humans

    OpenAIRE

    Langhorne, Jean; Buffet, Pierre; Galinski, Mary; Good, Michael; Harty, John; Leroy, Didier; Mota, Maria M; Pasini, Erica; Renia, Laurent; Riley, Eleanor; Stins, Monique; Duffy, Patrick

    2011-01-01

    Abstract At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host-Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models....

  17. Kinship structure and mating system in a solitary subterranean rodent, the silvery mole-rat

    Czech Academy of Sciences Publication Activity Database

    Patzenhauerová, Hana; Bryja, Josef; Šumbera, R.

    2010-01-01

    Roč. 64, č. 5 (2010), s. 757-767 ISSN 0340-5443 R&D Projects: GA AV ČR IAA601410802 Institutional research plan: CEZ:AV0Z60930519 Keywords : subterranean rodent * kinship structure * mating system * dispersal Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.565, year: 2010

  18. Histaminergic activity in a rodent model of Parkinson's disease.

    Science.gov (United States)

    Nowak, Przemysław; Noras, Lukasz; Jochem, Jerzy; Szkilnik, Ryszard; Brus, Halina; Körossy, Eva; Drab, Jacek; Kostrzewa, Richard M; Brus, Ryszard

    2009-04-01

    Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson's disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 microg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites L: -3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H(1); cimetidine, H(2); thioperamide, H(3) agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H(3) antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6

  19. Effect of Room Ventilation Rates in Rodent Rooms with Direct-Exhaust IVC Systems.

    Science.gov (United States)

    Geertsema, Roger S; Lindsell, Claire E

    2015-09-01

    When IVC are directly exhausted from a rodent housing room, the air quality of the room can become independent of the intracage air quality and may reduce the need for high room ventilation rates. This study assessed the effect of decreasing the ventilation rate in rodent rooms using direct-exhaust IVC systems. The study was conducted over 16 wk and compared conditions in 8 rodent rooms that had ventilation rates of 5 to 6 air changes per hour (ACH) with those in rooms at 10 to 12 ACH. At the low ventilation rate, rooms had higher CO₂ concentrations, higher dew point temperature, and lower particulate levels and spent a greater percentage of time above the temperature set point than did rooms at the high rate. The levels of allergens and endotoxins in room air were the same regardless of the ventilation rate. Differences seen in parameters within cages at the 2 ventilation rates were operationally irrelevant. We detected no total volatile organic compounds in the room that were attributable to ammonia, regardless of the ventilation rate. Clearing the air of ethanol after a spill took longer at the low compared with high rate. However, ethanol clearance was faster at the low rate when the demand-control system was activated than at the high ventilation rate alone. Air quality in the room and in the cages were acceptable with room ventilation rates of 5 to 6 ACH in rodent rooms that use direct-exhaust IVC systems.

  20. Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances

    Directory of Open Access Journals (Sweden)

    Jacques Auger

    2014-02-01

    Full Text Available In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance (EAS exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action (MOA of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool (together with the epidemiological approach for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction.

  1. Global and 3D spatial assessment of neuroinflammation in rodent models of Multiple Sclerosis.

    Directory of Open Access Journals (Sweden)

    Shashank Gupta

    Full Text Available Multiple Sclerosis (MS is a progressive autoimmune inflammatory and demyelinating disease of the central nervous system (CNS. T cells play a key role in the progression of neuroinflammation in MS and also in the experimental autoimmune encephalomyelitis (EAE animal models for the disease. A technology for quantitative and 3 dimensional (3D spatial assessment of inflammation in this and other CNS inflammatory conditions is much needed. Here we present a procedure for 3D spatial assessment and global quantification of the development of neuroinflammation based on Optical Projection Tomography (OPT. Applying this approach to the analysis of rodent models of MS, we provide global quantitative data of the major inflammatory component as a function of the clinical course. Our data demonstrates a strong correlation between the development and progression of neuroinflammation and clinical disease in several mouse and a rat model of MS refining the information regarding the spatial dynamics of the inflammatory component in EAE. This method provides a powerful tool to investigate the effect of environmental and genetic forces and for assessing the therapeutic effects of drug therapy in animal models of MS and other neuroinflammatory/neurodegenerative disorders.

  2. New Perspectives on Rodent Models of Advanced Paternal Age: Relevance to Autism

    Directory of Open Access Journals (Sweden)

    Claire J Foldi

    2011-06-01

    Full Text Available Offspring of older fathers have an increased risk of various adverse health outcomes, including autism and schizophrenia. With respect to biological mechanisms for this association, there are many more germline cell divisions in the life history of a sperm relative to that of an oocyte. This leads to more opportunities for copy error mutations in germ cells from older fathers. Evidence also suggests that epigenetic patterning in the sperm from older men is altered. Rodent models provide an experimental platform to examine the association between paternal age and brain development. Several rodent models of advanced paternal age (APA have been published with relevance to intermediate phenotypes related to autism. All four published APA models vary in key features creating a lack of consistency with respect to behavioural phenotypes. A consideration of common phenotypes that emerge from these APA-related mouse models may be informative in the exploration of the molecular and neurobiological correlates of APA.

  3. Stimulant and motivational effects of alcohol: lessons from rodent and primate models.

    Science.gov (United States)

    Brabant, Christian; Guarnieri, Douglas J; Quertemont, Etienne

    2014-07-01

    In several animal species including humans, the acute administration of low doses of alcohol increases motor activity. Different theories have postulated that alcohol-induced hyperactivity is causally related to alcoholism. Moreover, a common biological mechanism in the mesolimbic dopamine system has been proposed to mediate the stimulant and motivational effects of alcohol. Numerous studies have examined whether alcohol-induced hyperactivity is related to alcoholism using a great variety of animal models and several animal species. However, there is no review that has summarized this extensive literature. In this article, we present the various experimental models that have been used to study the relationship between the stimulant and motivational effects of alcohol in rodents and primates. Furthermore, we discuss whether the theories hypothesizing a causal link between alcohol-induced hyperactivity and alcoholism are supported by published results. The reviewed findings indicate that animal species that are stimulated by alcohol also exhibit alcohol preference. Additionally, the role of dopamine in alcohol-induced hyperactivity is well established since blocking dopaminergic activity suppresses the stimulant effects of alcohol. However, dopamine transmission plays a much more complex function in the motivational properties of alcohol and the neuronal mechanisms involved in alcohol stimulation and reward are distinct. Overall, the current review provides mixed support for theories suggesting that the stimulant effects of alcohol are related to alcoholism and highlights the importance of animal models as a way to gain insight into alcoholism. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Models of alcoholic liver disease in rodents: a critical evaluation

    DEFF Research Database (Denmark)

    de la M. Hall, P.; Lieber, C.S.; De Carli, L.M.

    2001-01-01

    ) Lieber-DeCarli liquid diet for alcohol-induced liver injury in rats, by C. S. Lieber and L. M. DeCarli; (3) Tsukamoto-French model of alcoholic liver injury, by S. W. French; (4) Animal models to study endotoxin-ethanol interactions, by K. O. Lindros and H. Järveläinen; and (5) Jejunoileal bypass...

  5. More than two decades of Apc modeling in rodents

    Science.gov (United States)

    Zeineldin, Maged; Neufeld, Kristi L.

    2013-01-01

    Mutation of tumor suppressor gene Adenomatous polyposis coli (APC) is an initiating step in most colon cancers. This review summarizes Apc models in mice and rats, with particular concentration on those most recently developed, phenotypic variation among different models, and genotype/ phenotype correlations. PMID:23333833

  6. Post-traumatic stress disorder and beyond: an overview of rodent stress models.

    Science.gov (United States)

    Schöner, Johanna; Heinz, Andreas; Endres, Matthias; Gertz, Karen; Kronenberg, Golo

    2017-10-01

    Post-traumatic stress disorder (PTSD) is a psychiatric disorder of high prevalence and major socioeconomic impact. Patients suffering from PTSD typically present intrusion and avoidance symptoms and alterations in arousal, mood and cognition that last for more than 1 month. Animal models are an indispensable tool to investigate underlying pathophysiological pathways and, in particular, the complex interplay of neuroendocrine, genetic and environmental factors that may be responsible for PTSD induction. Since the 1960s, numerous stress paradigms in rodents have been developed, based largely on Seligman's seminal formulation of 'learned helplessness' in canines. Rodent stress models make use of physiological or psychological stressors such as foot shock, underwater trauma, social defeat, early life stress or predator-based stress. Apart from the brief exposure to an acute stressor, chronic stress models combining a succession of different stressors for a period of several weeks have also been developed. Chronic stress models in rats and mice may elicit characteristic PTSD-like symptoms alongside, more broadly, depressive-like behaviours. In this review, the major existing rodent models of PTSD are reviewed in terms of validity, advantages and limitations; moreover, significant results and implications for future research-such as the role of FKBP5, a mediator of the glucocorticoid stress response and promising target for therapeutic interventions-are discussed. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  7. Vibration acceleration promotes bone formation in rodent models.

    Directory of Open Access Journals (Sweden)

    Ryohei Uchida

    Full Text Available All living tissues and cells on Earth are subject to gravitational acceleration, but no reports have verified whether acceleration mode influences bone formation and healing. Therefore, this study was to compare the effects of two acceleration modes, vibration and constant (centrifugal accelerations, on bone formation and healing in the trunk using BMP 2-induced ectopic bone formation (EBF mouse model and a rib fracture healing (RFH rat model. Additionally, we tried to verify the difference in mechanism of effect on bone formation by accelerations between these two models. Three groups (low- and high-magnitude vibration and control-VA groups were evaluated in the vibration acceleration study, and two groups (centrifuge acceleration and control-CA groups were used in the constant acceleration study. In each model, the intervention was applied for ten minutes per day from three days after surgery for eleven days (EBF model or nine days (RFH model. All animals were sacrificed the day after the intervention ended. In the EBF model, ectopic bone was evaluated by macroscopic and histological observations, wet weight, radiography and microfocus computed tomography (micro-CT. In the RFH model, whole fracture-repaired ribs were excised with removal of soft tissue, and evaluated radiologically and histologically. Ectopic bones in the low-magnitude group (EBF model had significantly greater wet weight and were significantly larger (macroscopically and radiographically than those in the other two groups, whereas the size and wet weight of ectopic bones in the centrifuge acceleration group showed no significant difference compared those in control-CA group. All ectopic bones showed calcified trabeculae and maturated bone marrow. Micro-CT showed that bone volume (BV in the low-magnitude group of EBF model was significantly higher than those in the other two groups (3.1±1.2mm3 v.s. 1.8±1.2mm3 in high-magnitude group and 1.3±0.9mm3 in control-VA group, but

  8. Classification of Multiple Seizure-Like States in Three Different Rodent Models of Epileptogenesis.

    Science.gov (United States)

    Guirgis, Mirna; Serletis, Demitre; Zhang, Jane; Florez, Carlos; Dian, Joshua A; Carlen, Peter L; Bardakjian, Berj L

    2014-01-01

    Epilepsy is a dynamical disease and its effects are evident in over fifty million people worldwide. This study focused on objective classification of the multiple states involved in the brain's epileptiform activity. Four datasets from three different rodent hippocampal preparations were explored, wherein seizure-like-events (SLE) were induced by the perfusion of a low - Mg(2+) /high-K(+) solution or 4-Aminopyridine. Local field potentials were recorded from CA3 pyramidal neurons and interneurons and modeled as Markov processes. Specifically, hidden Markov models (HMM) were used to determine the nature of the states present. Properties of the Hilbert transform were used to construct the feature spaces for HMM training. By sequentially applying the HMM training algorithm, multiple states were identified both in episodes of SLE and nonSLE activity. Specifically, preSLE and postSLE states were differentiated and multiple inner SLE states were identified. This was accomplished using features extracted from the lower frequencies (1-4 Hz, 4-8 Hz) alongside those of both the low- (40-100 Hz) and high-gamma (100-200 Hz) of the recorded electrical activity. The learning paradigm of this HMM-based system eliminates the inherent bias associated with other learning algorithms that depend on predetermined state segmentation and renders it an appropriate candidate for SLE classification.

  9. Intestinal tumorigenesis is not affected by progesterone signaling in rodent models.

    Directory of Open Access Journals (Sweden)

    Jarom Heijmans

    Full Text Available Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO to the Apc(Min/+ mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+ mice exhibited no change in polyp number, size or localization compared to Apc(Min/+. To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis.

  10. From the Rodent Spinal Cord Injury Model to Human Application: Promises and Challenges.

    Science.gov (United States)

    Dietz, Volker; Schwab, Martin E

    2017-05-01

    Repair of the spinal cord and improvement of mobility after injury has been a matter of basic and clinical research for several decades. A number of repair approaches were performed in animals, mainly rodent models of spinal cord injury (SCI). Some of these experimental therapies resulted in significant regeneration of tract fibers, formation of new connections and circuits, and associated improvement of mobility. Some clinical trials aiming at translating these approaches to the human condition of an SCI are currently on-going. The present therapy, however, remains rehabiliation: Mobility of patients with an SCI can be improved to a limited extent by the exploition of neuroplasticity. In this article the present state of the art in the field of SCI research will be discussed. Studies dealing with the promotion of spinal cord repair and those directed to improve mobility by exploition of neuroplasticity will be summarized. The promises and challenges of translational basic research in rodent SCI models will be presented.

  11. A model of Leptospirosis infection in an African rodent to determine risk to humans: Seasonal fluctuations and the impact of rodent control

    DEFF Research Database (Denmark)

    Holt, J; Davis, S; Leirs, Herwig

    2006-01-01

    Human leptospirosis (Leptospira spp. infection) is aworldwide public health problem that is of greatest concern for humid tropical and subtropical regions. The magnitude of the problem in these areas is larger because of the climatic and environmental conditions the bacterium face outside...... their hosts but also because of the frequency of contacts between people and sources of infection. Rodents are thought to play the most important role in the transmission of human leptospirosis. We here model the dynamics of infection in an African rodent (Mastomys natalensis) that is thought...... to be the principal source of infection in parts of Tanzania. Our model, representing the climatic conditions in central Tanzania, suggests a strong seasonality in the force of infection on humans with a peak in the abundance of infectious mice between January and April in agricultural environments. In urban areas...

  12. Timing of neuron development in the rodent vestibular system

    Science.gov (United States)

    Keefe, J. R.

    1982-01-01

    The timing of cell generation (onset and duration) in the developing rat vestibular and proprioceptive systems is investigated. The results clearly indicate a defined time-span for generation of all neurons in the central nervous system nuclei studied. This cytogenetic period in both vestibular and proprioceptive sensory nuclei is determined to occur during and immediately after placentation, a potentially critical period for spaceflight exposure due to alterations in maternal physiology.

  13. A Novel Rodent Model of Posterior Ischemic Optic Neuropathy

    Science.gov (United States)

    Wang, Yan; Brown, Dale P.; Duan, Yuanli; Kong, Wei; Watson, Brant D.; Goldberg, Jeffrey L.

    2014-01-01

    Objectives To develop a reliable, reproducible rat model of posterior ischemic optic neuropathy (PION) and study the cellular responses in the optic nerve and retina. Methods Posterior ischemic optic neuropathy was induced in adult rats by photochemically induced ischemia. Retinal and optic nerve vasculature was examined by fluorescein isothiocyanate–dextran extravasation. Tissue sectioning and immunohistochemistry were used to investigate the pathologic changes. Retinal ganglion cell survival at different times after PION induction, with or without neurotrophic application, was quantified by fluorogold retrograde labeling. Results Optic nerve injury was confirmed after PION induction, including local vascular leakage, optic nerve edema, and cavernous degeneration. Immunostaining data revealed microglial activation and focal loss of astrocytes, with adjacent astrocytic hypertrophy. Up to 23%, 50%, and 70% retinal ganglion cell loss was observed at 1 week, 2 weeks, and 3 weeks, respectively, after injury compared with a sham control group. Experimental treatment by brain-derived neurotrophic factor and ciliary neurotrophic factor remarkably prevented retinal ganglion cell loss in PION rats. At 3 weeks after injury, more than 40% of retinal ganglion cells were saved by the application of neurotrophic factors. Conclusions Rat PION created by photochemically induced ischemia is a reproducible and reliable animal model for mimicking the key features of human PION. Clinical Relevance The correspondence between the features of this rat PION model to those of human PION makes it an ideal model to study the pathophysiologic course of the disease, most of which remains to be elucidated. Furthermore, it provides an optimal model for testing therapeutic approaches for optic neuropathies. PMID:23544206

  14. Opioid Abuse after Traumatic Brain Injury: Evaluation Using Rodent Models

    Science.gov (United States)

    2015-09-01

    craniotomy was cut with a trephine by hand over the right motor cortex . An injury cannula was fashioned from the hub of a female leur-lock 20g needle...ABSTRACT This project evaluated the effect of a moderate-level brain injury on risk for opioid abuse using preclinical models in rats . We assessed the...effect of brain injury on the rewarding effects of oxycodone in three rat self-administration procedures and found significant differences in the

  15. Modelling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species– pharmacokinetic and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Felicitas S Boretti

    2014-10-01

    Full Text Available Preclinical studies suggest that haptoglobin (Hp supplementation could be an effective therapeutic modality during acute or chronic hemolytic diseases. Hp prevents Hb extravasation and neutralizes Hb’s oxidative and NO scavenging activity in the vasculature. Small animal models such as mouse, rat and guinea pig appear to be valuable to provide proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from human in the clearance of Hb:Hp complexes, which leads to long persistence of circulating Hb:Hp complexes after administration of human plasma derived Hp. Alternative animal models must therefore be explored to guide pre-clinical development of these potential therapeutics. In contrast to rodents, dogs have high Hp plasma concentrations comparable to human. In this study we show that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp phenotype complexes. The data reflect a drastically reduced volume of distribution (Vc of the complex compared to free Hb, increased exposures (Cmax and AUC and significantly reduced total body clearance (CL with a terminal half-life (t1/2 of approximately 12 hours. Distribution and clearance was identical for dog and human Hb (± glucocorticoid stimulation and for dimeric and multimeric Hp preparations bound to Hb. Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp therapeutics.

  16. An early warning system for IPM-based rodent control in smallholder farming systems in Tanzania

    DEFF Research Database (Denmark)

    Mwanjabe, Patrick S.; Leirs, Herwig

    1997-01-01

    numbers increased faster. Where abundant short rains were a normal condition returning every year, such effect was not clear. A method to assess rodent damage to germinating seedlings was found to be robust and can be used for monitoring rodent problems. Using this assessment technique, we showed...

  17. Social defeat models in animal science: What we have learned from rodent models.

    Science.gov (United States)

    Toyoda, Atsushi

    2017-07-01

    Studies on stress and its impacts on animals are very important in many fields of science, including animal science, because various stresses influence animal production and animal welfare. In particular, the social stresses within animal groups have profound impact on animals, with the potential to induce abnormal behaviors and health problems. In humans, social stress induces several health problems, including psychiatric disorders. In animal stress models, social defeat models are well characterized and used in various research fields, particularly in studies concerning mental disorders. Recently, we have focused on behavior, nutrition and metabolism in rodent models of social defeat to elucidate how social stresses affect animals. In this review, recent significant progress in studies related to animal social defeat models are described. In the field of animal science, these stress models may contribute to advances in the development of functional foods and in the management of animal welfare. © 2017 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.

  18. Handcrafted Electrocorticography Electrodes for a Rodent Behavioral Model

    Directory of Open Access Journals (Sweden)

    Nishat Tasnim

    2016-08-01

    Full Text Available Electrocorticography (ECoG is a minimally invasive neural recording method that has been extensively used for neuroscience applications. It has proven to have the potential to ease the establishment of proper links for neural interfaces that can offer disabled patients an alternative solution for their lost sensory and motor functions through the use of brain-computer interface (BCI technology. Although many neural recording methods exist, ECoG provides a combination of stability, high spatial and temporal resolution with chronic and mobile capabilities that could make BCI systems accessible for daily applications. However, many ECoG electrodes require MEMS fabricating techniques which are accompanied by various expenses that are obstacles for research projects. For this reason, this paper presents an animal study using a low cost and simple handcrafted ECoG electrode that is made of commercially accessible materials. The study is performed on a Lewis rat implanted with a handcrafted 32-channel non-penetrative ECoG electrode covering an area of 3 × 3 mm2 on the cortical surface. The ECoG electrodes were placed on the motor and somatosensory cortex to record the signal patterns while the animal was active on a treadmill. Using a Tucker-Davis Technologies acquisition system and the software Synapse to monitor and analyze the electrophysiological signals, the electrodes obtained signals within the amplitude range of 200 µV for local field potentials with reliable spatiotemporal profiles. It was also confirmed that the handcrafted ECoG electrode has the stability and chronic features found in other commercial electrodes.

  19. Polarization Raman spectroscopy to explain rodent models of brittle bone

    Science.gov (United States)

    Makowski, Alexander J.; Nyman, Jeffry S.; Mahadevan-Jansen, Anita

    2013-03-01

    Activation Transcription Factor 4 (Atf-4) is essential for osteoblast maturation and proper collagen synthesis. We recently found that these bones demonstrate a rare brittleness phenotype, which is independent of bone strength. We utilized a confocal Renishaw Raman microscope (50x objective; NA=.75) to evaluate embedded, polished cross-sections of mouse tibia from both wild-type and knockout mice at 8 weeks of age (24 mice, nmineral and collagen; however, compositional changes did not fully encompass biomechanical differences. To investigate the impact of material organization, we acquired colocalized spectra aligning the polarization angle parallel and perpendicular to the long bone axis from wet intact femurs. To validate our results, we used MMP9-/- mice, which have a brittleness phenotype that is not explained by compositional Raman measures. Polarization angle difference spectra show marked significant changes in orientation of these compositional differences when comparing wild type to knockout bones. Relative to wild-type, Atf4 -/- and MMP9 -/- bones show significant differences (t-test; pbones. Such findings could have alternate interpretations about net collagen orientation or the angular distribution of collagen molecules. Use of polarization specific Raman measurements has implicated a structural profile that furthers our understanding of models of bone brittleness. Polarization content of Raman spectra may prove significant in future studies of brittle fracture and human fracture risk.

  20. Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells

    Directory of Open Access Journals (Sweden)

    Tatiana I Novobrantseva

    2012-01-01

    Full Text Available Leukocytes are central regulators of inflammation and the target cells of therapies for key diseases, including autoimmune, cardiovascular, and malignant disorders. Efficient in vivo delivery of small interfering RNA (siRNA to immune cells could thus enable novel treatment strategies with broad applicability. In this report, we develop systemic delivery methods of siRNA encapsulated in lipid nanoparticles (LNP for durable and potent in vivo RNA interference (RNAi-mediated silencing in myeloid cells. This work provides the first demonstration of siRNA-mediated silencing in myeloid cell types of nonhuman primates (NHPs and establishes the feasibility of targeting multiple gene targets in rodent myeloid cells. The therapeutic potential of these formulations was demonstrated using siRNA targeting tumor necrosis factor-α (TNFα which induced substantial attenuation of disease progression comparable to a potent antibody treatment in a mouse model of rheumatoid arthritis (RA. In summary, we demonstrate a broadly applicable and therapeutically relevant platform for silencing disease genes in immune cells.

  1. Stress in adolescence and drugs of abuse in rodent models: Role of dopamine, CRF, and HPA axis

    Science.gov (United States)

    Burke, Andrew R.; Miczek, Klaus A.

    2014-01-01

    Rationale Research on adolescence and drug abuse increased substantially in the past decade. However, drug-addiction related behaviors following stressful experiences during adolescence are less studied. We focus on rodent models of adolescent stress cross-sensitization to drugs of abuse. Objectives Review the ontogeny of behavior, dopamine, corticotropin-releasing factor (CRF), and the hypothalamic pituitary adrenal (HPA) axis in adolescent rodents. We evaluate evidence that stressful experiences during adolescence engender hypersensitivity to drugs of abuse and offer potential neural mechanisms. Results and Conclusions Much evidence suggests that final maturation of behavior, dopamine systems, and HPA axis occurs during adolescence. Stress during adolescence increases amphetamine- and ethanol-stimulated locomotion, preference, and self-administration under many conditions. The influence of adolescent stress on subsequent cocaine- and nicotine-stimulated locomotion and preference is less clear. The type of adolescent stress, temporal interval between stress and testing, species, sex, and the drug tested are key methodological determinants for successful cross-sensitization procedures. The sensitization of the mesolimbic dopamine system is proposed to underlie stress cross-sensitization to drugs of abuse in both adolescents and adults through modulation by CRF. Reduced levels of mesocortical dopamine appear to be a unique consequence of social stress during adolescence. Adolescent stress may reduce the final maturation of cortical dopamine through D2 dopamine receptor regulation of dopamine synthesis or glucocorticoid-facilitated pruning of cortical dopamine fibers. Certain rodent models of adolescent adversity are useful for determining neural mechanisms underlying the cross-sensitization to drugs of abuse. PMID:24370534

  2. Morphological and functional maturation of Leydig cells: from rodent models to primates.

    Science.gov (United States)

    Teerds, Katja J; Huhtaniemi, Ilpo T

    2015-01-01

    Leydig cells (LC) are the sites of testicular androgen production. Development of LC occurs in the testes of most mammalian species as two distinct growth phases, i.e. as fetal and pubertal/adult populations. In primates there are indications of a third neonatal growth phase. LC androgen production begins in embryonic life and is crucial for the intrauterine masculinization of the male fetal genital tract and brain, and continues until birth after which it rapidly declines. A short post-natal phase of LC activity in primates (including human) termed 'mini-puberty' precedes the period of juvenile quiescence. The adult population of LC evolves, depending on species, in mid- to late-prepuberty upon reawakening of the hypothalamic-pituitary-testicular axis, and these cells are responsible for testicular androgen production in adult life, which continues with a slight gradual decline until senescence. This review is an updated comparative analysis of the functional and morphological maturation of LC in model species with special reference to rodents and primates. Pubmed, Scopus, Web of Science and Google Scholar databases were searched between December 2012 and October 2014. Studies published in languages other than English or German were excluded, as were data in abstract form only. Studies available on primates were primarily examined and compared with available data from specific animal models with emphasis on rodents. Expression of different marker genes in rodents provides evidence that at least two distinct progenitor lineages give rise to the fetal LC (FLC) population, one arising from the coelomic epithelium and the other from specialized vascular-associated cells along the gonad-mesonephros border. There is general agreement that the formation and functioning of the FLC population in rodents is gonadotrophin-responsive but not gonadotrophin-dependent. In contrast, although there is in primates some controversy on the role of gonadotrophins in the formation of

  3. Arvicanthis ansorgei, a Novel Model for the Study of Sleep and Waking in Diurnal Rodents

    Science.gov (United States)

    Hubbard, Jeffrey; Ruppert, Elisabeth; Calvel, Laurent; Robin-Choteau, Ludivine; Gropp, Claire-Marie; Allemann, Caroline; Reibel, Sophie; Sage-Ciocca, Dominique; Bourgin, Patrice

    2015-01-01

    Study Objectives: Sleep neurobiology studies use nocturnal species, mainly rats and mice. However, because their daily sleep/wake organization is inverted as compared to humans, a diurnal model for sleep studies is needed. To fill this gap, we phenotyped sleep and waking in Arvicanthis ansorgei, a diurnal rodent widely used for the study of circadian rhythms. Design: Video-electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG) recordings. Setting: Rodent sleep laboratory. Participants: Fourteen male Arvicanthis ansorgei, aged 3 mo. Interventions: 12 h light (L):12 h dark (D) baseline condition, 24-h constant darkness, 6-h sleep deprivation. Measurements and Results: Wake and rapid eye movement (REM) sleep showed similar electrophysiological characteristics as nocturnal rodents. On average, animals spent 12.9 h ± 0.4 awake per 24-h cycle, of which 6.88 h ± 0.3 was during the light period. NREM sleep accounted for 9.63 h ± 0.4, which of 5.13 h ± 0.2 during dark period, and REM sleep for 89.9 min ± 6.7, which of 52.8 min ± 4.4 during dark period. The time-course of sleep and waking across the 12 h light:12 h dark was overall inverted to that observed in rats or mice, though with larger amounts of crepuscular activity at light and dark transitions. A dominant crepuscular regulation of sleep and waking persisted under constant darkness, showing the lack of a strong circadian drive in the absence of clock reinforcement by external cues, such as a running wheel. Conservation of the homeostatic regulation was confirmed with the observation of higher delta power following sustained waking periods and a 6-h sleep deprivation, with subsequent decrease during recovery sleep. Conclusions: Arvicanthis ansorgei is a valid diurnal rodent model for studying the regulatory mechanisms of sleep and so represents a valuable tool for further understanding the nocturnality/diurnality switch. Citation: Hubbard J, Ruppert E, Calvel L, Robin-Choteau L, Gropp CM

  4. Multiparameter rodent chronic model for complex evaluation of alcoholism-mediated metabolic violations.

    Science.gov (United States)

    Shayakhmetova, Ganna M; Bondarenko, Larysa B; Kovalenko, Valentina M; Kharchenko, Olga I; Bohun, Larisa I; Omelchenko, Yuliya O

    2015-01-01

    Despite of the wide spectrum of alcoholism experimental models, the majority of them are very specialized on the short list of investigated parameters and could not provide reproduction of complex metabolic changes in the rats. The aim of the present study was to estimate whether rats selected by high alcohol preference, allowed free access to 15% alcohol for 150 days, develop simultaneous multilevel disturbances of cell macromolecules structure, metabolism and oxidative/nitrosative stress. Wistar albino male rats were divided into groups: I - rats selected by preferences to alcohol were used for chronic alcoholism modeling by replacing water with 15% ethanol (150 days), II - control. Contents of amino acids in serum, liver mRNA CYP2E1 and CYP3A2 expression, DNA fragmentation and lipid peroxidation levels, the reduced glutathione content, superoxide dismutase, catalase, iNOS and cNOS activities were evaluated. In serum of ethanol-treated rats contents of aspartic acid, serine, glycine, alanine and valine were decreased whereas contents of histidine, methionine and phenylalanine were increased. Liver CYP2E1, CYP3A2 mRNA expression, DNA fragmentation levels significantly elevated. Level of cNOS in ethanol-treated rat's hepatocytes was within the normal limits, whereas iNOS activity was raised 1.6 times. Liver pro- and anti-oxidant system alterations were shown. Rats' chronic 15% alcohol consumption (150 days) led solely to complex metabolomic changes at different levels, which simultaneously characterized cell macromolecules structure, metabolism, and oxidative/nitrosative stress. Rodent model of chronic alcoholism in the proposed modification could be an adequate and reasonably priced tool for further preclinical development and testing of pharmacotherapeutic agents.

  5. The relevance of non-human primate and rodent malaria models for humans

    Directory of Open Access Journals (Sweden)

    Riley Eleanor

    2011-02-01

    Full Text Available Abstract At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host-Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models. Several speakers took the opportunity to demonstrate the similarities between findings in rodent models and human severe disease, as well as points of difference. The variety of malaria presentations in the different experimental models parallels the wide diversity of human malaria disease and, therefore, might be viewed as a strength. Many of the key features of human malaria can be replicated in a variety of nonhuman primate models, which are very under-utilized. The importance of animal models in the discovery of new anti-malarial drugs was emphasized. The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material.

  6. Radiation-induced mammary carcinogenesis in rodent models. What's different from chemical carcinogenesis?

    International Nuclear Information System (INIS)

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Iizuka, Daisuke; Daino, Kazuhiro; Takabatake, Takashi; Okamoto, Mieko; Kakinuma, Shizuko; Shimada, Yoshiya

    2009-01-01

    Ionizing radiation is one of a few well-characterized etiologic factors of human breast cancer. Laboratory rodents serve as useful experimental models for investigating dose responses and mechanisms of cancer development. Using these models, a lot of information has been accumulated about mammary gland cancer, which can be induced by both chemical carcinogens and radiation. In this review, we first list some experimental rodent models of breast cancer induction. We then focus on several topics that are important in understanding the mechanisms and risk modification of breast cancer development, and compare radiation and chemical carcinogenesis models. We will focus on the pathology and natural history of cancer development in these models, genetic changes observed in induced cancers, indirect effects of carcinogens, and finally risk modification by reproductive factors and age at exposure to the carcinogens. In addition, we summarize the knowledge available on mammary stem/progenitor cells as a potential target of carcinogens. Comparison of chemical and radiation carcinogenesis models on these topics indicates certain similarities, but it also indicates clear differences in several important aspects, such as genetic alterations of induced cancers and modification of susceptibility by age and reproductive factors. Identification of the target cell type and relevant translational research for human risk management may be among the important issues that are addressed by radiation carcinogenesis models. (author)

  7. Vitamin D depletion does not affect key aspects of the preeclamptic phenotype in a transgenic rodent model for preeclampsia

    DEFF Research Database (Denmark)

    Andersen, Louise Bjørkholt; Golic, Michaela; Przybyl, Lukasz

    2016-01-01

    Maternal vitamin D deficiency is proposed as a risk factor for preeclampsia in humans. We tested the hypothesis that vitamin D depletion aggravates and high supplementation ameliorates the preeclampsia phenotype in an established transgenic rat model of human renin-angiotensin system......-mediated preeclampsia. Adult rat dams, transgenic for human angiotensinogen (hAGT) and mated with male rats transgenic for human renin (hREN), were fed either vitamin D-depleted chow (VDd) or enriched chow (VDh) 2 weeks before mating and during pregnancy. Mean blood pressure was recorded by tail-cuff, and 24-hour urine...... of the preeclampsia phenotype using the transgenic rodent model of human renin-angiotensin system-mediated pre-eclampsia, plausibly due to altered vitamin D metabolism or excretion in the transgenic rats....

  8. Rodent scope: a user-configurable digital wireless telemetry system for freely behaving animals.

    Directory of Open Access Journals (Sweden)

    David Ball

    Full Text Available This paper describes the design and implementation of a wireless neural telemetry system that enables new experimental paradigms, such as neural recordings during rodent navigation in large outdoor environments. RoSco, short for Rodent Scope, is a small lightweight user-configurable module suitable for digital wireless recording from freely behaving small animals. Due to the digital transmission technology, RoSco has advantages over most other wireless modules of noise immunity and online user-configurable settings. RoSco digitally transmits entire neural waveforms for 14 of 16 channels at 20 kHz with 8-bit encoding which are streamed to the PC as standard USB audio packets. Up to 31 RoSco wireless modules can coexist in the same environment on non-overlapping independent channels. The design has spatial diversity reception via two antennas, which makes wireless communication resilient to fading and obstacles. In comparison with most existing wireless systems, this system has online user-selectable independent gain control of each channel in 8 factors from 500 to 32,000 times, two selectable ground references from a subset of channels, selectable channel grounding to disable noisy electrodes, and selectable bandwidth suitable for action potentials (300 Hz-3 kHz and low frequency field potentials (4 Hz-3 kHz. Indoor and outdoor recordings taken from freely behaving rodents are shown to be comparable to a commercial wired system in sorting for neural populations. The module has low input referred noise, battery life of 1.5 hours and transmission losses of 0.1% up to a range of 10 m.

  9. The JCR:LA-cp rat: a novel rodent model of cystic medial necrosis.

    Science.gov (United States)

    Pung, Yuh Fen; Chilian, William M; Bennett, Martin R; Figg, Nichola; Kamarulzaman, Mohd Hamzah

    2017-03-01

    Although there are multiple rodent models of the metabolic syndrome, very few develop vascular complications. In contrast, the JCR:LA-cp rat develops both metabolic syndrome and early atherosclerosis in predisposed areas. However, the pathology of the normal vessel wall has not been described. We examined JCR:LA control (+/+) or cp/cp rats fed normal chow diet for 6 or 18 mo. JCR:LA-cp rats developed multiple features of advanced cystic medial necrosis including "cysts," increased collagen formation and proteoglycan deposition around cysts, apoptosis of vascular smooth muscle cells, and spotty medial calcification. These appearances began within 6 mo and were extensive by 18 mo. JCR:LA-cp rats had reduced medial cellularity, increased medial thickness, and vessel hypoxia that was most marked in the adventitia. In conclusion, the normal chow-fed JCR:LA-cp rat represents a novel rodent model of cystic medial necrosis, associated with multiple metabolic abnormalities, vascular smooth muscle cell apoptosis, and vessel hypoxia. NEW & NOTEWORTHY Triggers for cystic medial necrosis (CMN) have been difficult to study due to lack of animal models to recapitulate the pathologies seen in humans. Our study is the first description of CMN in the rat. Thus the JCR:LA-cp rat represents a useful model to investigate the underlying molecular changes leading to the development of CMN. Copyright © 2017 the American Physiological Society.

  10. Full field optical coherence tomography can identify spermatogenesis in a rodent sertoli-cell only model.

    Science.gov (United States)

    Ramasamy, Ranjith; Sterling, Joshua; Manzoor, Maryem; Salamoon, Bekheit; Jain, Manu; Fisher, Erik; Li, Phillip S; Schlegel, Peter N; Mukherjee, Sushmita

    2012-01-01

    Microdissection testicular sperm extraction (micro-TESE) has replaced conventional testis biopsies as a method of choice for obtaining sperm for in vitro fertilization for men with nonobstructive azoospermia. A technical challenge of micro-TESE is that the low magnification inspection of the tubules with a surgical microscope is insufficient to definitively identify sperm-containing tubules, necessitating tissue removal and cytologic assessment. Full field optical coherence tomography (FFOCT) uses white light interference microscopy to generate quick high-resolution tomographic images of fresh (unprocessed and unstained) tissue. Furthermore, by using a nonlaser safe light source (150 W halogen lamp) for tissue illumination, it ensures that the sperm extracted for in vitro fertilization are not photo-damaged or mutagenized. A focal Sertoli-cell only rodent model was created with busulfan injection in adult rats. Ex vivo testicular tissues from both normal and busulfan-treated rats were imaged with a commercial modified FFOCT system, Light-CT™, and the images were correlated with gold standard hematoxylin and eosin staining. Light-CT™ identified spermatogenesis within the seminiferous tubules in freshly excised testicular tissue, without the use of exogenous contrast or fixation. Normal adult rats exhibited tubules with uniform size and shape (diameter 328 ±11 μm). The busulfan-treated animals showed marked heterogeneity in tubular size and shape (diameter 178 ± 35 μm) and only 10% contained sperm within the lumen. FFOCT has the potential to facilitate real-time visualization of spermatogenesis in humans, and aid in micro-TESE for men with infertility.

  11. Cognitive and behavioral evaluation of nutritional interventions in rodent models of brain aging and dementia

    Directory of Open Access Journals (Sweden)

    Wahl D

    2017-09-01

    Full Text Available Devin Wahl,1,2 Sean CP Coogan,1,3 Samantha M Solon-Biet,1,2 Rafael de Cabo,4 James B Haran,5 David Raubenheimer,1,6,7 Victoria C Cogger,1,2 Mark P Mattson,8 Stephen J Simpson,1,2,7 David G Le Couteur1,2 1Charles Perkins Centre, University of Sydney, Sydney, 2Aging and Alzheimers Institute, ANZAC Research Institute, Concord Clinical School/Sydney Medical School, Concord, NSW, Australia; 3Department of Renewable Resources, University of Alberta, Edmonton, AB, Canada; 4Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; 5Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA; 6Faculty of Veterinary Science, 7School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia; 8Laboratory of Neurosciences, National Institute on Aging’s Intramural Research Program, National Institutes of Health, Baltimore, MD, USA Abstract: Evaluation of behavior and cognition in rodent models underpins mechanistic and interventional studies of brain aging and neurodegenerative diseases, especially ­dementia. Commonly used tests include Morris water maze, Barnes maze, object recognition, fear ­conditioning, radial arm water maze, and Y maze. Each of these tests reflects some aspects of human memory including episodic memory, recognition memory, semantic memory, spatial memory, and emotional memory. Although most interventional studies in rodent models of dementia have focused on pharmacological agents, there are an increasing number of studies that have evaluated nutritional interventions including caloric restriction, intermittent fasting, and manipulation of macronutrients. Dietary interventions have been shown to influence ­various cognitive and behavioral tests in rodents indicating that nutrition can influence brain aging and possibly neurodegeneration. Keywords: calorie restriction, intermittent fasting, aging, memory, macronutrients

  12. Barriers to developing a valid rodent model of Alzheimer's disease: from behavioural analysis to etiologicalmechanisms

    Directory of Open Access Journals (Sweden)

    Darryl Christopher Gidyk

    2015-07-01

    Full Text Available Sporadic Alzheimer's disease is the most prevalent form of age-related dementia. As such, great effort has been put forth to investigate the etiology, progression, and underlying mechanisms of the disease. Countless studies have been conducted however the details of this disease remain largely unknown. Rodent models provide opportunities to investigate certain aspects of AD that cannot be ethically studied in humans. These animal models vary from study to study and have provided some insight, but no real advancements in the prevention or treatment of the disease. In this Hypothesis and Theory paper, we discuss what we perceive as barriers to impactful discovery in rodent AD research and we offer solutions for moving forward. Although no single model of AD is capable of providing the solution to the growing epidemic of the disease, we encourage a comprehensive approach that acknowledges the complex etiology of AD with the goal of enhancing the bidirectional translatability from bench to bedside and vice versa.

  13. Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses

    Directory of Open Access Journals (Sweden)

    Joseph W. Golden

    2015-01-01

    Full Text Available Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs.

  14. Optical imaging of oxidative stress in retinitis pigmentosa (RP) in rodent model

    Science.gov (United States)

    Ghanian, Zahra; Maleki, Sepideh; Gopalakrishnan, Sandeep; Sepehr, Reyhaneh; Eells, Janis T.; Ranji, Mahsa

    2013-02-01

    Oxidative stress (OS), which increases during retinal degenerative disorders, contributes to photoreceptor cell loss. The objective of this study was to investigate the changes in the metabolic state of the eye tissue in rodent models of retinitis pigmentosa by using the cryofluorescence imaging technique. The mitochondrial metabolic coenzymes NADH and FADH2 are autofluorescent and can be monitored without exogenous labels using optical techniques. The NADH redox ratio (RR), which is the ratio of the fluorescence intensity of these fluorophores (NADH/FAD), was used as a quantitative diagnostic marker. The NADH RR was examined in an established rodent model of retinitis pigmentosa (RP), the P23H rat, and compared to that of control Sprague-Dawley (SD) rats and P23H NIR treated rats. Our results demonstrated 24% decrease in the mean NADH RR of the eyes from P23H transgenic rats compared to normal rats and 20% increase in the mean NADH RR of the eyes from the P23H NIR treated rats compared to P23H non-treated rats.

  15. Optical imaging of mitochondrial redox state in rodent model of retinitis pigmentosa

    Science.gov (United States)

    Maleki, Sepideh; Gopalakrishnan, Sandeep; Ghanian, Zahra; Sepehr, Reyhaneh; Schmitt, Heather; Eells, Janis; Ranji, Mahsa

    2013-01-01

    Oxidative stress (OS) and mitochondrial dysfunction contribute to photoreceptor cell loss in retinal degenerative disorders. The metabolic state of the retina in a rodent model of retinitis pigmentosa (RP) was investigated using a cryo-fluorescence imaging technique. The mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent and can be monitored without exogenous labels using optical techniques. The cryo-fluorescence redox imaging technique provides a quantitative assessment of the metabolism. More specifically, the ratio of the fluorescence intensity of these fluorophores (NADH/FAD), the NADH redox ratio (RR), is a marker of the metabolic state of the tissue. The NADH RR and retinal function were examined in an established rodent model of RP, the P23H rat compared to that of nondystrophic Sprague-Dawley (SD) rats. The NADH RR mean values were 1.11±0.03 in the SD normal and 0.841±0.01 in the P23H retina, indicating increased OS in the P23H retina. Electroretinographic data revealed a significant reduction in photoreceptor function in P23H animals compared to SD nozrmal rats. Thus, cryo-fluorescence redox imaging was used as a quantitative marker of OS in eyes from transgenic rats and demonstrated that alterations in the oxidative state of eyes occur during the early stages of RP.

  16. [Biological and neural bases of partner preferences in rodents: models to understand human pair bonds].

    Science.gov (United States)

    Coria-Avila, G A; Hernández-Aguilar, M E; Toledo-Cárdenas, R; García-Hernández, L I; Manzo, J; Pacheco, P; Miquel, M; Pfaus, J G

    To analyse the biological and neural bases of partner preference formation in rodents as models to understand human pair bonding. Rodents are social individuals, capable of forming short- or long-lasting partner preferences that develop slowly by stimuli like cohabitation, or rapidly by stimuli like sex and stress. Dopamine, corticosteroids, oxytocin, vasopressin, and opioids form the neurochemical substrate for pair bonding in areas like the nucleus accumbens, the prefrontal cortex, the piriform cortex, the medial preoptic area, the ventral tegmental area and the medial amygdala, among others. Additional areas may participate depending on the nature of the conditioned stimuli by which and individual recognizes a preferred partner. Animal models help us understand that the capacity of an individual to display long-lasting and selective preferences depends on neural bases, selected throughout evolution. The challenge in neuroscience is to use this knowledge to create new solutions for mental problems associated with the incapacity of an individual to display a social bond, keep one, or cope with the disruption of a consolidated one.

  17. Sirc-cvs cytotoxicity test: an alternative for predicting rodent acute systemic toxicity.

    Science.gov (United States)

    Kitagaki, Masato; Wakuri, Shinobu; Hirota, Morihiko; Tanaka, Noriho; Itagaki, Hiroshi

    2006-10-01

    An in vitro crystal violet staining method using the rabbit cornea-derived cell line (SIRC-CVS) has been developed as an alternative to predict acute systemic toxicity in rodents. Seventy-nine chemicals, the in vitro cytotoxicity of which was already reported by the Multicenter Evaluation of In vitro Toxicity (MEIC) and ICCVAM/ECVAM, were selected as test compounds. The cells were incubated with the chemicals for 72 hrs and the IC(50) and IC(35) values (microg/mL) were obtained. The results were compared to the in vivo (rat or mouse) "most toxic" oral, intraperitoneal, subcutaneous and intravenous LD(50) values (mg/kg) taken from the RTECS database for each of the chemicals by using Pearson's correlation statistics. The following parameters were calculated: accuracy, sensitivity, specificity, prevalence, positive predictability, and negative predictability. Good linear correlations (Pearson's coefficient; r>0.6) were observed between either the IC(50) or the IC(35) values and all the LD(50) values. Among them, a statistically significant high correlation (r=0.8102, p50) values and the oral LD(50) values. By using the cut-off concentrations of 2,000 mg/kg (LD(50)) and 4,225 microg/mL (IC(50)), no false negatives were observed, and the accuracy was 84.8%. From this, it is concluded that this method could be used to predict the acute systemic toxicity potential of chemicals in rodents.

  18. Modeling natural photic entrainment in a subterranean rodent (Ctenomys aff. knighti, the Tuco-Tuco.

    Directory of Open Access Journals (Sweden)

    Danilo E F L Flôres

    Full Text Available Subterranean rodents spend most of the day inside underground tunnels, where there is little daily change in environmental variables. Our observations of tuco-tucos (Ctenomys aff. knighti in a field enclosure indicated that these animals perceive the aboveground light-dark cycle by several bouts of light-exposure at irregular times during the light hours of the day. To assess whether such light-dark pattern acts as an entraining agent of the circadian clock, we first constructed in laboratory the Phase Response Curve for 1 h light-pulses (1000lux. Its shape is qualitatively similar to other curves reported in the literature and to our knowledge it is the first Phase Response Curve of a subterranean rodent. Computer simulations were performed with a non-linear limit-cycle oscillator subjected to a simple model of the light regimen experienced by tuco-tucos. Results showed that synchronization is achieved even by a simple regimen of a single daily light pulse scattered uniformly along the light hours of the day. Natural entrainment studies benefit from integrated laboratory, field and computational approaches.

  19. Effects of early life adverse experiences on brain activity: Implications from maternal separation models in rodents

    Directory of Open Access Journals (Sweden)

    Mayumi eNishi

    2014-06-01

    Full Text Available During postnatal development, adverse early life experiences can affect the formation of neuronal circuits and exert long-lasting influences on neural function. Many studies have shown that daily repeated MS, an animal model of early life stress, can modulate the hypothalamic-pituitary-adrenal axis (HPA axis and can affect subsequent brain function and emotional behavior during adulthood. However, the molecular basis of the long-lasting effects of early life stress on brain function has not been completely elucidated. In this review, we introduce various cases of MS in rodents and illustrate the alterations in HPA axis activity by focusing on corticosterone (CORT, an end product of the HPA axis in rodents. We then present a characterization of the brain regions affected by various patterns of MS, including repeated MS and single time MS at various stages before weaning, by investigating c-Fos expression, a biological marker of neuronal activity. These CORT and c-Fos studies suggest that repeated early life stress may affect neuronal function in region- and temporal-specific manners, indicating a critical period for habituation to early life stress. Next, we discuss how early life stress can impact behavior, namely by inducing depression, anxiety or eating disorders. Furthermore, alterations in gene expression in adult mice exposed to MS, especially epigenetic changes of DNA methylation, are discussed.

  20. Effect of tramadol on pain-related behaviors and bladder overactivity in rodent cystitis models.

    Science.gov (United States)

    Oyama, Tatsuya; Homan, Takashi; Kyotani, Junko; Oka, Michiko

    2012-02-15

    Tramadol is a widely used analgesic that stimulates the μ opioid receptor and inhibits serotonin and noradrenalin reuptake. There have been studies on the analgesic effects of tramadol based on the tail-flick test, the formalin test, and the induction of allodynia by sciatic-nerve ligation. However, the effects of tramadol on behaviors related to bladder pain and bladder overactivity induced by cystitis have not been reported. To investigate the usefulness of tramadol for patients with cystitis, we investigated these effects of tramadol in rodent cystitis models. Intraperitoneal injection of cyclophosphamide caused bladder-specific inflammation and increases in pain-related behaviors, the number of voids and bladder weight in mice. Tramadol suppressed the cyclophosphamide-induced pain-related behaviors but did not affect the number of voids or the bladder weight. During continuous-infusion cystometrograms in anesthetized rats, cyclophosphamide shortened the intercontraction interval, indicating bladder overactivity. Tramadol significantly prolonged the intercontraction interval, and the effect was partially blocked by the opioid antagonist naloxone. This finding indicates that μ opioid receptors may be involved in the action of tramadol. In conclusion, tramadol ameliorated cyclophosphamide-induced bladder-pain-related behaviors and bladder overactivity in rodents. These findings suggest that tramadol might be a treatment option for cystitis-induced bladder pain and bladder overactivity. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Manual versus Automated Rodent Behavioral Assessment: Comparing Efficacy and Ease of Bederson and Garcia Neurological Deficit Scores to an Open Field Video-Tracking System

    OpenAIRE

    Fiona A. Desland; Aqeela Afzal; Zuha Warraich; J Mocco

    2014-01-01

    Animal models of stroke have been crucial in advancing our understanding of the pathophysiology of cerebral ischemia. Currently, the standards for determining neurological deficit in rodents are the Bederson and Garcia scales, manual assessments scoring animals based on parameters ranked on a narrow scale of severity. Automated open field analysis of a live-video tracking system that analyzes animal behavior may provide a more sensitive test. Results obtained from the manual Bederson and Garc...

  2. Mathematical methods to model rodent behavior in the elevated plus-maze.

    Science.gov (United States)

    Arantes, Rafael; Tejada, Julián; Bosco, Geraldine G; Morato, Silvio; Roque, Antonio C

    2013-11-15

    The elevated plus maze is a widely used experimental test to study anxiety-like rodent behavior. It is made of four arms, two open and two closed, connected at a central area forming a plus shaped maze. The whole apparatus is elevated 50 cm from the floor. The anxiety of the animal is usually assessed by the number of entries and duration of stay in each arm type during a 5-min period. Different mathematical methods have been proposed to model the mechanisms that control the animal behavior in the maze, such as factor analysis, statistical inference on Markov chains and computational modeling. In this review we discuss these methods and propose possible extensions of them as a direction for future research. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Behavioral testing in rodent models of orofacial neuropathic and inflammatory pain

    Science.gov (United States)

    Krzyzanowska, Agnieszka; Avendaño, Carlos

    2012-01-01

    Orofacial pain conditions are often very debilitating to the patient and difficult to treat. While clinical interest is high, the proportion of studies performed in the orofacial region in laboratory animals is relatively low, compared with other body regions. This is partly due to difficulties in testing freely moving animals and therefore lack of reliable testing methods. Here we present a comprehensive review of the currently used rodent models of inflammatory and neuropathic pain adapted to the orofacial areas, taking into account the difficulties and drawbacks of the existing approaches. We examine the available testing methods and procedures used for assessing the behavioral responses in the face in both mice and rats and provide a summary of some pharmacological agents used in these paradigms to date. The use of these agents in animal models is also compared with outcomes observed in the clinic. PMID:23139912

  4. Alternative conceptions of memory consolidation and the role of the hippocampus at the systems level in rodents.

    Science.gov (United States)

    Sutherland, R J; Lehmann, H

    2011-06-01

    We discuss very recent experiments with rodents addressing the idea that long-term memories initially depending on the hippocampus, over a prolonged period, become independent of it. No unambiguous recent evidence exists to substantiate that this occurs. Most experiments find that recent and remote memories are equally affected by hippocampus damage. Nearly all experiments that report spared remote memories suffer from two problems: retrieval could be based upon substantial regions of spared hippocampus and recent memory is tested at intervals that are of the same order of magnitude as cellular consolidation. Accordingly, we point the way beyond systems consolidation theories, both the Standard Model of Consolidation and the Multiple Trace Theory, and propose a simpler multiple storage site hypothesis. On this view, with event reiterations, different memory representations are independently established in multiple networks. Many detailed memories always depend on the hippocampus; the others may be established and maintained independently. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. A unique rodent model of cardiometabolic risk associated with the metabolic syndrome and polycystic ovary syndrome.

    Science.gov (United States)

    Shi, Danni; Dyck, Michael K; Uwiera, Richard R E; Russell, Jim C; Proctor, Spencer D; Vine, Donna F

    2009-09-01

    Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-/anovulation, and polycystic ovarian morphology and is a complex endocrine disorder that also presents with features of the metabolic syndrome, including obesity, insulin resistance, and dyslipidemia. These latter symptoms form cardiometabolic risk factors predisposing individuals to the development of type 2 diabetes and cardiovascular disease (CVD). To date, animal models to study PCOS in the context of the metabolic syndrome and CVD risk have been lacking. The aim of this study was to investigate the JCR:LA-cp rodent as an animal model of PCOS associated with the metabolic syndrome. Metabolic indices were measured at 6 and 12 wk, and reproductive parameters including ovarian morphology and estrous cyclicity were assessed at 12 wk or adulthood. At 6 wk of age, the cp/cp genotype of the JCR:LA-cp strain developed visceral obesity, insulin resistance, and dyslipidemia (hypertriglyceridemia and hypercholesterolemia) compared with control animals. Serum testosterone concentrations were not significantly different between groups at 6 wk of age. However, at 12 wk, the cp/cp genotype had higher serum testosterone concentrations, compared with control animals, and presented with oligoovulation, a decreased number of corpora lutea, and an increased number of total follicles, in particular atretic and cystic follicles. The cardiometabolic risk factors in the cp/cp animals were exacerbated at 12 wk including obesity, insulin resistance, and dyslipidemia. The results of this study demonstrate that the JCR:LA-cp rodent may be a useful PCOS-like model to study early mechanisms involved in the etiology of cardiometabolic risk factors in the context of both PCOS and the metabolic syndrome.

  6. Olfactory discrimination and memory deficits in the Flinders Sensitive Line rodent model of depression.

    Science.gov (United States)

    Cook, A; Pfeiffer, L-M; Thiele, S; Coenen, V A; Döbrössy, M D

    2017-10-01

    Major Depressive Disorder (MDD) is a heterogeneous psychiatric disorder with broad symptomatic manifestations. The current study examined, for the first time, olfactory memory and discrimination in the Flinders Sensitive Line (FSL) rodent model of depression. Male FSL rats and controls were trained on an Olfactory Discrimination (OD) and a Social Interaction (SI) test. On the OD test, the FSL and controls performed similarly at the shortest inter-trial interval (5min), however, with extended delay of 30min, the FSLs had a recall and odour discrimination deficit. At the longest delay (60min) both groups performed poorly. The FSL rats i.) had a deficit in olfactory discrimination suggesting impairment in olfactory memory and recall; ii.) were less likely to socialize with unfamiliar rats. The data suggests that FSL animals have an impaired olfactory information processing capacity. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Intraoperative laser speckle contrast imaging improves the stability of rodent middle cerebral artery occlusion model

    Science.gov (United States)

    Yuan, Lu; Li, Yao; Li, Hangdao; Lu, Hongyang; Tong, Shanbao

    2015-09-01

    Rodent middle cerebral artery occlusion (MCAO) model is commonly used in stroke research. Creating a stable infarct volume has always been challenging for technicians due to the variances of animal anatomy and surgical operations. The depth of filament suture advancement strongly influences the infarct volume as well. We investigated the cerebral blood flow (CBF) changes in the affected cortex using laser speckle contrast imaging when advancing suture during MCAO surgery. The relative CBF drop area (CBF50, i.e., the percentage area with CBF less than 50% of the baseline) showed an increase from 20.9% to 69.1% when the insertion depth increased from 1.6 to 1.8 cm. Using the real-time CBF50 marker to guide suture insertion during the surgery, our animal experiments showed that intraoperative CBF-guided surgery could significantly improve the stability of MCAO with a more consistent infarct volume and less mortality.

  8. Using the Activity-based Anorexia Rodent Model to Study the Neurobiological Basis of Anorexia Nervosa.

    Science.gov (United States)

    Chowdhury, Tara Gunkali; Chen, Yi-Wen; Aoki, Chiye

    2015-10-22

    Anorexia nervosa (AN) is a psychiatric illness characterized by excessively restricted caloric intake and abnormally high levels of physical activity. A challenging illness to treat, due to the lack of understanding of the underlying neurobiology, AN has the highest mortality rate among psychiatric illnesses. To address this need, neuroscientists are using an animal model to study how neural circuits may contribute toward vulnerability to AN and may be affected by AN. Activity-based anorexia (ABA) is a bio-behavioral phenomenon described in rodents that models the key symptoms of anorexia nervosa. When rodents with free access to voluntary exercise on a running wheel experience food restriction, they become hyperactive - running more than animals with free access to food. Here, we describe the procedures by which ABA is induced in adolescent female C57BL/6 mice. On postnatal day 36 (P36), the animal is housed with access to voluntary exercise on a running wheel. After 4 days of acclimation to the running wheel, on P40, all food is removed from the cage. For the next 3 days, food is returned to the cage (allowing animals free food access) for 2 hr daily. After the fourth day of food restriction, free access to food is returned and the running wheel is removed from the cage to allow the animals to recover. Continuous multi-day analysis of running wheel activity shows that mice become hyperactive within 24 hr following the onset of food restriction. The mice run even during the limited time during which they have access to food. Additionally, the circadian pattern of wheel running becomes disrupted by the experience of food restriction. We have been able to correlate neurobiological changes with various aspects of the animals' wheel running behavior to implicate particular brain regions and neurochemical changes with resilience and vulnerability to food-restriction induced hyperactivity.

  9. Functional characterization and expression of thalamic GABA(B) receptors in a rodent model of Parkinson's disease

    NARCIS (Netherlands)

    de Groote, C; Wullner, U; Loschmann, PA; Luiten, PGM; Klockgether, T

    1999-01-01

    Increased GABAergic neurotransmission of the basal ganglia output nuclei projecting to the motor thalamus is thought to contribute to the pathophysiology of Parkinson's disease. We investigated the functional role of thalamic GABA(B) receptors in a rodent model of Parkinson's disease. First, we

  10. Opportunities for improving animal welfare in rodent models of epilepsy and seizures.

    Science.gov (United States)

    Lidster, Katie; Jefferys, John G; Blümcke, Ingmar; Crunelli, Vincenzo; Flecknell, Paul; Frenguelli, Bruno G; Gray, William P; Kaminski, Rafal; Pitkänen, Asla; Ragan, Ian; Shah, Mala; Simonato, Michele; Trevelyan, Andrew; Volk, Holger; Walker, Matthew; Yates, Neil; Prescott, Mark J

    2016-02-15

    Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling

    International Nuclear Information System (INIS)

    Valerio, Luis G.; Arvidson, Kirk B.; Chanderbhan, Ronald F.; Contrera, Joseph F.

    2007-01-01

    Consistent with the U.S. Food and Drug Administration (FDA) Critical Path Initiative, predictive toxicology software programs employing quantitative structure-activity relationship (QSAR) models are currently under evaluation for regulatory risk assessment and scientific decision support for highly sensitive endpoints such as carcinogenicity, mutagenicity and reproductive toxicity. At the FDA's Center for Food Safety and Applied Nutrition's Office of Food Additive Safety and the Center for Drug Evaluation and Research's Informatics and Computational Safety Analysis Staff (ICSAS), the use of computational SAR tools for both qualitative and quantitative risk assessment applications are being developed and evaluated. One tool of current interest is MDL-QSAR predictive discriminant analysis modeling of rodent carcinogenicity, which has been previously evaluated for pharmaceutical applications by the FDA ICSAS. The study described in this paper aims to evaluate the utility of this software to estimate the carcinogenic potential of small, organic, naturally occurring chemicals found in the human diet. In addition, a group of 19 known synthetic dietary constituents that were positive in rodent carcinogenicity studies served as a control group. In the test group of naturally occurring chemicals, 101 were found to be suitable for predictive modeling using this software's discriminant analysis modeling approach. Predictions performed on these compounds were compared to published experimental evidence of each compound's carcinogenic potential. Experimental evidence included relevant toxicological studies such as rodent cancer bioassays, rodent anti-carcinogenicity studies, genotoxic studies, and the presence of chemical structural alerts. Statistical indices of predictive performance were calculated to assess the utility of the predictive modeling method. Results revealed good predictive performance using this software's rodent carcinogenicity module of over 1200 chemicals

  12. A Geographic Information Systems (GIS)-based analysis of modern South African rodent distributions, habitat use, and environmental tolerances.

    Science.gov (United States)

    Campbell, Timothy L; Lewis, Patrick J; Thies, Monte L; Williams, Justin K

    2012-11-01

    GOALS OF THIS STUDY WERE TO: (1) develop distributional maps of modern rodent genera throughout the countries of South Africa, Lesotho, and Swaziland by georeferencing museum specimens; (2) assess habitat preferences for genera by cross-referencing locality position with South African vegetation; and (3) identify mean annual precipitation and temperature range where the genera are located. Conterminous South Africa including the countries of Lesotho and Swaziland Digital databases of rodent museum specimens housed in the Ditsong National Museum of Natural History, South Africa (DM), and the Division of Mammals, National Museum of Natural History, Smithsonian Institution, United States (NMNH), were acquired and then sorted into a subset of specimens with associated coordinate data. The coordinate data were then used to develop distributional maps for the rodent genera present within the study area. Percent habitat occupation and descriptive statistics for six climatic variables were then determined for each genus by cross-referencing locality positions with vegetation and climatic maps. This report presents a series of maps illustrating the distribution of 35 rodent genera based on 19,471 geo-referenced specimens obtained from two major collections. Inferred habitat use by taxon is provided for both locality and specimen percent occurrence at three hierarchical habitat levels: biome, bioregion, and vegetation unit. Descriptive statistics for six climatic variables are also provided for each genus based on locality and specimen percent incidence. As rodent faunas are commonly used in paleoenvironmental reconstructions, an accurate assessment of rodent environmental tolerance ranges is necessary before confidence can be placed in an actualistic model. While the data presented here represent only a subset of the modern geographic distributions for many of the taxa examined, a wide range of environmental regimes are observed, suggesting that more research is necessary

  13. A Geographic Information Systems (GIS)-based analysis of modern South African rodent distributions, habitat use, and environmental tolerances

    Science.gov (United States)

    Campbell, Timothy L; Lewis, Patrick J; Thies, Monte L; Williams, Justin K

    2012-01-01

    Goals of this study were to: (1) develop distributional maps of modern rodent genera throughout the countries of South Africa, Lesotho, and Swaziland by georeferencing museum specimens; (2) assess habitat preferences for genera by cross-referencing locality position with South African vegetation; and (3) identify mean annual precipitation and temperature range where the genera are located. Conterminous South Africa including the countries of Lesotho and Swaziland Digital databases of rodent museum specimens housed in the Ditsong National Museum of Natural History, South Africa (DM), and the Division of Mammals, National Museum of Natural History, Smithsonian Institution, United States (NMNH), were acquired and then sorted into a subset of specimens with associated coordinate data. The coordinate data were then used to develop distributional maps for the rodent genera present within the study area. Percent habitat occupation and descriptive statistics for six climatic variables were then determined for each genus by cross-referencing locality positions with vegetation and climatic maps. This report presents a series of maps illustrating the distribution of 35 rodent genera based on 19,471 geo-referenced specimens obtained from two major collections. Inferred habitat use by taxon is provided for both locality and specimen percent occurrence at three hierarchical habitat levels: biome, bioregion, and vegetation unit. Descriptive statistics for six climatic variables are also provided for each genus based on locality and specimen percent incidence. As rodent faunas are commonly used in paleoenvironmental reconstructions, an accurate assessment of rodent environmental tolerance ranges is necessary before confidence can be placed in an actualistic model. While the data presented here represent only a subset of the modern geographic distributions for many of the taxa examined, a wide range of environmental regimes are observed, suggesting that more research is necessary

  14. Using tests and models to assess antidepressant-like activity in rodents

    Directory of Open Access Journals (Sweden)

    Kedzierska Ewa

    2016-06-01

    Full Text Available In today's world, depression is one of the more prevalent forms of mental illness. According to WHO, about 10%-30% of all women and 7%-15% of all men are afflicted by depression at least once in their life-times. Today, depression is assessed to be affecting 350 million people. Regarding this issue, an important challenge for current psychopharmacology is to develop new, more effective pharmacotherapy and to understand the mechanism of action of known antidepressants. Furthermore, there is the necessity to improve the effectiveness of anti-depression treatment by way of bringing about an understanding of the neurobiology of this illness. In achieving these objectives, animal models of depression can be useful. Yet, presently, all available animal models of depression rely on two principles: the actions of known antidepressants or the responses to stress. In this paper, we present an overview of the most widely used animal tests and models that are employed in assessing antidepressant-like activity in rodents. These include amphetamine potentiation, reversal of reserpine action, the forced swimming test, the tail suspension test, learned helplessness, chronic mild stress and social defeat stress. Moreover, the advantages and major drawbacks of each model are also discussed.

  15. Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.

    Science.gov (United States)

    Sweeney, Timothy E; Lofgren, Shane; Khatri, Purvesh; Rogers, Angela J

    2017-08-01

    The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.

  16. Rodent Models of Alcoholic Liver Disease: Role of Binge Ethanol Administration

    Directory of Open Access Journals (Sweden)

    Shubha Ghosh Dastidar

    2018-01-01

    Full Text Available Both chronic and acute (binge alcohol drinking are important health and economic concerns worldwide and prominent risk factors for the development of alcoholic liver disease (ALD. There are no FDA-approved medications to prevent or to treat any stage of ALD. Therefore, discovery of novel therapeutic strategies remains a critical need for patients with ALD. Relevant experimental animal models that simulate human drinking patterns and mimic the spectrum and severity of alcohol-induced liver pathology in humans are critical to our ability to identify new mechanisms and therapeutic targets. There are several animal models currently in use, including the most widely utilized chronic ad libitum ethanol (EtOH feeding (Lieber–DeCarli liquid diet model, chronic intragastric EtOH administration (Tsukamoto–French model, and chronic-plus-binge EtOH challenge (Bin Gao—National Institute on Alcohol Abuse and Alcoholism (NIAAA model. This review provides an overview of recent advances in rodent models of binge EtOH administration which help to recapitulate different features and etiologies of progressive ALD. These models include EtOH binge alone, and EtOH binge coupled with chronic EtOH intake, a high fat diet, or endotoxin challenge. We analyze the strengths, limitations, and translational relevance of these models, as well as summarize the liver injury outcomes and mechanistic insights. We further discuss the application(s of binge EtOH models in examining alcohol-induced multi-organ pathology, sex- and age-related differences, as well as circadian rhythm disruption.

  17. Early life stress paradigms in rodents: potential animal models of depression?

    Science.gov (United States)

    Schmidt, Mathias V; Wang, Xiao-Dong; Meijer, Onno C

    2011-03-01

    While human depressive illness is indeed uniquely human, many of its symptoms may be modeled in rodents. Based on human etiology, the assumption has been made that depression-like behavior in rats and mice can be modulated by some of the powerful early life programming effects that are known to occur after manipulations in the first weeks of life. Here we review the evidence that is available in literature for early life manipulation as risk factors for the development of depression-like symptoms such as anhedonia, passive coping strategies, and neuroendocrine changes. Early life paradigms that were evaluated include early handling, separation, and deprivation protocols, as well as enriched and impoverished environments. We have also included a small number of stress-related pharmacological models. We find that for most early life paradigms per se, the actual validity for depression is limited. A number of models have not been tested with respect to classical depression-like behaviors, while in many cases, the outcome of such experiments is variable and depends on strain and additional factors. Because programming effects confer vulnerability rather than disease, a number of paradigms hold promise for usefulness in depression research, in combination with the proper genetic background and adult life challenges.

  18. Translational rodent models of Korsakoff syndrome reveal the critical neuroanatomical substrates of memory dysfunction and recovery.

    Science.gov (United States)

    Savage, Lisa M; Hall, Joseph M; Resende, Leticia S

    2012-06-01

    Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS.

  19. Comparison of two rodent models of maternal separation on juvenile social behavior

    Directory of Open Access Journals (Sweden)

    Betty eZimmerberg

    2011-06-01

    Full Text Available Early childhood deprivation is associated with an increased risk of attachment disorders and psychopathology. The neural consequences of exposure to stress early in life have used two major rodent models to provide important tools for translational research. Although both models have been termed Maternal Separation, the paradigms differ in ways that clearly shift the focus of stress between maternal and offspring units. The first model, here called Early Deprivation (ED, isolates pups individually while the dam is left not alone, but with a subset of littermates in the home nest (Stay-at-homes. The other model, here called Maternal Separation (MS, isolates the dam in a novel cage while the pups are separated together. In this study, these two early stress models were directly compared for their effects on social behaviors in male and female juvenile offspring. Although both models altered play behavior compared to controls, patterns of prosocial behaviors versus submissive behaviors differed by model and sex. Additionally, there were main effects of sex, with female ED subjects exhibited masculinizing effects of early stress during play sessions. Maternal behavior upon reunion with the isolated subjects was significantly increased in the MS condition compared to both ED and control conditions, which also differed but by a lesser magnitude. Stay-at-homes were tested since some laboratories use them for controls rather than undisturbed litters; they displayed significantly different sex-dependent play compared to undisturbed subjects. These results indicate that early stress effects vary by paradigm of separation. We suggest that MS produces greater stress on the dam and thus greater maternal mediation, while ED causes greater stress on the neonates, resulting in different behavioral sequela that warrant attention when using these models for translational research.

  20. Accelerated cognitive decline in a rodent model for temporal lobe epilepsy

    NARCIS (Netherlands)

    Schipper, Sandra; Aalbers, Marlien W.; Rijkers, Kim; Lagiere, Melanie; Bogaarts, Jan G.; Blokland, Arjan; Klinkenberg, Sylvia; Hoogland, Govert; Vles, Johan S. H.

    2016-01-01

    Objective: Cognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent

  1. Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain.

    Directory of Open Access Journals (Sweden)

    Michael R Due

    Full Text Available Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4 may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG, we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ, a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p. were observed in TNI rodents at post-injury day (PID 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p. alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28. In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a

  2. Preclinical Magnetic Resonance Fingerprinting (MRF) at 7 T: Effective Quantitative Imaging for Rodent Disease Models

    Science.gov (United States)

    Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A.; Vincent, Jason A.; Dell, Katherine M.; Drumm, Mitchell L.; Brady-Kalnay, Susann M.; Griswold, Mark A.; Flask, Chris A.; Lu, Lan

    2015-01-01

    High field, preclinical magnetic resonance imaging (MRI) scanners are now commonly used to quantitatively assess disease status and efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical, 7.0 T MRI implementation of the highly novel Magnetic Resonance Fingerprinting (MRF) methodology that has been previously described for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a Fast Imaging with Steady-state Free Precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 minutes. This initial high field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. PMID:25639694

  3. Accelerated cognitive decline in a rodent model for temporal lobe epilepsy.

    Science.gov (United States)

    Schipper, Sandra; Aalbers, Marlien W; Rijkers, Kim; Lagiere, Melanie; Bogaarts, Jan G; Blokland, Arjan; Klinkenberg, Sylvia; Hoogland, Govert; Vles, Johan S H

    2016-12-01

    Cognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent model for temporal lobe epilepsy. Neurobehavioral assessment was performed before and after surgery, after the induction of self-sustaining limbic status epilepticus (SSLSE), and in the chronic phase in which rats experienced recurrent seizures. Furthermore, we assessed potential confounders of memory performance. Rats showed a deficit in spatial working memory after the induction of the SSLSE, which endured in the chronic phase. A progressive decline in recognition memory developed in SSLSE rats. Confounding factors were absent. Seizure frequency and also the severity of the status epilepticus were not correlated with the severity of cognitive deficits. The effect of the seizure frequency on cognitive comorbidity in epilepsy has long been debated, possibly because of confounders such as antiepileptic medication and the heterogeneity of epileptic etiologies. In an animal model of temporal lobe epilepsy, we showed that a decrease in spatial working memory does not relate to the seizure frequency. This suggests for other mechanisms are responsible for memory decline and potentially a common pathophysiology of cognitive deterioration and the occurrence and development of epileptic seizures. Identifying this common denominator will allow development of more targeted interventions treating cognitive decline in patients with epilepsy. The treatment of interictal symptoms will increase the quality of life of many patients with epilepsy. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. A Radio Frequency Radiation Exposure System for Rodents based on Reverberation Chambers.

    Science.gov (United States)

    Capstick, Myles; Kuster, Niels; Kuehn, Sven; Berdinas-Torres, Veronica; Gong, Yijian; Wilson, Perry; Ladbury, John; Koepke, Galen; McCormick, David L; Gauger, James; Melnick, Ronald L

    2017-08-01

    In this paper we present the novel design features, their technical implementation, and an evaluation of the radio Frequency (RF) exposure systems developed for the National Toxicology Program (NTP) of the National Institute of Environmental Health Sciences (NIEHS) studies on the potential toxicity and carcinogenicity of 2nd and 3rd generation mobile-phone signals. The system requirements for this 2-year NTP cancer bioassay study were the tightly-controlled lifetime exposure of rodents (1568 rats and 1512 mice) to three power levels plus sham simulating typical daily, and higher, exposures of users of GSM and CDMA (IS95) signals. Reverberation chambers and animal housing were designed to allow extended exposure time per day for free-roaming individually-housed animals. The performance of the chamber was characterized in terms of homogeneity, stirred to unstirred energy, efficiency. The achieved homogeneity was 0.59 dB and 0.48 dB at 900 and 1900 MHz respectively. The temporal variation in the electric field strength was optimized to give similar characteristics to that of the power control of a phone in a real network using the two stirrers. Experimental dosimetry was performed to validate the SAR sensitivity and determine the SAR uniformity throughout the exposure volume; SAR uniformities of 0.46 dB and 0.40 dB, respectively, for rats and mice were achieved.

  5. Microvascular anastomosis in rodent model evaluated by Fourier domain Doppler optical coherence tomography

    Science.gov (United States)

    Huang, Yong; Tong, Dedi; Zhu, Shan; Wu, Lehao; Ibrahim, Zuhaib; Lee, WP Andrew; Brandacher, Gerald; Kang, Jin U.

    2014-03-01

    Vascular and microvascular anastomosis are critical components of reconstructive microsurgery, vascular surgery and transplant surgery. Imaging modality that provides immediate, real-time in-depth view and 3D structure and flow information of the surgical site can be a great valuable tool for the surgeon to evaluate surgical outcome following both conventional and innovative anastomosis techniques, thus potentially increase the surgical success rate. Microvascular anastomosis for vessels with outer diameter smaller than 1.0 mm is extremely challenging and effective evaluation of the outcome is very difficult if not impossible using computed tomography (CT) angiograms, magnetic resonance (MR) angiograms and ultrasound Doppler. Optical coherence tomography (OCT) is a non-invasive high-resolution (micron level), high-speed, 3D imaging modality that has been adopted widely in biomedical and clinical applications. Phaseresolved Doppler OCT that explores the phase information of OCT signals has been shown to be capable of characterizing dynamic blood flow clinically. In this work, we explore the capability of Fourier domain Doppler OCT as an evaluation tool to detect commonly encountered post-operative complications that will cause surgical failure and to confirm positive result with surgeon's observation. Both suture and cuff based techniques were evaluated on the femoral artery and vein in the rodent model.

  6. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

    Energy Technology Data Exchange (ETDEWEB)

    Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Coelho, A.M.M. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Xerfan, M.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Cogliati, B. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Barbeiro, D.F. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Mazo, D.F.C. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Kubrusly, M.S.; D' Albuquerque, L.A.C. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Souza, H.P. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Carrilho, F.J.; Oliveira, C.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-02-24

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg{sup -1}·day{sup -1} by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

  7. Bipolar electrocautery: A rodent model of Sunderland third-degree nerve injury.

    Science.gov (United States)

    Moradzadeh, Arash; Brenner, Michael J; Whitlock, Elizabeth L; Tong, Alice Y; Luciano, Janina P; Hunter, Daniel A; Myckatyn, Terence M; Mackinnon, Susan E

    2010-01-01

    To determine the Sunderland classification of a bipolar electrocautery injury. Twenty-two rats received crush (a reproducible Sunderland second-degree injury) or bipolar electrocautery injury and were evaluated for functional, histomorphometric, and immunohistochemical recovery at 21 or 42 days. Animal experiments were performed between July 3 and December 12, 2007. Axonal regeneration and end plate reinnervation were evaluated in double transgenic cyan fluorescent protein-conjugated Thy1 and green fluorescent protein-conjugated S100 mice. Compared with crush injury, bipolar electrocautery injury caused greater disruption of myelin and neurofilament architecture at the injury site and decreased nerve fiber counts and percentage of neural tissue distal to the injury (P =.007). Complete functional recovery was seen after crush but not bipolar electrocautery injury. Serial live imaging demonstrated axonal regeneration at week 1 after crush and at week 3 after bipolar electrocautery injury. Qualitative assessment of motor end plate reinnervation at 42 days demonstrated complete neuromuscular end plate reinnervation in the crush group and only limited reinnervation in the bipolar electrocautery group. Bipolar electrocautery injury in a rodent model resulted in a Sunderland third-degree injury, characterized by gradual, incomplete recovery without intervention.

  8. PAIN IN A PARKINSON`S DISEASE RODENT ANIMAL MODEL INDUCED WITH 6-HYDROXYDOPAMINE

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    Antioch, I

    2017-06-01

    Full Text Available Pain phenomenon, the unpleasant sensory and emotional event, appears to evidently intrude in Parkinson disease (PD, a disease formally considered to be restricted only to motor deficits. Although over a half of persons with PD suffer from pain manifestations, there are very few reports targeting this issue. Considering the cases when motor symptoms of PD are eclipsed by severe pain disclosure, there is an obvious need of clarifying the intricate implications of pain in PD context. Because there are few studies researching the link between pain and PD in clinical context, but as well in animal models we chose to explore the effects of pain stimuli on a rodent model of PD. Materials and methods: We experimentally induced a PD model in Wistar rats (n=12 by injecting in the substantia nigra, a brain area known to be involved in PD occurrence, one dose of a 6-hydroxidopamine (6-OHDA solution (8µm 6-OHDA base and 4µm physiological saline, utilizing neurosurgery, while their control peers received same dose of saline solution. Two weeks after the intervention the animals were subjected to the hot-plate test, a behavioral task for acquiring pain sensitivity. Results: There was noticed a statistical significant (F(1,10 = 5.67, p=0.038 sensibility of the 6-OHDA rats to thermal pain stimuli (8.2 s ± 0.8 s in 6-OHDA group as compared to their peers (13.8 s ± 1.6 s in controls. Conclusions: The involvement of pain in PD animal models is demonstrated raising questions of how it influences PD evolution. Moreover, this result increases awareness of deficient diagnostic methods of pain in PD and as a consequence, poor treatment of pain manifestations.

  9. Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models

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    Tim eKarl

    2013-08-01

    Full Text Available Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the ‘two-hit hypothesis’ of schizophrenia predicting that genetic and environmental risk factors (GxE interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1 with particular environmental factors. It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types (e.g. transmembrane domain Nrg1, Type II Nrg1, which have been exposed to different forms of stress (acute versus chronic, restraint versus social and housing conditions (standard laboratory versus minimally enriched housing. These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms.

  10. Plasmalemmal Vesicle Associated Protein-1 (PV-1 is a marker of blood-brain barrier disruption in rodent models

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    Ali Zarina S

    2008-02-01

    Full Text Available Abstract Background Plasmalemmal vesicle associated protein-1 (PV-1 is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state. Results We demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated. Conclusion Our results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.

  11. Dietary fructose in pregnancy induces hyperglycemia, hypertension, and pathologic kidney and liver changes in a rodent model.

    Science.gov (United States)

    Shortliffe, Linda M Dairiki; Hammam, Olfat; Han, Xiaoyuan; Kouba, Erik; Tsao, Philip S; Wang, Bingyin

    2015-10-01

    The incidence of pregnancies complicated by hyperglycemia and hypertension is increasing along with associated morbidities to mother and offspring. The high fructose diet is a well-studied model that induces hyperglycemia and hypertension in male rodents, but may not affect females. We hypothesized that the physiologic stress of pregnancy may alter metabolic responses to dietary fructose. In this study female Sprague-Dawley rats were divided into two gestational dietary groups: (1) 60% carbohydrate standard rat chow (Pregnant-S-controls) and (2) 60% fructose enriched chow (Pregnant-F). Body weight, blood pressure, blood glucose, triglycerides, and insulin were measured in pregnancy and during the post-partum period. Maternal organ weight and histological changes were also assessed after delivery. By midpregnancy Pregnant-F rats had increased weight, elevated blood pressure, higher fasting glucose, and elevated triglycerides compared with Pregnant-S rats. Both groups demonstrated elevated gestational insulin levels with signs of insulin resistance (increased HOMA-IR). Pregnant-F rats showed significant histopathologic hepatic steatosis and renal tubular changes characterized by tubular dilation and glomerulosclerosis. Our study provides a model in which dietary change during pregnancy can be examined. We demonstrate, moreover, that high dietary fructose ingestion in pregnant rats may result in profound systemic and pathologic changes not appreciated during routine pregnancy. Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.

  12. Regulatory System for Stem/Progenitor Cell Niches in the Adult Rodent Pituitary

    Science.gov (United States)

    Yoshida, Saishu; Kato, Takako; Kato, Yukio

    2016-01-01

    The anterior lobe of the pituitary gland is a master endocrine tissue composed of five types of endocrine cells. Although the turnover rate of pituitary endocrine cells is as low as about 1.6% per day, recent studies have demonstrated that Sex-determining region Y-box 2 (SOX2)+-cells exist as pituitary stem/progenitor cells in the adult anterior lobe and contribute to cell regeneration. Notably, SOX2+-pituitary stem/progenitor cells form two types of niches in this tissue: the marginal cell layer (MCL-niche) and the dense cell clusters scattering in the parenchyma (parenchymal-niche). However, little is known about the mechanisms and factors for regulating the pituitary stem/progenitor cell niches, as well as the functional differences between the two types of niches. Elucidation of the regulatory mechanisms in the niches might enable us to understand the cell regeneration system that acts in accordance with physiological demands in the adult pituitary. In this review, so as to reveal the regulatory mechanisms of the two types of niche, we summarize the regulatory factors and their roles in the adult rodent pituitary niches by focusing on three components: soluble factors, cell surface proteins and extracellular matrixes. PMID:26761002

  13. Regulatory System for Stem/Progenitor Cell Niches in the Adult Rodent Pituitary

    Directory of Open Access Journals (Sweden)

    Saishu Yoshida

    2016-01-01

    Full Text Available The anterior lobe of the pituitary gland is a master endocrine tissue composed of five types of endocrine cells. Although the turnover rate of pituitary endocrine cells is as low as about 1.6% per day, recent studies have demonstrated that Sex-determining region Y-box 2 (SOX2+-cells exist as pituitary stem/progenitor cells in the adult anterior lobe and contribute to cell regeneration. Notably, SOX2+-pituitary stem/progenitor cells form two types of niches in this tissue: the marginal cell layer (MCL-niche and the dense cell clusters scattering in the parenchyma (parenchymal-niche. However, little is known about the mechanisms and factors for regulating the pituitary stem/progenitor cell niches, as well as the functional differences between the two types of niches. Elucidation of the regulatory mechanisms in the niches might enable us to understand the cell regeneration system that acts in accordance with physiological demands in the adult pituitary. In this review, so as to reveal the regulatory mechanisms of the two types of niche, we summarize the regulatory factors and their roles in the adult rodent pituitary niches by focusing on three components: soluble factors, cell surface proteins and extracellular matrixes.

  14. Activity of nucleic acid polymers in rodent models of HBV infection.

    Science.gov (United States)

    Schöneweis, Katrin; Motter, Neil; Roppert, Pia L; Lu, Mengji; Wang, Baoju; Roehl, Ingo; Glebe, Dieter; Yang, Dongliang; Morrey, John D; Roggendorf, Michael; Vaillant, Andrew

    2018-01-01

    Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes. These compounds have been previously shown to have the unique ability to eliminate serum surface antigen in DHBV-infected Pekin ducks and achieve multilog reduction of HBsAg or HBsAg loss in patients with chronic HBV infection and HBV/HDV coinfection. In ducks and humans, the blockage of HBsAg release by NAPs occurs by the selective targeting of the assembly and/or secretion of subviral particles (SVPs). The clinically active NAP species REP 2055 and REP 2139 were investigated in other relevant animal models of HBV infection including woodchucks chronically infected with WHV, HBV transgenic mice and HBV infected SCID-Hu mice. The liver accumulation of REP 2139 in woodchucks following subcutaneous administration was examined and was found to be similar to that observed in mice and ducks. However, in woodchucks, NAP treatment was associated with only mild (36-79% relative to baseline) reductions in WHsAg (4/10 animals) after 3-5 weeks of treatment without changes in serum WHV DNA. In HBV infected SCID-Hu mice, REP 2055 treatment was not associated with any reduction of HBsAg, HBeAg or HBV DNA in the serum after 28 days of treatment. In HBV transgenic mice, no reductions in serum HBsAg were observed with REP 2139 with up to 12 weeks of treatment. In conclusion, the antiviral effects of NAPs in DHBV infected ducks and patients with chronic HBV infection were weak or absent in woodchuck and mouse models despite similar liver accumulation of NAPs in all these species, suggesting that the mechanisms of SVP assembly and or secretion present in rodent models differs from that in DHBV and chronic HBV infections. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

    Science.gov (United States)

    Damasceno, Marina B M V; de Melo Júnior, José de Maria A; Santos, Sacha Aubrey A R; Melo, Luana T M; Leite, Laura Hévila I; Vieira-Neto, Antonio E; Moreira, Renato de A; Monteiro-Moreira, Ana Cristina de O; Campos, Adriana R

    2016-08-25

    Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor. Copyright © 2016. Published by Elsevier Ireland Ltd.

  16. The response of the natriuretic peptide system to water deprivation in the desert rodent, Notomys alexis.

    Science.gov (United States)

    Heimeier, Rachel A; Donald, John A

    2006-02-01

    Natriuretic peptides (NPs) are regulatory molecules that cause cGMP-mediated diuresis and natriuresis in mammals. Accordingly, it is interesting to consider their role in desert-adapted animals in which water is often limited. This study investigated the response of the natriuretic peptide (NP) system to varying periods of water deprivation (WD) in the Australian desert rodent species, Notomys alexis. It was hypothesised that the expression of the NP system will be down-regulated in water-deprived N. alexis compared to water-replete animals. The plasma levels of ANP were significantly reduced after 3 days of WD, but were unaffected by 7, 14 and 28 days of WD. Water deprivation for 3, 7, 14 days had a variable effect on the mRNA expression of ANP, CNP, NPR-A, NPR-B, and NPR-C, and a uniform down-regulation was not observed. However, after 28 days of WD, mRNA expression was similar to water-replete animals, except for NPR-A. Surprisingly, 7 and 14 days of WD caused an up-regulation in the ability of ANP to stimulate cGMP; this also occurred at 14 days for CNP. Taken together, the mRNA expression and peptide mediated guanylyl cyclase activity data after WD were in the opposite direction to what was predicted. Interestingly, after 28 days of WD, most parameters were similar to those of water-replete animals, which indicates that a down-regulation of the NP system is not part of the physiological response to an absence of free water in N. alexis.

  17. Investigating the Abscopal Effects of Radioablation on Shielded Bone Marrow in Rodent Models Using Multimodality Imaging.

    Science.gov (United States)

    Afshar, Solmaz F; Zawaski, Janice A; Inoue, Taeko; Rendon, David A; Zieske, Arthur W; Punia, Jyotinder N; Sabek, Omaima M; Gaber, M Waleed

    2017-07-01

    The abscopal effect is the response to radiation at sites that are distant from the irradiated site of an organism, and it is thought to play a role in bone marrow (BM) recovery by initiating responses in the unirradiated bone marrow. Understanding the mechanism of this effect has applications in treating BM failure (BMF) and BM transplantation (BMT), and improving survival of nuclear disaster victims. Here, we investigated the use of multimodality imaging as a translational tool to longitudinally assess bone marrow recovery. We used positron emission tomography/computed tomography (PET/CT), magnetic resonance imaging (MRI) and optical imaging to quantify bone marrow activity, vascular response and marrow repopulation in fully and partially irradiated rodent models. We further measured the effects of radiation on serum cytokine levels, hematopoietic cell counts and histology. PET/CT imaging revealed a radiation-induced increase in proliferation in the shielded bone marrow (SBM) compared to exposed bone marrow (EBM) and sham controls. T 2 -weighted MRI showed radiation-induced hemorrhaging in the EBM and unirradiated SBM. In the EBM and SBM groups, we found alterations in serum cytokine and hormone levels and in hematopoietic cell population proportions, and histological evidence of osteoblast activation at the bone marrow interface. Importantly, we generated a BMT mouse model using fluorescent-labeled bone marrow donor cells and performed fluorescent imaging to reveal the migration of bone marrow cells from shielded to radioablated sites. Our study validates the use of multimodality imaging to monitor bone marrow recovery and provides evidence for the abscopal response in promoting bone marrow recovery after irradiation.

  18. Human amniotic mesenchymal stromal cell transplantation improves endometrial regeneration in rodent models of intrauterine adhesions.

    Science.gov (United States)

    Gan, Lu; Duan, Hua; Xu, Qian; Tang, Yi-Qun; Li, Jin-Jiao; Sun, Fu-Qing; Wang, Sha

    2017-05-01

    Intrauterine adhesion (IUA) is a common uterine cavity disease characterized by the unsatisfactory regeneration of damaged endometria. Recently, stem cell transplantation has been proposed to promote the recovery process. Here we investigated whether human amniotic mesenchymal stromal cells (hAMSCs), a valuable resource for transplantation therapy, could improve endometrial regeneration in rodent IUA models. Forty female Sprague-Dawley rats were randomly assigned to five groups: normal, sham-operated, mechanical injury, hAMSC transplantation, and negative control group. One week after intervention and transplantation, histological analyses were performed, and immunofluorescent and immunohistochemical expression of cell-specific markers and messenger RNA expression of cytokines were measured. Thicker endometria, increased gland numbers and fewer fibrotic areas were found in the hAMSC transplantation group compared with the mechanical injury group. Engraftment of hAMSCs was detected by the presence of anti-human nuclear antigen-positive cells in the endometrial glands of the transplantation uteri. Transplantation of hAMSCs significantly decreased messenger RNA levels of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β), and increased those of anti-inflammatory cytokines (basic fibroblast growth factor, and interleukin-6) compared with the injured uterine horns. Immunohistochemical expression of endometrial epithelial cells was revealed in specimens after hAMSC transplantation, whereas it was absent in the mechanically injured uteri. hAMSC transplantation promotes endometrial regeneration after injury in IUA rat models, possibly due to immunomodulatory properties. These cells provide a more easily accessible source of stem cells for future research into the impact of cell transplantation on damaged endometria. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  19. Glutamate and GABA in autism spectrum disorder-a translational magnetic resonance spectroscopy study in man and rodent models.

    Science.gov (United States)

    Horder, Jamie; Petrinovic, Marija M; Mendez, Maria A; Bruns, Andreas; Takumi, Toru; Spooren, Will; Barker, Gareth J; Künnecke, Basil; Murphy, Declan G

    2018-05-25

    Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with a high human and economic burden. The pathophysiology of ASD is largely unclear, thus hampering development of pharmacological treatments for the core symptoms of the disorder. Abnormalities in glutamate and GABA signaling have been hypothesized to underlie ASD symptoms, and may form a therapeutic target, but it is not known whether these abnormalities are recapitulated in humans with ASD, as well as in rodent models of the disorder. We used translational proton magnetic resonance spectroscopy ([1H]MRS) to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies. [1H]MRS was performed in the striatum and the medial prefrontal cortex, of the humans, mice, and rats in order to allow for direct cross-species comparisons in specific cortical and subcortical brain regions implicated in ASD. In humans with ASD, glutamate concentration was reduced in the striatum and this was correlated with the severity of social symptoms. GABA levels were not altered in either brain region. The reduction in striatal glutamate was recapitulated in mice prenatally exposed to valproate, and in mice and rats carrying Nlgn3 mutations, but not in rodent ASD models with other etiologies. Our findings suggest that glutamate/GABA abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD; and may be linked to alterations in the neuroligin-neurexin signaling complex.

  20. In vivo efficacy of acyl CoA: diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidemia.

    Science.gov (United States)

    King, Andrew J; Segreti, Jason A; Larson, Kelly J; Souers, Andrew J; Kym, Philip R; Reilly, Regina M; Collins, Christine A; Voorbach, Martin J; Zhao, Gang; Mittelstadt, Scott W; Cox, Bryan F

    2010-07-10

    Postprandial serum triglyceride concentrations have recently been identified as a major, independent risk factor for future cardiovascular events. As a result, postprandial hyperlipidemia has emerged as a potential therapeutic target. The purpose of this study was two-fold. Firstly, to describe and characterize a standardized model of postprandial hyperlipidemia in multiple rodent species; and secondly, apply these rodent models to the evaluation of a novel class of pharmacologic agent; acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitors. Serum triglycerides were measured before and for 4h after oral administration of a standardized volume of corn oil, to fasted C57BL/6, ob/ob, apoE(-/-) and CD-1 mice; Sprague-Dawley and JCR/LA-cp rats; and normolipidemic and hyperlipidemic hamsters. Intragastric administration of corn oil increased serum triglycerides in all animals evaluated, however the magnitude and time-course of the postprandial triglyceride excursion varied. The potent and selective DGAT-1 inhibitor A-922500 (0.03, 0.3 and 3 mg/kg, p.o.), dose-dependently attenuated the maximal postprandial rise in serum triglyceride concentrations in all species tested. At the highest dose of DGAT-1 inhibitor, the postprandial triglyceride response was abolished. This study provides a comprehensive characterization of the time-course of postprandial hyperlipidemia in rodents. In addition, the ability of DGAT-1 inhibitors to attenuate postprandial hyperlipidemia in multiple rodent models, including those that feature insulin resistance, is documented. Exaggerated postprandial hyperlipidemia is inherent to insulin-resistant states in humans and contributes to the substantially elevated cardiovascular risk observed in these patients. Therefore, by attenuating postprandial hyperlipidemia, DGAT-1 inhibition may represent a novel therapeutic approach to reduce cardiovascular risk. Copyright 2010 Elsevier B.V. All rights reserved.

  1. Transgene regulation using the tetracycline-inducible TetR-KRAB system after AAV-mediated gene transfer in rodents and nonhuman primates.

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    Caroline Le Guiner

    Full Text Available Numerous studies have demonstrated the efficacy of the Adeno-Associated Virus (AAV-based gene delivery platform in vivo. The control of transgene expression in many protocols is highly desirable for therapeutic applications and/or safety reasons. To date, the tetracycline and the rapamycin dependent regulatory systems have been the most widely evaluated. While the long-term regulation of the transgene has been obtained in rodent models, the translation of these studies to larger animals, especially to nonhuman primates (NHP, has often resulted in an immune response against the recombinant regulator protein involved in transgene expression regulation. These immune responses were dependent on the target tissue and vector delivery route. Here, using AAV vectors, we evaluated a doxycyclin-inducible system in rodents and macaques in which the TetR protein is fused to the human Krüppel associated box (KRAB protein. We demonstrated long term gene regulation efficiency in rodents after subretinal and intramuscular administration of AAV5 and AAV1 vectors, respectively. However, as previously described for other chimeric transactivators, the TetR-KRAB-based system failed to achieve long term regulation in the macaque after intramuscular vector delivery because of the development of an immune response. Thus, immunity against the chimeric transactivator TetR-KRAB emerged as the primary limitation for the clinical translation of the system when targeting the skeletal muscle, as previously described for other regulatory proteins. New developments in the field of chimeric drug-sensitive transactivators with the potential to not trigger the host immune system are still needed.

  2. Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models.

    Science.gov (United States)

    Esquejo, Ryan M; Salatto, Christopher T; Delmore, Jake; Albuquerque, Bina; Reyes, Allan; Shi, Yuji; Moccia, Rob; Cokorinos, Emily; Peloquin, Matthew; Monetti, Mara; Barricklow, Jason; Bollinger, Eliza; Smith, Brennan K; Day, Emily A; Nguyen, Chuong; Geoghegan, Kieran F; Kreeger, John M; Opsahl, Alan; Ward, Jessica; Kalgutkar, Amit S; Tess, David; Butler, Lynne; Shirai, Norimitsu; Osborne, Timothy F; Steinberg, Gregory R; Birnbaum, Morris J; Cameron, Kimberly O; Miller, Russell A

    2018-04-08

    Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Mechanical Elongation of the Small Intestine: Evaluation of Techniques for Optimal Screw Placement in a Rodent Model

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    P. A. Hausbrandt

    2013-01-01

    Full Text Available Introduction. The aim of this study was to evaluate techniques and establish an optimal method for mechanical elongation of small intestine (MESI using screws in a rodent model in order to develop a potential therapy for short bowel syndrome (SBS. Material and Methods. Adult female Sprague Dawley rats (n=24 with body weight from 250 to 300 g (Σ=283 were evaluated using 5 different groups in which the basic denominator for the technique involved the fixation of a blind loop of the intestine on the abdominal wall with the placement of a screw in the lumen secured to the abdominal wall. Results. In all groups with accessible screws, the rodents removed the implants despite the use of washers or suits to prevent removal. Subcutaneous placement of the screw combined with antibiotic treatment and dietary modifications was finally successful. In two animals autologous transplantation of the lengthened intestinal segment was successful. Discussion. While the rodent model may provide useful basic information on mechanical intestinal lengthening, further investigations should be performed in larger animals to make use of the translational nature of MESI in human SBS treatment.

  4. Risk, reward, and decision-making in a rodent model of cognitive aging

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    Ryan J Gilbert

    2012-01-01

    Full Text Available Impaired decision-making in aging can directly impact factors (financial security, quality of healthcare that are critical to maintaining quality of life and independence at advanced ages. Naturalistic rodent models mimic human aging in other cognitive domains, and afford the opportunity to parse the effects of age on discrete aspects of decision-making in a manner relatively uncontaminated by experiential factors. Young adult (5-7 mo. and aged (23-25 mo. male F344 rats were trained on a probability discounting task in which they made discrete-trial choices between a small certain reward (1 food pellet and a large but uncertain reward (2 food pellets with varying probabilities of delivery ranging from 100% to 0%. Young rats chose the large reward when it was associated with a high probability of delivery and shifted to the smaller but certain reward as probability of the large reward decreased. As a group, aged rats performed comparably to young, but there was significantly greater variance among aged rats. One subgroup of aged rats showed strong preference for the small certain reward. This preference was maintained under conditions in which large reward delivery was certain, suggesting decreased sensitivity to reward magnitude. In contrast, another subgroup of aged rats showed strong preference for the large reward at low probabilities of delivery. Interestingly, this subgroup also showed elevated preference for probabilistic rewards when reward magnitudes were equalized. Previous findings using this same aged study population described strongly attenuated discounting of delayed rewards with age, together suggesting that a subgroup of aged rats may have deficits associated with accounting for costs (i.e., delay, probability. These deficits in cost-accounting were dissociable from the age-related differences in sensitivity to reward magnitude, suggesting that aging influences multiple, distinct neural mechanisms that can impact cost

  5. Risk, reward, and decision-making in a rodent model of cognitive aging.

    Science.gov (United States)

    Gilbert, Ryan J; Mitchell, Marci R; Simon, Nicholas W; Bañuelos, Cristina; Setlow, Barry; Bizon, Jennifer L

    2011-01-01

    Impaired decision-making in aging can directly impact factors (financial security, health care) that are critical to maintaining quality of life and independence at advanced ages. Naturalistic rodent models mimic human aging in other cognitive domains, and afford the opportunity to parse the effects of age on discrete aspects of decision-making in a manner relatively uncontaminated by experiential factors. Young adult (5-7 months) and aged (23-25 months) male F344 rats were trained on a probability discounting task in which they made discrete-trial choices between a small certain reward (one food pellet) and a large but uncertain reward (two food pellets with varying probabilities of delivery ranging from 100 to 0%). Young rats chose the large reward when it was associated with a high probability of delivery and shifted to the small but certain reward as probability of the large reward decreased. As a group, aged rats performed comparably to young, but there was significantly greater variance among aged rats. One subgroup of aged rats showed strong preference for the small certain reward. This preference was maintained under conditions in which large reward delivery was also certain, suggesting decreased sensitivity to reward magnitude. In contrast, another subgroup of aged rats showed strong preference for the large reward at low probabilities of delivery. Interestingly, this subgroup also showed elevated preference for probabilistic rewards when reward magnitudes were equalized. Previous findings using this same aged study population described strongly attenuated discounting of delayed rewards with age, together suggesting that a subgroup of aged rats may have deficits associated with accounting for reward costs (i.e., delay or probability). These deficits in cost-accounting were dissociable from the age-related differences in sensitivity to reward magnitude, suggesting that aging influences multiple, distinct mechanisms that can impact cost-benefit decision-making.

  6. Characterization of the innate immune response to chronic aspiration in a novel rodent model

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    Lin Shu S

    2007-11-01

    Full Text Available Abstract Background Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung. Methods Gastric fluid or normal saline was instilled into the left lung of rats (n = 48 weekly for 4, 8, 12, or 16 weeks (n = 6 each group. Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined. Results Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline. Conclusion This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.

  7. Intentional weight loss reduces mortality rate in a rodent model of dietary obesity.

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    Vasselli, Joseph R; Weindruch, Richard; Heymsfield, Steven B; Pi-Sunyer, F Xavier; Boozer, Carol N; Yi, Nengjun; Wang, Chenxi; Pietrobelli, Angelo; Allison, David B

    2005-04-01

    We used a rodent model of dietary obesity to evaluate effects of caloric restriction-induced weight loss on mortality rate. Research Measures and Procedures: In a randomized parallel-groups design, 312 outbred Sprague-Dawley rats (one-half males) were assigned at age 10 weeks to one of three diets: low fat (LF; 18.7% calories as fat) with caloric intake adjusted to maintain body weight 10% below that for ad libitum (AL)-fed rat food, high fat (HF; 45% calories as fat) fed at the same level, or HF fed AL. At age 46 weeks, the lightest one-third of the AL group was discarded to ensure a more obese group; the remaining animals were randomly assigned to one of three diets: HF-AL, HF with energy restricted to produce body weights of animals restricted on the HF diet throughout life, or LF with energy restricted to produce the body weights of animals restricted on the LF diet throughout life. Life span, body weight, and leptin levels were measured. Animals restricted throughout life lived the longest (p < 0.001). Life span was not different among animals that had been obese and then lost weight and animals that had been nonobese throughout life (p = 0.18). Animals that were obese and lost weight lived substantially longer than animals that remained obese throughout life (p = 0.002). Diet composition had no effect on life span (p = 0.52). Weight loss after the onset of obesity during adulthood leads to a substantial increase in longevity in rats.

  8. Long-lived cancer-resistant rodents as new model species for cancer research

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    Jorge eAzpurua

    2013-01-01

    Full Text Available Most rodents are small and short-lived, but several lineages have independently evolved long lifespans without a concomitant increase in body mass. Most notably, the two subterranean species naked mole rat (NMR and blind mole rat (BMR which have maximum lifespans of 32 and 21 years respectively. The longevity of these species has sparked interest in the tumor suppression strategies that may have also evolved, because for many rodent species (including mice, rats, guinea pigs, gerbils and hamsters tumors are major source of late-life mortality. Here, we review the recent literature on anticancer mechanisms in long-lived rodents. Both NMR and BMR seem to have developed tumor defenses that rely on extra-cellular signals. However, while the NMR relies on a form of contact inhibition to suppress growth, the BMR evolved a mechanism mediated by the release of interferon and rapid necrotic cell death. Although both organisms ultimately rely on canonical downstream tumor suppressors (pRB and p53 the studies reveal species can evolve different strategies to achieve tumor-resistance. Importantly, studies of these cancer-resistant rodents may benefit human health if such mechanisms can be activated in human cells.

  9. Electroacupuncture Promotes Recovery of Motor Function and Reduces Dopaminergic Neuron Degeneration in Rodent Models of Parkinson's Disease.

    Science.gov (United States)

    Lin, Jaung-Geng; Chen, Chao-Jung; Yang, Han-Bin; Chen, Yi-Hung; Hung, Shih-Ya

    2017-08-24

    Parkinson's disease (PD) is a common neurodegenerative disease. The pathological hallmark of PD is a progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta in the brain, ultimately resulting in severe striatal dopamine deficiency and the development of primary motor symptoms (e.g., resting tremor, bradykinesia) in PD. Acupuncture has long been used in traditional Chinese medicine to treat PD for the control of tremor and pain. Accumulating evidence has shown that using electroacupuncture (EA) as a complementary therapy ameliorates motor symptoms of PD. However, the most appropriate timing for EA intervention and its effect on dopamine neuronal protection remain unclear. Thus, this study used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model (systemic-lesioned by intraperitoneal injection) and the 1-methyl-4-phenylpyridinium (MPP⁺)-lesioned rat model (unilateral-lesioned by intra-SN infusion) of PD, to explore the therapeutic effects and mechanisms of EA at the GB34 (Yanglingquan) and LR3 (Taichong) acupoints. We found that EA increased the latency to fall from the accelerating rotarod and improved striatal dopamine levels in the MPTP studies. In the MPP⁺ studies, EA inhibited apomorphine induced rotational behavior and locomotor activity, and demonstrated neuroprotective effects via the activation of survival pathways of Akt and brain-derived neurotrophic factor (BDNF) in the SN region. In conclusion, we observed that EA treatment reduces motor symptoms of PD and dopaminergic neurodegeneration in rodent models, whether EA is given as a pretreatment or after the initiation of disease symptoms. The results indicate that EA treatment may be an effective therapy for patients with PD.

  10. Immunomodulatory and antioxidant function of albumin stabilises the endothelium and improves survival in a rodent model of chronic liver failure.

    Science.gov (United States)

    Garcia-Martinez, Rita; Andreola, Fausto; Mehta, Gautam; Poulton, Katie; Oria, Marc; Jover, Maria; Soeda, Junpei; Macnaughtan, Jane; De Chiara, Francesco; Habtesion, Abeba; Mookerjee, Rajeshwar P; Davies, Nathan; Jalan, Rajiv

    2015-04-01

    Liver failure is characterized by endothelial dysfunction, which results in hemodynamic disturbances leading to renal failure. Albumin infusion improves hemodynamics and prevents renal dysfunction in advance liver failure. These effects are only partly explained by the oncotic properties of albumin. This study was designed to test the hypothesis that albumin exerts its beneficial effects by stabilising endothelial function. In vivo: systemic hemodynamics, renal function, markers of endothelial dysfunction (ADMA) and inflammation were studied in analbuminaemic and Sprague-Dawley rats, 6-weeks after sham/bile duct ligation surgery. In vitro: human umbilical vein endothelial cells were stimulated with LPS with or without albumin. We studied protein expression and gene expression of adhesion molecules, intracellular reactive oxygen species, and cell stress markers. Compared to controls, analbuminaemic rats had significantly greater hemodynamic deterioration after bile duct ligation, resulting in worse renal function and shorter survival. This was associated with significantly greater plasma renin activity, worse endothelial function, and disturbed inflammatory response. In vitro studies showed that albumin was actively taken up by endothelial cells. Incubation of albumin pre-treated endothelial cells with LPS was associated with significantly less activation compared with untreated cells, decreased intracellular reactive oxygen species, and markers of cell stress. These results show, for the first time, that absence of albumin is characterised by worse systemic hemodynamics, renal function and higher mortality in a rodent model of chronic liver failure and illustrates the important non-oncotic properties of albumin in protecting against endothelial dysfunction. Copyright © 2015. Published by Elsevier B.V.

  11. The effect of tear size and nerve injury on rotator cuff muscle fatty degeneration in a rodent animal model.

    Science.gov (United States)

    Kim, H Mike; Galatz, Leesa M; Lim, Chanteak; Havlioglu, Necat; Thomopoulos, Stavros

    2012-07-01

    Irreversible muscle changes after rotator cuff tears is a well-known negative prognostic factor after shoulder surgery. Currently, little is known about the pathomechanism of fatty degeneration of the rotator cuff muscles after chronic cuff tears. The purposes of this study were to (1) develop a rodent animal model of chronic rotator cuff tears that can reproduce fatty degeneration of the cuff muscles seen clinically, (2) describe the effects of tear size and concomitant nerve injury on muscle degeneration, and (3) evaluate the changes in gene expression of relevant myogenic and adipogenic factors after rotator cuff tears using the animal model. Rotator cuff tears were created in rodents with and without transection of the suprascapular nerve. The supraspinatus and infraspinatus muscles were examined at 2, 8, and 16 weeks after injury for histologic evidence of fatty degeneration and expression of myogenic and adipogenic genes. Histologic analysis revealed adipocytes, intramuscular fat globules, and intramyocellular fat droplets in the tenotomized and neurotomized supraspinatus and infraspinatus muscles. Changes increased with time and were most severe in the muscles with combined tenotomy and neurotomy. Adipogenic and myogenic transcription factors and markers were upregulated in muscles treated with tenotomy or tenotomy combined with neurotomy compared with normal muscles. The rodent animal model described in this study produces fatty degeneration of the rotator cuff muscles similar to human muscles after chronic cuff tears. The severity of changes was associated with tear size and concomitant nerve injury. Copyright © 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.

  12. Large scale serial two-photon microscopy to investigate local vascular changes in whole rodent brain models of Alzheimer's disease

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    Delafontaine-Martel, P.; Lefebvre, J.; Damseh, R.; Castonguay, A.; Tardif, P.; Lesage, F.

    2018-02-01

    In this study, an automated serial two-photon microscope was used to image a fluorescent gelatin filled rodent's brain in 3D. A method to compute vascular density using automatic segmentation was combined with coregistration techniques to build group-level vasculature metrics. By studying the medial prefrontal cortex and the hippocampal formation of 3 age groups (2, 4.5 and 8 months old), we compared vascular density for both WT and an Alzheimer model transgenic brain (APP/PS1). We observe a loss of vascular density caused by the ageing process and we propose further analysis to confirm our results.

  13. OBscure but not OBsolete: Perturbations of the frontal cortex in common between rodent olfactory bulbectomy model and major depression.

    Science.gov (United States)

    Rajkumar, Ramamoorthy; Dawe, Gavin S

    2018-04-07

    Olfactory bulbectomy (OBX) has been used as a model of depression over several decades. This model presupposes a mechanism that is still not proven in clinical depression. A wealth of clinical literature has focused on the derangements in frontal cortex (prefrontal, orbitofrontal and anterior cingulate cortices) associated with depression. In this comprehensive review, anatomical, electrophysiological and molecular sequelae of bulbectomy in the rodent frontal cortex are explored and compared with findings on brains of humans with major depression. Certain commonalities in neurobiological features of the perturbed frontal cortex in the bulbectomised rodent and the depressed human brain are evident. Also, meta-analysis reports on clinical studies on depressed patients provide prima facie evidence that perturbations in the frontal cortex are associated with major depression. Analysing the pattern of perturbations in the chemical neuroanatomy of the frontal cortex will contribute to understanding of the neurobiology of depression. Revisiting the OBX model of depression to examine these neurobiological changes in frontal cortex with contemporary imaging, proteomics, lipidomics, metabolomics and epigenomics technologies is proposed as an approach to enhance the translational value of this animal model to facilitate identification of targets and biomarkers for clinical depression. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Sustained neuroprotection from a single intravitreal injection of PGJ2 in a rodent model of anterior ischemic optic neuropathy.

    Science.gov (United States)

    Touitou, Valerie; Johnson, Mary A; Guo, Yan; Miller, Neil R; Bernstein, Steven L

    2013-11-11

    Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve-related vision loss in persons older than 50 in the United States. There currently is no treatment for this disorder. We previously showed that systemic administration of 15-deoxy, delta (12, 14) prostaglandin J2 (PGJ2) is neuroprotective in our rodent model of AION (rAION). In this study, we determined if a single intravitreal (IVT) injection of PGJ2 is neuroprotective after rAION, and if this method of administration is toxic to the retina, optic nerve, or both. TOXICITY was assessed after a single IVT injection of PGJ2 in one eye and PBS in the contralateral eye of normal, adult Long-Evans rats. EFFICACY was assessed by inducing rAION in one eye and injecting either PGJ2 or vehicle immediately following induction, with the fellow eye serving as naïve control. Visual evoked potentials (VEPs) and ERGs were performed before induction and at specific intervals thereafter. Animals were euthanized 30 days after induction, after which immunohistochemistry, transmission electron microscopy, and quantitative stereology of retinal ganglion cell (RGC) numbers were performed. IVT PGJ2 did not alter the VEP or ERG compared with PBS-injected control eyes, and neither IVT PGJ2 nor PBS reduced overall RGC numbers. IVT PGJ2 preserved VEP amplitude, reduced optic nerve edema, and resulted in significant preservation of RGCs and axons in eyes with rAION. A single IVT injection of PGJ2 is nontoxic to the retina and optic nerve and neuroprotective when given immediately after rAION induction.

  15. Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection.

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    Melanie T Cushion

    2010-01-01

    Full Text Available Fungi in the genus Pneumocystis cause pneumonia (PCP in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express beta -1,3-D-glucan synthetase and contain abundant beta -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of beta -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased beta -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

  16. Cardiometabolic and reproductive benefits of early dietary energy restriction and voluntary exercise in an obese PCOS-prone rodent model.

    Science.gov (United States)

    Diane, Abdoulaye; Kupreeva, Maria; Borthwick, Faye; Proctor, Spencer D; Pierce, W David; Vine, Donna F

    2015-09-01

    Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age characterized by ovulatory dysfunction, hyperandrogenism and cardiometabolic risk. The overweight-obese PCOS phenotype appears to have exacerbated reproductive dysfunction and cardiometabolic risk. In overweight-obese adult women with PCOS, exercise and energy restricted diets have shown limited and inconsistent effects on both cardiometabolic indices and reproductive outcomes. We hypothesized that an early lifestyle intervention involving exercise and dietary energy restriction to prevent or reduce the propensity for adiposity would modulate reproductive indices and cardiometabolic risk in an obese PCOS-prone rodent model. Weanling obese PCOS-prone and Lean-Control JCR:LA-cp rodents were given a chow diet ad libitum or an energy-restricted diet combined with or without voluntary exercise (4  h/day) for 8 weeks. Dietary energy restriction and exercise lowered total body weight gain and body fat mass by 30% compared to free-fed sedentary or exercising obese PCOS-prone animals (Pexercise intensity compared to free-feeding plus exercise conditions. Energy restriction and exercise decreased fasting plasma triglycerides and apoB48 concentrations in obese PCOS-prone animals compared to free-fed and exercise or sedentary groups. The energy restriction and exercise combination in obese PCOS-prone animals significantly increased plasma sex-hormone binding globulin, hypothalamic cocaine-and amphetamine-regulated transcript (CART) and Kisspeptin mRNA expression to levels of the Lean-Control group, and this was further associated with improvements in estrous cyclicity. The combination of exercise and dietary energy restriction when initiated in early life exerts beneficial effects on cardiometabolic and reproductive indices in an obese PCOS-prone rodent model, and this may be associated with normalization of the hypothalamic neuropeptides, Kisspeptin and CART

  17. Mycobacterial lesions in fish, amphibians, reptiles, rodents, lagomorphs, and ferrets with reference to animal models.

    Science.gov (United States)

    Reavill, Drury R; Schmidt, Robert E

    2012-01-01

    Mycobacteriosis is a serious disease across many animal species. Approximately more than 120 species are currently recognized in the genus Mycobacterium. This article describes the zoonotic potential of mycobacteria and mycobacteriosis in fish, amphibians, rodents, rabbits, and ferrets. It considers clinical signs; histology; molecular methods of identification, such as polymerase chain reaction and DNA sequencing; routes of infection; and disease progression. Studying the disease in animals may aid in understanding the pathogenesis of mycobacterial infections in humans and identify better therapy and preventative options such as vaccines.

  18. A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part II: comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents.

    Science.gov (United States)

    Manwell, Laurie A; Ford, Brittany; Matthews, Brittany A; Heipel, Heather; Mallet, Paul E

    2014-01-01

    Studies of the rewarding and addictive properties of cannabinoids using rodents as animal models of human behaviour often fail to replicate findings from human studies. Animal studies typically employ parenteral routes of administration, whereas humans typically smoke cannabis, thus discrepancies may be related to different pharmacokinetics of parenteral and pulmonary routes of administration. Accordingly, a novel delivery system of vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) was developed and assessed for its pharmacokinetic, pharmacodynamic, and behavioural effects in rodents. A commercially available vapourizer was used to assess the effects of pulmonary (vapourized) administration of Δ(9)-THC and directly compared to parenteral (intraperitoneal, IP) administration of Δ(9)-THC. Sprague-Dawley rats were exposed to pure Δ(9)-THC vapour (1, 2, 5, 10, and 20mg/pad), using a Volcano® vapourizing device (Storz and Bickel, Germany) or IP-administered Δ(9)-THC (0.1, 0.3, 0.5, 1.0mg/kg), and drug effects on locomotor activity, food and water consumption, and cross-sensitization to morphine (5mg/kg) were measured. Vapourized Δ(9)-THC significantly increased feeding during the first hour following exposure, whereas IP-administered Δ(9)-THC failed to produce a reliable increase in feeding at all doses tested. Acute administration of 10mg of vapourized Δ(9)-THC induced a short-lasting stimulation in locomotor activity compared to control in the first of four hours of testing over 7days of repeated exposure; this chronic exposure to 10mg of vapourized Δ(9)-THC did not induce behavioural sensitization to morphine. These results suggest vapourized Δ(9)-THC administration produces behavioural effects qualitatively different from those induced by IP administration in rodents. Furthermore, vapourized Δ(9)-THC delivery in rodents may produce behavioural effects more comparable to those observed in humans. We conclude that some of the conflicting findings in animal

  19. Altered Tracer Distribution and Clearance in the Extracellular Space of the Substantia Nigra in a Rodent Model of Parkinson's Disease

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    Yuan Fang

    2017-07-01

    Full Text Available The relationship between extracellular space (ECS diffusion parameters and brain drug clearance is not well-studied, especially in the context of Parkinson's disease (PD. Therefore, we used a rodent model of PD to explore the distribution and clearance of a magnetic resonance tracer. Forty male Sprague Dawley rats were randomized into four different groups: a PD group, a Madopar group (PD + Madopar treatment, a sham group, and a control group. All rats received an injection of the extracellular tracer gadolinium-diethylene triaminepentacetic acid (Gd-DTPA directly into the substantia nigra (SN. ECS diffusion parameters including the effective diffusion coefficient (D*, clearance coefficient (k', ratio of the maximum distribution volume of the tracer (Vd-max%, and half-life (t1/2 were measured. We found that all parameters were significantly increased in the PD group compared to the other three groups (D*: F = 5.774, p = 0.0025; k': F = 20.00, P < 0.0001; Vd-max%: F = 12.81, P < 0.0001; and t1/2: F = 23.35, P < 0.0001. In conclusion, the PD group exhibited a wider distribution and lower clearance of the tracer compared to the other groups. Moreover, k' was more sensitive than D* for monitoring morphological and functional changes in the ECS in a rodent model of PD.

  20. Immune tolerance induction using fetal directed placental injection in rodent models: a murine model.

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    Kei Takahashi

    Full Text Available Induction of the immune response is a major problem in replacement therapies for inherited protein deficiencies. Tolerance created in utero can facilitate postnatal treatment. In this study, we aimed to induce immune tolerance towards a foreign protein with early gestational cell transplantation into the chorionic villi under ultrasound guidance in the murine model.Pregnant C57BL/6 (B6 mice on day 10 of gestation were anesthetized and imaged by high resolution ultrasound. Murine embryos and their placenta were positioned to get a clear view in B-mode with power mode of the labyrinth, which is the equivalent of chorionic villi in the human. Bone marrow cells (BMCs from B6-Green Fluorescence Protein (B6GFP transgenic mice were injected into the fetal side of the placenta which includes the labyrinth with glass microcapillary pipettes. Each fetal mouse received 2 x 105 viable GFP-BMCs. After birth, we evaluated the humoral and cell-mediated immune response against GFP.Bone marrow transfer into fetal side of placenta efficiently distributed donor cells to the fetal mice. The survival rate of this procedure was 13.5%(5 out of 37. Successful engraftment of the B6-GFP donor skin grafts was observed in all recipient (5 out of 5 mice 6 weeks after birth. Induction of anti-GFP antibodies was completely inhibited. Cytotoxic immune reactivity of thymic cells against cells harboring GFP was suppressed by ELISPOT assay.In this study, we utilized early gestational placental injection targeting the murine fetus, to transfer donor cells carrying a foreign protein into the fetal circulation. This approach is sufficient to induce both humoral and cell-mediated immune tolerance against the foreign protein.

  1. Global and 3D Spatial Assessment of Neuroinflammation in Rodent Models of Multiple Sclerosis

    DEFF Research Database (Denmark)

    Gupta, Shashank; Utoft, Regine Egeholm; Hasseldam, Henrik

    2013-01-01

    Multiple Sclerosis (MS) is a progressive autoimmune inflammatory and demyelinating disease of the central nervous system (CNS). T cells play a key role in the progression of neuroinflammation in MS and also in the experimental autoimmune encephalomyelitis (EAE) animal models for the disease. A te...

  2. Tissue expander stimulated lengthening of arteries (TESLA) induces early endothelial cell proliferation in a novel rodent model.

    Science.gov (United States)

    Potanos, Kristina; Fullington, Nora; Cauley, Ryan; Purcell, Patricia; Zurakowski, David; Fishman, Steven; Vakili, Khashayar; Kim, Heung Bae

    2016-04-01

    We examine the mechanism of aortic lengthening in a novel rodent model of tissue expander stimulated lengthening of arteries (TESLA). A rat model of TESLA was examined with a single stretch stimulus applied at the time of tissue expander insertion with evaluation of the aorta at 2, 4 and 7day time points. Measurements as well as histology and proliferation assays were performed and compared to sham controls. The aortic length was increased at all time points without histologic signs of tissue injury. Nuclear density remained unchanged despite the increase in length suggesting cellular hyperplasia. Cellular proliferation was confirmed in endothelial cell layer by Ki-67 stain. Aortic lengthening may be achieved using TESLA. The increase in aortic length can be achieved without tissue injury and results at least partially from cellular hyperplasia. Further studies are required to define the mechanisms involved in the growth of arteries under increased longitudinal stress. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Self-organised criticality in the evolution of a thermodynamic model of rodent thermoregulatory huddling.

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    Stuart P Wilson

    2017-01-01

    Full Text Available A thermodynamic model of thermoregulatory huddling interactions between endotherms is developed. The model is presented as a Monte Carlo algorithm in which animals are iteratively exchanged between groups, with a probability of exchanging groups defined in terms of the temperature of the environment and the body temperatures of the animals. The temperature-dependent exchange of animals between groups is shown to reproduce a second-order critical phase transition, i.e., a smooth switch to huddling when the environment gets colder, as measured in recent experiments. A peak in the rate at which group sizes change, referred to as pup flow, is predicted at the critical temperature of the phase transition, consistent with a thermodynamic description of huddling, and with a description of the huddle as a self-organising system. The model was subjected to a simple evolutionary procedure, by iteratively substituting the physiologies of individuals that fail to balance the costs of thermoregulation (by huddling in groups with the costs of thermogenesis (by contributing heat. The resulting tension between cooperative and competitive interactions was found to generate a phenomenon called self-organised criticality, as evidenced by the emergence of avalanches in fitness that propagate across many generations. The emergence of avalanches reveals how huddling can introduce correlations in fitness between individuals and thereby constrain evolutionary dynamics. Finally, a full agent-based model of huddling interactions is also shown to generate criticality when subjected to the same evolutionary pressures. The agent-based model is related to the Monte Carlo model in the way that a Vicsek model is related to an Ising model in statistical physics. Huddling therefore presents an opportunity to use thermodynamic theory to study an emergent adaptive animal behaviour. In more general terms, huddling is proposed as an ideal system for investigating the interaction

  4. Manual versus Automated Rodent Behavioral Assessment: Comparing Efficacy and Ease of Bederson and Garcia Neurological Deficit Scores to an Open Field Video-Tracking System.

    Science.gov (United States)

    Desland, Fiona A; Afzal, Aqeela; Warraich, Zuha; Mocco, J

    2014-01-01

    Animal models of stroke have been crucial in advancing our understanding of the pathophysiology of cerebral ischemia. Currently, the standards for determining neurological deficit in rodents are the Bederson and Garcia scales, manual assessments scoring animals based on parameters ranked on a narrow scale of severity. Automated open field analysis of a live-video tracking system that analyzes animal behavior may provide a more sensitive test. Results obtained from the manual Bederson and Garcia scales did not show significant differences between pre- and post-stroke animals in a small cohort. When using the same cohort, however, post-stroke data obtained from automated open field analysis showed significant differences in several parameters. Furthermore, large cohort analysis also demonstrated increased sensitivity with automated open field analysis versus the Bederson and Garcia scales. These early data indicate use of automated open field analysis software may provide a more sensitive assessment when compared to traditional Bederson and Garcia scales.

  5. Manual versus Automated Rodent Behavioral Assessment: Comparing Efficacy and Ease of Bederson and Garcia Neurological Deficit Scores to an Open Field Video-Tracking System

    Directory of Open Access Journals (Sweden)

    Fiona A. Desland

    2014-01-01

    Full Text Available Animal models of stroke have been crucial in advancing our understanding of the pathophysiology of cerebral ischemia. Currently, the standards for determining neurological deficit in rodents are the Bederson and Garcia scales, manual assessments scoring animals based on parameters ranked on a narrow scale of severity. Automated open field analysis of a live-video tracking system that analyzes animal behavior may provide a more sensitive test. Results obtained from the manual Bederson and Garcia scales did not show significant differences between pre- and post-stroke animals in a small cohort. When using the same cohort, however, post-stroke data obtained from automated open field analysis showed significant differences in several parameters. Furthermore, large cohort analysis also demonstrated increased sensitivity with automated open field analysis versus the Bederson and Garcia scales. These early data indicate use of automated open field analysis software may provide a more sensitive assessment when compared to traditional Bederson and Garcia scales.

  6. Impaired brain glymphatic flow in a rodent model of chronic liver disease and minimal hepatic encephalopathy

    OpenAIRE

    Lythgoe, Mark; Hosford, Patrick; Arias, Natalia; Gallego-Duran, Rocio; Hadjihambi, Anna; Jalan, Rajiv; Gourine, Alexander; Habtesion, Abeba; Davies, Nathan; Harrison, Ian

    2017-01-01

    Neuronal function is exquisitely sensitive to alterations in extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain may contribute to neuronal dysfunction and cognitive impairment. In a rat model of chronic liver disease, we used an emerging dynamic contrast-enhanced MRI technique to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from t...

  7. Characterization of the early proliferative response of the rodent bladder to subtotal cystectomy: a unique model of mammalian organ regeneration.

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    Charles C Peyton

    previous observations and further establishes the rodent bladder as an excellent model for studying novel aspects of mammalian organ regeneration.

  8. An in-vitro–in-vivo model for the transdermal delivery of cholecalciferol for the purposes of rodent management

    Science.gov (United States)

    Davies, J.; Ingham, A.

    2015-01-01

    The natural selection of anticoagulant resistant rats has resulted in a need for an alternative to anticoagulant rodenticides which differs in both active ingredient and in the method of dosing. Cholecalciferol toxicity to rodents using the dermal route is demonstrated using a variety of penetration enhancing formulations in two in-vitro models and finally in-vivo. A 1 ml dose of 50/50 (v/v) DMSO/ethanol containing 15% (v/v) PEG 200 and 20% (w/v) cholecalciferol was judged as ‘sufficiently effective’ in line with the European Union’s Biocidal Products Regulation (No. 528/2012) during in-vivo studies. This dose was found to cause 100% mortality in a rat population in 64.4 h (±22 h). PMID:25835266

  9. An in-vitro-in-vivo model for the transdermal delivery of cholecalciferol for the purposes of rodent management.

    Science.gov (United States)

    Davies, J; Ingham, A

    2015-06-20

    The natural selection of anticoagulant resistant rats has resulted in a need for an alternative to anticoagulant rodenticides which differs in both active ingredient and in the method of dosing. Cholecalciferol toxicity to rodents using the dermal route is demonstrated using a variety of penetration enhancing formulations in two in-vitro models and finally in-vivo. A 1 ml dose of 50/50 (v/v) DMSO/ethanol containing 15% (v/v) PEG 200 and 20% (w/v) cholecalciferol was judged as 'sufficiently effective' in line with the European Union's Biocidal Products Regulation (No. 528/2012) during in-vivo studies. This dose was found to cause 100% mortality in a rat population in 64.4h (± 22h). Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Inhibiting C-Reactive Protein for the Treatment of Cardiovascular Disease: Promising Evidence from Rodent Models

    Directory of Open Access Journals (Sweden)

    Alexander J. Szalai

    2014-01-01

    Full Text Available Raised blood C-reactive protein (CRP level is a predictor of cardiovascular events, but whether blood CRP is causal in the disease process is unknown. The latter would best be defined by pharmacological inhibition of the protein in the context of a randomized case-control study. However, no CRP specific drug is currently available so such a prospective study cannot be performed. Blood CRP is synthesized primarily in the liver and the liver is an organ where antisense oligonucleotide (ASO drugs accumulate. Taking advantage of this we evaluated the efficacy of CRP specific ASOs in rodents with experimentally induced cardiovascular damage. Treating rats for 4 weeks with a rat CRP-specific ASO achieved >60% reduction of blood CRP. Notably, this effect was associated with improved heart function and pathology following myocardial infarction (induced by ligation of the left anterior descending artery. Likewise in human CRP transgenic mice treated for 2 weeks with a human CRP-specific ASO, blood human CRP was reduced by >70% and carotid artery patency was improved (2 weeks after surgical ligation. CRP specific ASOs might pave the way towards a placebo-controlled trial that could clarify the role of CRP in cardiovascular disease.

  11. A system utilizing radio frequency identification (RFID) technology to monitor individual rodent behavior in complex social settings.

    Science.gov (United States)

    Howerton, Christopher L; Garner, Joseph P; Mench, Joy A

    2012-07-30

    Pre-clinical investigation of human CNS disorders relies heavily on mouse models. However these show low predictive validity for translational success to humans, partly due to the extensive use of rapid, high-throughput behavioral assays. Improved assays to monitor rodent behavior over longer time scales in a variety of contexts while still maintaining the efficiency of data collection associated with high-throughput assays are needed. We developed an apparatus that uses radio frequency identification device (RFID) technology to facilitate long-term automated monitoring of the behavior of mice in socially or structurally complex cage environments. Mice that were individually marked and implanted with transponders were placed in pairs in the apparatus, and their locations continuously tracked for 24 h. Video observation was used to validate the RFID readings. The apparatus and its associated software accurately tracked the locations of all mice, yielding information about each mouse's location over time, its diel activity patterns, and the amount of time it was in the same location as the other mouse in the pair. The information that can be efficiently collected in this apparatus has a variety of applications for pre-clinical research on human CNS disorders, for example major depressive disorder and autism spectrum disorder, in that it can be used to quantify validated endophenotypes or biomarkers of these disorders using rodent models. While the specific configuration of the apparatus described here was designed to answer particular experimental questions, it can be modified in various ways to accommodate different experimental designs. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Ketamine is a potent antidepressant in two rodent models of depression

    DEFF Research Database (Denmark)

    Mathe, A.; Sousa, V.; Fischer, C. W.

    2013-01-01

    pathophysiological factor and converging evidence indicates that other systems, such as the glutamatergic are of paramount importance. Indeed, work at the Yale University, NIMH, and Icahn School of Medicine at Mount Sinai demonstrated the marked antidepressant effects of intravenously infused ketamine to treatment...... resistant patients diagnosed with major depressive disorder. In order to better understand the mechanisms of ketamine effects we decided to test it on animal models. Methods: All experiments were approved by the Karolinska Institutet's Committee for Animal Protection. Two rat models, bred at the Karolinska...... Institutet, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL), and the SERT KO (homozygous, heterozygous, and the wild type rats) were used. Male animals were injected 10 mg ketamine/kg body weight or vehicle and the Open Field Test (OF) and Forced Swim Test (FST...

  13. Mechanisms underlying weight loss and metabolic improvements in rodent models of bariatric surgery

    Science.gov (United States)

    Arble, Deanna M.; Sandoval, Darleen A.; Seeley, Randy J.

    2014-01-01

    Obesity is a growing health risk with few successful treatment options and fewer still that target both obesity and obesity-associated comorbidities. Despite ongoing scientific efforts, the most effective treatment option to date was not developed from basic research but by surgeons observing outcomes in the clinic. Bariatric surgery is the most successful treatment for significant weight loss, resolution of type 2 diabetes and the prevention of future weight gain. Recent work with animal models has shed considerable light on the molecular underpinnings of the potent effects of these ‘metabolic’ surgical procedures. Here we review data from animal models and how these studies have evolved our understanding of the critical signalling systems that mediate the effects of bariatric surgery. These insights could lead to alternative therapies able to accomplish effects similar to bariatric surgery in a less invasive manner. PMID:25374275

  14. Adjustment of the dynamic weight distribution as a sensitive parameter for diagnosis of postural alteration in a rodent model of vestibular deficit.

    Directory of Open Access Journals (Sweden)

    Brahim Tighilet

    Full Text Available Vestibular disorders, by inducing significant posturo-locomotor and cognitive disorders, can significantly impair the most basic tasks of everyday life. Their precise diagnosis is essential to implement appropriate therapeutic countermeasures. Monitoring their evolution is also very important to validate or, on the contrary, to adapt the undertaken therapeutic actions. To date, the diagnosis methods of posturo-locomotor impairments are restricted to examinations that most often lack sensitivity and precision. In the present work we studied the alterations of the dynamic weight distribution in a rodent model of sudden and complete unilateral vestibular loss. We used a system of force sensors connected to a data analysis system to quantify in real time and in an automated way the weight bearing of the animal on the ground. We show here that sudden, unilateral, complete and permanent loss of the vestibular inputs causes a severe alteration of the dynamic ground weight distribution of vestibulo lesioned rodents. Characteristics of alterations in the dynamic weight distribution vary over time and follow the sequence of appearance and disappearance of the various symptoms that compose the vestibular syndrome. This study reveals for the first time that dynamic weight bearing is a very sensitive parameter for evaluating posturo-locomotor function impairment. Associated with more classical vestibular examinations, this paradigm can considerably enrich the methods for assessing and monitoring vestibular disorders. Systematic application of this type of evaluation to the dizzy or unstable patient could improve the detection of vestibular deficits and allow predicting better their impact on posture and walk. Thus it could also allow a better follow-up of the therapeutic approaches for rehabilitating gait and balance.

  15. Adjustment of the dynamic weight distribution as a sensitive parameter for diagnosis of postural alteration in a rodent model of vestibular deficit.

    Science.gov (United States)

    Tighilet, Brahim; Péricat, David; Frelat, Alais; Cazals, Yves; Rastoldo, Guillaume; Boyer, Florent; Dumas, Olivier; Chabbert, Christian

    2017-01-01

    Vestibular disorders, by inducing significant posturo-locomotor and cognitive disorders, can significantly impair the most basic tasks of everyday life. Their precise diagnosis is essential to implement appropriate therapeutic countermeasures. Monitoring their evolution is also very important to validate or, on the contrary, to adapt the undertaken therapeutic actions. To date, the diagnosis methods of posturo-locomotor impairments are restricted to examinations that most often lack sensitivity and precision. In the present work we studied the alterations of the dynamic weight distribution in a rodent model of sudden and complete unilateral vestibular loss. We used a system of force sensors connected to a data analysis system to quantify in real time and in an automated way the weight bearing of the animal on the ground. We show here that sudden, unilateral, complete and permanent loss of the vestibular inputs causes a severe alteration of the dynamic ground weight distribution of vestibulo lesioned rodents. Characteristics of alterations in the dynamic weight distribution vary over time and follow the sequence of appearance and disappearance of the various symptoms that compose the vestibular syndrome. This study reveals for the first time that dynamic weight bearing is a very sensitive parameter for evaluating posturo-locomotor function impairment. Associated with more classical vestibular examinations, this paradigm can considerably enrich the methods for assessing and monitoring vestibular disorders. Systematic application of this type of evaluation to the dizzy or unstable patient could improve the detection of vestibular deficits and allow predicting better their impact on posture and walk. Thus it could also allow a better follow-up of the therapeutic approaches for rehabilitating gait and balance.

  16. MR microscopy of the lung in small rodents

    International Nuclear Information System (INIS)

    Takahashi, Masaya; Kubo, Shigeto; Kiryu, Shigeru; Gee, James; Hatabu, Hiroto

    2007-01-01

    Understanding how the mammalian respiratory system works and how it changes in disease states and under the influence of drugs is frequently pursued in model systems such as small rodents. These have many advantages, including being easily obtained in large numbers as purebred strains. Studies in small rodents are valuable for proof of concept studies and for increasing our knowledge about disease mechanisms. Since the recent developments in the generation of genetically designed animal models of disease, one needs the ability to assess morphology and function in in vivo systems. In this article, we first review previous reports regarding thoracic imaging. We then discuss approaches to take in making use of small rodents to increase MR microscopic sensitivity for these studies and to establish MR methods for clinically relevant lung imaging

  17. A modified beam-walking apparatus for assessment of anxiety in a rodent model of blast traumatic brain injury.

    Science.gov (United States)

    Sweis, Brian M; Bachour, Salam P; Brekke, Julia A; Gewirtz, Jonathan C; Sadeghi-Bazargani, Homayoun; Hevesi, Mario; Divani, Afshin A

    2016-01-01

    The elevated plus maze (EPM) is used to assess anxiety in rodents. Beam-walking tasks are used to assess vestibulomotor function. Brain injury in rodents can disrupt performance on both of these tasks. Developing novel paradigms that integrate tasks like these can reduce the need for multiple tests when attempting to assess multiple behaviors in the same animal. Using adult male rats, we evaluated the use of a modified beam-walking (MBW) apparatus as a surrogate indicator for anxiety. We used a model of blast-induced traumatic brain injury (bTBI). A total of 39 rats were assessed before and at 3, 6, 24, 72, and 168h either post- bTBI (n=33) or no-injury (n=6) using both EPM and MBW. A novel anxiety index was calculated that encompassed peeks and re-emergences on MBW. The proposed MBW anxiety index was compared with the standard anxiety index calculated from exploration into different sections of EPM. Post- bTBI, rats had an increased anxiety index when measured using EPM. Similarly, they peeked or fully emerged less out of the safe box on MBW. It was found that this novel MBW anxiety index captured similar aspects of behavior when compared to the standard anxiety index obtained from EPM. Further, these effects were dissociated from the effects of bTBI on motor function simultaneously measured on MBW. Over the course of 168h post-bTBI, rats gradually recovered on both EPM and MBW. The MBW apparatus succeeded at capturing and dissociating two separate facets of rat behavior, motor function and anxiety, simultaneously. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Mitogen activated protein kinase phosphatase-1 prevents the development of tactile sensitivity in a rodent model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Ndong Christian

    2012-04-01

    Full Text Available Abstract Background Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of spinal MKP-1 will prevent the development of peripheral nerve-injury-induced hypersensitivity and p-p38 overexpression. Results We cloned rat spinal cord MKP-1 and optimize MKP-1 cDNA in vitro using transfections to BV-2 cells. We observed that in vitro overexpression of MKP-1 blocked lipopolysaccharide-induced phosphorylation of p38 (and other MAPKs as well as release of pro-algesic effectors (i.e., cytokines, chemokines, nitric oxide. Using this cDNA MKP-1 and a non-viral, in vivo nanoparticle transfection approach, we found that spinal cord overexpression of MKP-1 prevented development of peripheral nerve-injury-induced tactile hypersensitivity and reduced pro-inflammatory cytokines and chemokines and the phosphorylated form of p38. Conclusions Our results indicate that MKP-1, the natural regulator of p-p38, mediates resolution of the spinal cord pro-inflammatory milieu induced by peripheral nerve injury, resulting in prevention of chronic mechanical hypersensitivity. We propose that MKP-1 is a potential therapeutic target for pain treatment or prevention.

  19. Modeling specific phobias and posttraumatic stress disorder in rodents: the challenge to convey both cognitive and emotional features.

    Science.gov (United States)

    Berardi, Andrea; Trezza, Viviana; Campolongo, Campolongo

    2012-01-01

    Aberrant emotional memory processing is a core, disabling feature of both specific phobias and posttraumatic stress disorder (PTSD), two psychiatric diseases of significant prevalence and morbidity whose cognitive symptoms cannot be adequately treated by current psychopharmacological tools. Elucidating the neurobiological mechanisms involved in the etiology of these diseases is of great interest for the identification of new therapeutics that improve not only the symptomatology but also the full recovery from the pathology. To this aim, several animal models have been proposed based on substantial resemblance between the behavioral alterations seen in animals and the human pathology. The purpose of this review is to describe and comment on the most commonly used rodent models of specific phobias and PTSD. A particular focus will be reserved to the cued version of fear conditioning, as the highly specific stimulus-bound conditioned fear response seems to fit well with clinical descriptions of phobic fear.Moreover, animal models of PTSD will be evaluated by referring to three elements that are considered essential ina valid model of this disease: stressor exposure, memory for the stressor, and anxiety-related behaviors. Finally, current therapeutic directions, with a focus on cannabinoid and glucocorticoid compounds, will be briefly outlined.

  20. A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part I: development and validation of a pulmonary cannabinoid route of exposure for experimental pharmacology studies in rodents.

    Science.gov (United States)

    Manwell, Laurie A; Charchoglyan, Armen; Brewer, Dyanne; Matthews, Brittany A; Heipel, Heather; Mallet, Paul E

    2014-01-01

    Most studies evaluating the effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in animal models administer it via a parenteral route (e.g., intraperitoneal (IP) or intravenous injection (IV)), however, the common route of administration for human users is pulmonary (e.g., smoking or vapourizing marijuana). A vapourized Δ(9)-THC delivery system for rodents was developed and used to compare the effects of pulmonary and parenteral Δ(9)-THC administration on blood cannabinoid levels and behaviour. Sprague-Dawley rats were exposed to pulmonary Δ(9)-THC (1, 5, and 10mg of inhaled vapour) delivered via a Volcano® vapourizing device (Storz and Bickel, Germany) or to parenteral Δ(9)-THC (0.25, 0.5, 1.0, and 1.5mg/kg injected IP). Quantification of Δ(9)-THC and its psychoactive metabolite, 11-hydroxy-Δ(9)-THC (11-OH-Δ(9)-THC), in blood was determined by liquid chromatography/mass spectrometry (LC/MS). In order to verify the potential for the vapourization procedure to produce a robust conditioned place preference (CPP) or conditioned place avoidance CPA, classical conditioning procedures were systematically varied by altering the exposure time (10 or 20min) and number of exposed rats (1 or 2) while maintaining the same vapourization dose (10mg). Blood collected at 20min intervals showed similar dose-dependent and time-dependent changes in Δ(9)-THC and 11-OH-Δ(9)-THC for both pulmonary and parenteral administration of Δ(9)-THC. However, vapourized Δ(9)-THC induced CPP under certain conditions whereas IP-administered Δ(9)-THC induced CPA. These results support and extend the limited evidence (e.g., in humans, Naef et al., 2004; in rodents, Niyuhire et al., 2007) that Δ(9)-THC produces qualitatively different effects on behaviour depending upon the route of administration. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Consequences of adolescent use of alcohol and other drugs: Studies using rodent models

    Science.gov (United States)

    Spear, Linda Patia

    2016-01-01

    Studies using animal models of adolescent exposure to alcohol, nicotine, cannabinoids, and the stimulants cocaine, 3,4-Methylenedioxymethampethamine and methamphetamine have revealed a variety of persisting neural and behavioral consequences. Affected brain regions often include mesolimbic and prefrontal regions undergoing notable ontogenetic change during adolescence, although it is unclear whether this represents areas of specific vulnerability or particular scrutiny to date. Persisting alterations in forebrain systems critical for modulating reward, socioemotional processing and cognition have emerged, including apparent induction of a hyper-dopaminergic state with some drugs and/or attenuations in neurons expressing cholinergic markers. Disruptions in cognitive functions such as working memory, alterations in affect including increases in social anxiety, and mixed evidence for increases in later drug self-administration have also been reported. When consequences of adolescent and adult exposure were compared, adolescents were generally found to be more vulnerable to alcohol, nicotine, and cannabinoids, but generally not to stimulants. More work is needed to determine how adolescent drug exposure influences sculpting of the adolescent brain, and provide approaches to prevent/reverse these effects. PMID:27484868

  2. Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

    Science.gov (United States)

    Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie ZM; Baily, James E; Sharp, Matthew GF; Garden, O James; Hughes, Jeremy; Howie, Sarah EM; Holmes, Duncan S; Liddle, John; Iredale, John P

    2015-01-01

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness. PMID:26752518

  3. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.

    Science.gov (United States)

    Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie Z M; Baily, James E; Sharp, Matthew G F; Garden, O James; Hughes, Jeremy; Howie, Sarah E M; Holmes, Duncan S; Liddle, John; Iredale, John P

    2016-02-01

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

  4. Water deprivation affects serotoninergic system and glycoprotein secretion in the sub-commissural organ of a desert rodent Meriones shawi.

    Science.gov (United States)

    Elgot, Abdeljalil; Ahboucha, Samir; Bouyatas, My Mustapha; Fèvre-Montange, Michèlle; Gamrani, Halima

    2009-11-27

    Water deprivation is a stress that has been associated with activation of several endocrine systems, including circumventricular organs of the central nervous system. The sub-comissural organ (SCO), characterized by its glycoprotein secretion called Reissner's fiber has been suggested to play a role in the regulation of body water balance. Meriones shawi, a semi-desertic rodent characterized by its resistance to long periods of thirst was subjected to water deprivation for 1 and 3 months. Effect of water deprivation was evaluated immunohistochemically on 5-hydroxytryptamine (5-HT; serotonin) system and glycoprotein secretion of the SCO. Our findings demonstrate significant reduction of anti-Reissner's fiber immunoreactive materials within basal and apical parts of the SCO ependymocytes. These changes seem to be the consequence of reduced control by 5-HT fibers reaching the SCO as a concomitant and significant reduction of anti-5-HT immunoreactive fibers are also observed following water deprivation. 5-HT immunoreactive reduction is seen in several regions in the brain including the neurons of origin within the dorsal raphe nucleus and the projecting supra and sub-ependymal fibers reaching the classical ependyma of the third ventricle. The extent of Reissner's fiber and 5-HT immunoreactive changes significantly correlates with the severity of water restriction. We suggest that water deprivation causes changes of the classical ependyma and the specialized ependyma that differentiates into the SCO as well as other cirumventricular organs such as the subfornical organ and the organum vasculosum laminae terminalis known to control drinking behaviors.

  5. Piper umbellatum L.: A medicinal plant with gastric-ulcer protective and ulcer healing effects in experimental rodent models.

    Science.gov (United States)

    da Silva Junior, Iberê Ferreira; Balogun, Sikiru Olaitan; de Oliveira, Ruberlei Godinho; Damazo, Amílcar Sabino; Martins, Domingos Tabajara de Oliveira

    2016-11-04

    Piper umbellatum L. (Piperaceae) is a shrub found in the Amazon, Savannah and Atlantic Forest region of Brazil. It is widely used in folk medicine in many countries primarily for the treatment of gastric disorders. The aim of this study was to evaluate the gastroprotective and anti-ulcer effects of hydroethanolic extract of P. umbellatum (HEPu) leaves in experimental rodents. In addition, the anti-Helicobacter pylori activity of the extract was assessed. The leaves of P. umbellatum were macerated in 75% (1:3w/v) hydroethanolic solution to obtain HEPu. The gastroprotective and ulcer healing activities of HEPu were evaluated using acidified ethanol (acute) and acetic acid (chronic) gastric ulcer models in rodents. The anti-H. pylori activity was evaluated by in vitro broth microdilution assay using H. pylori cagA + and vacA + strain. The probable mechanism of action of HEPu was evaluated by determining gastric secretory parameters, antioxidant enzyme (catalase), non-protein sulfhydryl (glutathione) and malondialdehyde levels in gastric tissue, including pro-inflammatory (IL-1β, TNF-a, IL -17, RANTES, IFN-γ and MIP-2) and anti-inflammatory (IL-10) cytokines. HEPu demonstrated potent gastroprotection against acute ulcer induced by acidified ethanol and excellent healing effect of the chronic ulcer induced by acetic acid. The gastroprotective activity in acidified ethanol is partly attributed to the antioxidant mechanisms, while anti-secretory, anti-inflammatory and regeneration of the gastric mucosa are evoked as part of its antiulcer mechanism of action. The gastric ulcer healing of HEPu also involves restoration of the altered cytokines levels to near normal. However, it has no in vitro anti-H. pylori activity. The results of this study showed that HEPu possesses preventive and curative effects in experimental models of gastric ulcers in animals. These effects are partially dependent on antioxidant, antisecretory, anti-inflammatory and mucosa regeneration. It is

  6. Preventive effects of Flos Perariae (Gehua water extract and its active ingredient puerarin in rodent alcoholism models

    Directory of Open Access Journals (Sweden)

    Wang Yuqiang

    2010-10-01

    Full Text Available Abstract Background Radix Puerariae is used in Chinese medicine to treat alcohol addiction and intoxication. The present study investigates the effects of Flos puerariae lobatae water extract (FPE and its active ingredient puerarin on alcoholism using rodent models. Methods Alcoholic animals were given FPE or puerarin by oral intubation prior or after alcohol treatment. The loss of righting reflex (LORR assay was used to evaluate sedative/hypnotic effects. Changes of gama-aminobutyric acid type A receptor (GABAAR subunits induced by alcohol treatment in hippocampus were measured with western blot. In alcoholic mice, body weight gain was monitored throughout the experiments. Alcohol dehydrogenase (ADH levels in liver were measured. Results FPE and puerarin pretreatment significantly prolonged the time of LORR induced by diazepam in acute alcoholic rat. Puerarin increased expression of gama-aminobutyric acid type A receptor alpha1 subunit and decreased expression of alpha4 subunit. In chronic alcoholic mice, puerarin pretreatment significantly increased body weight and liver ADH activity in a dose-dependent manner. Puerarin pretreatment, but not post-treatment, can reverse the changes of gama-aminobutyric acid type A receptor subunit expression and increase ADH activity in alcoholism models. Conclusion The present study demonstrates that FPE and its active ingredient puerarin have preventive effects on alcoholism related disorders.

  7. Gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves against acute gastric lesion models in rodents

    Directory of Open Access Journals (Sweden)

    Hélio B Fernandes

    2010-01-01

    Full Text Available Parkia platycephala Benth. (Leguminosae - Mimosoideae, popularly known as "visgueira", fava bean tree or "fava-de-bolota", is widely found in the Northern and Northeastern regions of Brazil. Its pods are used as cattle food supplement in the drought period. Compounds with a gastroprotective activity were obtained from the genus Parkia. Therefore, this study aimed at investigating the gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves (Pp-EtOH, as well as evaluating its possible mechanisms of action in experimental ulcer induction models. Lesions were induced by absolute ethanol, ethanol-HCl, ischemia-reperfusion and indomethacin in rodents. Pp-EtOH showed a protective effect in the lesion models (66, 48 and 52 %, respectively, but it was not able to protect gastric mucosa against indomethacin-induced lesions. Results show a possible participation of the NO-synthase pathway in the gastroprotection and an antioxidant activity, by the increase of the catalase activity. The participation of prostaglandins and potassium channels sensitive to ATP in the gastroprotective effect of Pp-EtOH seems less likely to occur. More comprehensive studies, therefore, should be carried out to elucidate the antiulcerative effects of this promising natural product against this gastrointestinal disorder.

  8. Interaction of genotype and environment: Effect of strain and housing condition on cognitive behaviour in rodent models of schizophrenia

    Directory of Open Access Journals (Sweden)

    Karly M. Turner

    2013-07-01

    Full Text Available Schizophrenia is associated with many genetic and environmental risk factors and there is growing evidence that the interactions between genetic and environmental ‘hits’ are critical for disease onset. Animal models of schizophrenia have traditionally used specific strain and housing conditions to test potential risk factors. As the field moves towards testing gene (G x environment (E interactions the impact of these choices should be considered. Given the surge of research focused on cognitive deficits, we have examined studies of cognition in rodents from the perspective of GxE interactions, in which strain or housing manipulations have been varied. Behaviour is clearly altered by these factors, yet few animal models of schizophrenia have investigated cognitive deficits using different strain and housing conditions. It is important to recognise the large variation in behaviour observed when using different strain and housing combinations because GxE interactions may mask or exacerbate cognitive outcomes. Further consideration will improve our understanding of GxE interactions and the underlying neurobiology of cognitive impairments in neuropsychiatric disorders.

  9. Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease.

    Science.gov (United States)

    Lecommandeur, Emmanuelle; Baker, David; Cox, Timothy M; Nicholls, Andrew W; Griffin, Julian L

    2017-07-01

    Drug-induced phospholipidosis (DIPL) is characterized by an increase in the phospholipid content of the cell and the accumulation of drugs and lipids inside the lysosomes of affected tissues, including in the liver. Although of uncertain pathological significance for patients, the condition remains a major impediment for the clinical development of new drugs. Human Sandhoff disease (SD) is caused by inherited defects of the β subunit of lysosomal β-hexosaminidases (Hex) A and B, leading to a large array of symptoms, including neurodegeneration and ultimately death by the age of 4 in its most common form. The substrates of Hex A and B, gangliosides GM2 and GA2, accumulate inside the lysosomes of the CNS and in peripheral organs. Given that both DIPL and SD are associated with lysosomes and lipid metabolism in general, we measured the hepatic lipid profiles in rodent models of these two conditions using untargeted LC/MS to examine potential commonalities. Both model systems shared a number of perturbed lipid pathways, notably those involving metabolism of cholesteryl esters, lysophosphatidylcholines, bis(monoacylglycero)phosphates, and ceramides. We report here profound alterations in lipid metabolism in the SD liver. In addition, DIPL induced a wide range of lipid changes not previously observed in the liver, highlighting similarities with those detected in the model of SD and raising concerns that these lipid changes may be associated with underlying pathology associated with lysosomal storage disorders. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  10. Embryonic kidney function in a chronic renal failure model in rodents.

    Science.gov (United States)

    Fujimoto, Eisuke; Yamanaka, Shuichiro; Kurihara, Sho; Tajiri, Susumu; Izuhara, Luna; Katsuoka, Yuichi; Yokote, Shinya; Matsumoto, Kei; Kobayashi, Eiji; Okano, Hirotaka James; Chikaraishi, Tatsuya; Yokoo, Takashi

    2017-08-01

    Rapid advancements have been made in alternative treatments for renal diseases. Our goal for renal regeneration is to establish a kidney graft derived from human embryonic tissues. In this study, we investigated the effects of host renal failure on the structure and activity of transplanted embryonic kidney and bladder, and found that diuretics effectively induced urine production in the transplanted kidney. Uremic conditions were reproduced using a 5/6 renal infarction rat model. An embryonic kidney plus bladder (embryonic day 15) was isolated from a pregnant Lewis rat and transplanted into the para-aortic area of a 5/6 renal-infarcted Lewis rat. Following growth, the embryonic bladder was successfully anastomosed to the host ureter. We assessed graft function in terms of survival rates and found no differences between normal (n = 5) and renal failure (n = 8) groups (median survival: 70.5 vs 74.5 h; p = 0.331) in terms of survival, indicating that the grafts prolonged rat survival, even under renal failure conditions. Furosemide (n = 9) significantly increased urine volume compared with saline-treated controls (n = 7; p < 0.05), confirming that the grafts were functional. We also demonstrated the possibilities of an in vivo imaging system for determining the viability of transplanted embryonic kidney with bladder. The results of this study demonstrate that transplanted embryonic kidney and bladder can grow and function effectively, even under uremic conditions.

  11. Differential effects of subcutaneous electrical stimulation (SQS) and transcutaneous electrical nerve stimulation (TENS) in rodent models of chronic neuropathic or inflammatory pain.

    Science.gov (United States)

    Vera-Portocarrero, Louis P; Cordero, Toni; Billstrom, Tina; Swearingen, Kim; Wacnik, Paul W; Johanek, Lisa M

    2013-01-01

    Electrical stimulation has been used for many years for the treatment of pain. Present-day research demonstrates that stimulation targets and parameters impact the induction of specific pain-modulating mechanisms. New targets are increasingly being investigated clinically, but the scientific rationale for a particular target is often not well established. This present study compares the behavioral effects of targeting peripheral axons by electrode placement in the subcutaneous space vs. electrode placement on the surface of the skin in a rodent model. Rodent models of inflammatory and neuropathic pain were used to investigate subcutaneous electrical stimulation (SQS) vs. transcutaneous electrical nerve stimulation (TENS). Electrical parameters and relative location of the leads were held constant under each condition. SQS had cumulative antihypersensitivity effects in both inflammatory and neuropathic pain rodent models, with significant inhibition of mechanical hypersensitivity observed on days 3-4 of treatment. In contrast, reduction of thermal hyperalgesia in the inflammatory model was observed during the first four days of treatment with SQS, and reduction of cold allodynia in the neuropathic pain model was seen only on the first day with SQS. TENS was effective in the inflammation model, and in agreement with previous studies, tolerance developed to the antihypersensitivity effects of TENS. With the exception of a reversal of cold hypersensitivity on day 1 of testing, TENS did not reveal significant analgesic effects in the neuropathic pain rodent model. The results presented show that TENS and SQS have different effects that could point to unique biologic mechanisms underlying the analgesic effect of each therapy. Furthermore, this study is the first to demonstrate in an animal model that SQS attenuates neuropathic and inflammatory-induced pain behaviors. © 2013 Medtronic, Inc.

  12. Statistical analysis and decoding of neural activity in the rodent geniculate ganglion using a metric-based inference system.

    Directory of Open Access Journals (Sweden)

    Wei Wu

    Full Text Available We analyzed the spike discharge patterns of two types of neurons in the rodent peripheral gustatory system, Na specialists (NS and acid generalists (AG to lingual stimulation with NaCl, acetic acid, and mixtures of the two stimuli. Previous computational investigations found that both spike rate and spike timing contribute to taste quality coding. These studies used commonly accepted computational methods, but they do not provide a consistent statistical evaluation of spike trains. In this paper, we adopted a new computational framework that treated each spike train as an individual data point for computing summary statistics such as mean and variance in the spike train space. We found that these statistical summaries properly characterized the firing patterns (e. g. template and variability and quantified the differences between NS and AG neurons. The same framework was also used to assess the discrimination performance of NS and AG neurons and to remove spontaneous background activity or "noise" from the spike train responses. The results indicated that the new metric system provided the desired decoding performance and noise-removal improved stimulus classification accuracy, especially of neurons with high spontaneous rates. In summary, this new method naturally conducts statistical analysis and neural decoding under one consistent framework, and the results demonstrated that individual peripheral-gustatory neurons generate a unique and reliable firing pattern during sensory stimulation and that this pattern can be reliably decoded.

  13. Automated evaluation of liver fibrosis in thioacetamide, carbon tetrachloride, and bile duct ligation rodent models using second-harmonic generation/two-photon excited fluorescence microscopy.

    Science.gov (United States)

    Liu, Feng; Chen, Long; Rao, Hui-Ying; Teng, Xiao; Ren, Ya-Yun; Lu, Yan-Qiang; Zhang, Wei; Wu, Nan; Liu, Fang-Fang; Wei, Lai

    2017-01-01

    Animal models provide a useful platform for developing and testing new drugs to treat liver fibrosis. Accordingly, we developed a novel automated system to evaluate liver fibrosis in rodent models. This system uses second-harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy to assess a total of four mouse and rat models, using chemical treatment with either thioacetamide (TAA) or carbon tetrachloride (CCl 4 ), and a surgical method, bile duct ligation (BDL). The results obtained by the new technique were compared with that using Ishak fibrosis scores and two currently used quantitative methods for determining liver fibrosis: the collagen proportionate area (CPA) and measurement of hydroxyproline (HYP) content. We show that 11 shared morphological parameters faithfully recapitulate Ishak fibrosis scores in the models, with high area under the receiver operating characteristic (ROC) curve (AUC) performance. The AUC values of 11 shared parameters were greater than that of the CPA (TAA: 0.758-0.922 vs 0.752-0.908; BDL: 0.874-0.989 vs 0.678-0.966) in the TAA mice and BDL rat models and similar to that of the CPA in the TAA rat and CCl 4 mouse models. Similarly, based on the trends in these parameters at different time points, 9, 10, 7, and 2 model-specific parameters were selected for the TAA rats, TAA mice, CCl 4 mice, and BDL rats, respectively. These parameters identified differences among the time points in the four models, with high AUC accuracy, and the corresponding AUC values of these parameters were greater compared with those of the CPA in the TAA rat and mouse models (rats: 0.769-0.894 vs 0.64-0.799; mice: 0.87-0.93 vs 0.739-0.836) and similar to those of the CPA in the CCl 4 mouse and BDL rat models. Similarly, the AUC values of 11 shared parameters and model-specific parameters were greater than those of HYP in the TAA rats, TAA mice, and CCl 4 mouse models and were similar to those of HYP in the BDL rat models. The automated

  14. Image-based in vivo assessment of targeting accuracy of stereotactic brain surgery in experimental rodent models

    Science.gov (United States)

    Rangarajan, Janaki Raman; Vande Velde, Greetje; van Gent, Friso; de Vloo, Philippe; Dresselaers, Tom; Depypere, Maarten; van Kuyck, Kris; Nuttin, Bart; Himmelreich, Uwe; Maes, Frederik

    2016-11-01

    Stereotactic neurosurgery is used in pre-clinical research of neurological and psychiatric disorders in experimental rat and mouse models to engraft a needle or electrode at a pre-defined location in the brain. However, inaccurate targeting may confound the results of such experiments. In contrast to the clinical practice, inaccurate targeting in rodents remains usually unnoticed until assessed by ex vivo end-point histology. We here propose a workflow for in vivo assessment of stereotactic targeting accuracy in small animal studies based on multi-modal post-operative imaging. The surgical trajectory in each individual animal is reconstructed in 3D from the physical implant imaged in post-operative CT and/or its trace as visible in post-operative MRI. By co-registering post-operative images of individual animals to a common stereotaxic template, targeting accuracy is quantified. Two commonly used neuromodulation regions were used as targets. Target localization errors showed not only variability, but also inaccuracy in targeting. Only about 30% of electrodes were within the subnucleus structure that was targeted and a-specific adverse effects were also noted. Shifting from invasive/subjective 2D histology towards objective in vivo 3D imaging-based assessment of targeting accuracy may benefit a more effective use of the experimental data by excluding off-target cases early in the study.

  15. Predictors of the nicotine reinforcement threshold, compensation, and elasticity of demand in a rodent model of nicotine reduction policy*

    Science.gov (United States)

    Grebenstein, Patricia E.; Burroughs, Danielle; Roiko, Samuel A.; Pentel, Paul R.; LeSage, Mark G.

    2015-01-01

    Background The FDA is considering reducing the nicotine content in tobacco products as a population-based strategy to reduce tobacco addiction. Research is needed to determine the threshold level of nicotine needed to maintain smoking and the extent of compensatory smoking that could occur during nicotine reduction. Sources of variability in these measures across sub-populations also need to be identified so that policies can take into account the risks and benefits of nicotine reduction in vulnerable populations. Methods The present study examined these issues in a rodent nicotine self- administration model of nicotine reduction policy to characterize individual differences in nicotine reinforcement thresholds, degree of compensation, and elasticity of demand during progressive reduction of the unit nicotine dose. The ability of individual differences in baseline nicotine intake and nicotine pharmacokinetics to predict responses to dose reduction was also examined. Results Considerable variability in the reinforcement threshold, compensation, and elasticity of demand was evident. High baseline nicotine intake was not correlated with the reinforcement threshold, but predicted less compensation and less elastic demand. Higher nicotine clearance predicted low reinforcement thresholds, greater compensation, and less elastic demand. Less elastic demand also predicted lower reinforcement thresholds. Conclusions These findings suggest that baseline nicotine intake, nicotine clearance, and the essential value of nicotine (i.e. elasticity of demand) moderate the effects of progressive nicotine reduction in rats and warrant further study in humans. They also suggest that smokers with fast nicotine metabolism may be more vulnerable to the risks of nicotine reduction. PMID:25891231

  16. Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model.

    Science.gov (United States)

    Ressler, Ilana B; Grayson, Bernadette E; Ulrich-Lai, Yvonne M; Seeley, Randy J

    2015-06-15

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Although a comorbidity of PCOS is obesity, many are lean. We hypothesized that increased saturated fat consumption and obesity would exacerbate metabolic and stress indices in a rodent model of PCOS. Female rats were implanted with the nonaromatizable androgen dihydrotestosterone (DHT) or placebo pellets prior to puberty. Half of each group was maintained ad libitum on either a high-fat diet (HFD; 40% butter fat calories) or nutrient-matched low-fat diet (LFD). Irrespective of diet, DHT-treated animals gained more body weight, had irregular cycles, and were glucose intolerant compared with controls on both diets. HFD/DHT animals had the highest levels of fat mass and insulin resistance. DHT animals demonstrated increased anxiety-related behavior in the elevated plus maze by decreased distance traveled and time in the open arms. HFD consumption increased immobility during the forced-swim test. DHT treatment suppressed diurnal corticosterone measurements in both diet groups. In parallel, DHT treatment significantly dampened stress responsivity to a mild stressor. Brains of DHT animals showed attenuated c-Fos activation in the ventromedial hypothalamus and arcuate nucleus; irrespective of DHT-treatment, however, all HFD animals had elevated hypothalamic paraventricular nucleus c-Fos activation. Whereas hyperandrogenism drives overall body weight gain, glucose intolerance, anxiety behaviors, and stress responsivity, HFD consumption exacerbates the effect of androgens on adiposity, insulin resistance, and depressive behaviors. Copyright © 2015 the American Physiological Society.

  17. Searching for the gut microbial contributing factors to social behavior in rodent models of autism spectrum disorder.

    Science.gov (United States)

    Needham, Brittany D; Tang, Weiyi; Wu, Wei-Li

    2018-05-01

    Social impairment is one of the major symptoms in multiple psychiatric disorders, including autism spectrum disorder (ASD). Accumulated studies indicate a crucial role for the gut microbiota in social development, but these mechanisms remain unclear. This review focuses on two strategies adopted to elucidate the complicated relationship between gut bacteria and host social behavior. In a top-down approach, researchers have attempted to correlate behavioral abnormalities with altered gut microbial profiles in rodent models of ASD, including BTBR mice, maternal immune activation (MIA), maternal valproic acid (VPA) and maternal high-fat diet (MHFD) offspring. In a bottom-up approach, researchers use germ-free (GF) animals, antibiotics, probiotics or pathogens to manipulate the intestinal environment and ascertain effects on social behavior. The combination of both approaches will hopefully pinpoint specific bacterial communities that control host social behavior. Further discussion of how brain development and circuitry is impacted by depletion of gut microbiota is also included. The converging evidence strongly suggests that gut microbes affect host social behavior through the alteration of brain neural circuits. Investigation of intestinal microbiota and host social behavior will unveil any bidirectional communication between the gut and brain and provide alternative therapeutic targets for ASD. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 474-499, 2018. © 2018 Wiley Periodicals, Inc.

  18. Intermittent Hypoxia and Stem Cell Implants Preserve Breathing Capacity in a Rodent Model of Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Nichols, Nicole L.; Gowing, Genevieve; Satriotomo, Irawan; Nashold, Lisa J.; Dale, Erica A.; Suzuki, Masatoshi; Avalos, Pablo; Mulcrone, Patrick L.; McHugh, Jacalyn

    2013-01-01

    Rationale: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing paralysis and death from respiratory failure. Strategies to preserve and/or restore respiratory function are critical for successful treatment. Although breathing capacity is maintained until late in disease progression in rodent models of familial ALS (SOD1G93A rats and mice), reduced numbers of phrenic motor neurons and decreased phrenic nerve activity are observed. Decreased phrenic motor output suggests imminent respiratory failure. Objectives: To preserve or restore phrenic nerve activity in SOD1G93A rats at disease end stage. Methods: SOD1G93A rats were injected with human neural progenitor cells (hNPCs) bracketing the phrenic motor nucleus before disease onset, or exposed to acute intermittent hypoxia (AIH) at disease end stage. Measurements and Main Results: The capacity to generate phrenic motor output in anesthetized rats at disease end stage was: (1) transiently restored by a single presentation of AIH; and (2) preserved ipsilateral to hNPC transplants made before disease onset. hNPC transplants improved ipsilateral phrenic motor neuron survival. Conclusions: AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS. PMID:23220913

  19. Clonidine reduces norepinephrine and improves bone marrow function in a rodent model of lung contusion, hemorrhagic shock, and chronic stress.

    Science.gov (United States)

    Alamo, Ines G; Kannan, Kolenkode B; Ramos, Harry; Loftus, Tyler J; Efron, Philip A; Mohr, Alicia M

    2017-03-01

    Propranolol has been shown previously to restore bone marrow function and improve anemia after lung contusion/hemorrhagic shock. We hypothesized that daily clonidine administration would inhibit central sympathetic outflow and restore bone marrow function in our rodent model of lung contusion/hemorrhagic shock with chronic stress. Male Sprague-Dawley rats underwent 6 days of restraint stress after lung contusion/hemorrhagic shock during which the animals received clonidine (75 μg/kg) after the restraint stress. On postinjury day 7, we assessed urine norepinephrine, blood hemoglobin, plasma granulocyte colony stimulating factor, and peripheral blood mobilization of hematopoietic progenitor cells, as well as bone marrow cellularity and erythroid progenitor cell growth. The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress significantly decreased urine norepinephrine levels, improved bone marrow cellularity, restored erythroid progenitor colony growth, and improved hemoglobin (14.1 ± 0.6 vs 10.8 ± 0.6 g/dL). The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress significantly decreased hematopoietic progenitor cells mobilization and restored granulocyte colony stimulating factor levels. After lung contusion/hemorrhagic shock with chronic restraint stress, daily administration of clonidine restored bone marrow function and improved anemia. Alleviating chronic stress and decreasing norepinephrine is a key therapeutic target to improve bone marrow function after severe injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Neurogenetics of aggressive behavior: studies in rodents.

    Science.gov (United States)

    Takahashi, Aki; Miczek, Klaus A

    2014-01-01

    Aggressive behavior is observed in many animal species, such as insects, fish, lizards, frogs, and most mammals including humans. This wide range of conservation underscores the importance of aggressive behavior in the animals' survival and fitness, and the likely heritability of this behavior. Although typical patterns of aggressive behavior differ between species, there are several concordances in the neurobiology of aggression among rodents, primates, and humans. Studies with rodent models may eventually help us to understand the neurogenetic architecture of aggression in humans. However, it is important to recognize the difference between the ecological and ethological significance of aggressive behavior (species-typical aggression) and maladaptive violence (escalated aggression) when applying the findings of aggression research using animal models to human or veterinary medicine. Well-studied rodent models for aggressive behavior in the laboratory setting include the mouse (Mus musculus), rat (Rattus norvegicus), hamster (Mesocricetus auratus), and prairie vole (Microtus ochrogaster). The neural circuits of rodent aggression have been gradually elucidated by several techniques, e.g., immunohistochemistry of immediate-early gene (c-Fos) expression, intracranial drug microinjection, in vivo microdialysis, and optogenetics techniques. Also, evidence accumulated from the analysis of gene-knockout mice shows the involvement of several genes in aggression. Here, we review the brain circuits that have been implicated in aggression, such as the hypothalamus, prefrontal cortex (PFC), dorsal raphe nucleus (DRN), nucleus accumbens (NAc), and olfactory system. We then discuss the roles of glutamate and γ-aminobutyric acid (GABA), excitatory and inhibitory amino acids in the brain, as well as their receptors, in controlling aggressive behavior, focusing mainly on recent findings. At the end of this chapter, we discuss how genes can be identified that underlie individual

  1. A review of applied aspects of dealing with gut microbiota impact on rodent models

    DEFF Research Database (Denmark)

    Hansen, Axel Kornerup; Krych, Lukasz; Nielsen, Dennis Sandris

    2015-01-01

    -negative phylum Bacteroidetes. Other important phyla are the gram-negative phyla Proteobacteria and Verrucomicrobia, and the gram-positive phylum Actinobacteria. GM members influence models for diseases, such as inflammatory bowel diseases, allergies, autoimmunity, cancer, and neuropsychiatric diseases. GM...

  2. A Physiologically Based Pharmacokinetic Model for the Oxime TMB-4: Simulation of Rodent and Human Data

    Science.gov (United States)

    2013-01-13

    later, Garrigue and other colleagues (Maurizis et al. 1992) pub- lished an in vitro binding study of TMB-4 with rabbit cartilaginous tissue cultures...as well as fat, kidney, liver, rapidly perfused tissues and slowly perfused tissues . All tissue compartments are diffusion limited. Model...pharmacokinetic data from the literature. The model was parameterized using rat plasma, tissue and urine time course data from intramuscular administration, as

  3. The brain acid-base homeostasis and serotonin: A perspective on the use of carbon dioxide as human and rodent experimental model of panic.

    Science.gov (United States)

    Leibold, N K; van den Hove, D L A; Esquivel, G; De Cort, K; Goossens, L; Strackx, E; Buchanan, G F; Steinbusch, H W M; Lesch, K P; Schruers, K R J

    2015-06-01

    Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning.

    Science.gov (United States)

    Lindner, Mark D; Hodges, Donald B; Hogan, John B; Orie, Anitra F; Corsa, Jason A; Barten, Donna M; Polson, Craig; Robertson, Barbara J; Guss, Valerie L; Gillman, Kevin W; Starrett, John E; Gribkoff, Valentin K

    2003-11-01

    Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.

  5. Molecular Mechanism of Gastric Carcinogenesis in Helicobacter pylori-Infected Rodent Models

    Directory of Open Access Journals (Sweden)

    Takeshi Toyoda

    2014-06-01

    Full Text Available Since the discovery of Helicobacter pylori (H. pylori, many efforts have been made to establish animal models for the investigation of the pathological features and molecular mechanisms of gastric carcinogenesis. Among the animal models, Mongolian gerbils and mice are particularly useful for the analysis of H. pylori-associated inflammatory reactions and gastric cancer development. Inhibitors of oxidative stress, cyclooxygenase-2 (COX-2 and nuclear factor-κB, exert preventive effects on chronic gastritis and the development of adenocarcinomas in H. pylori-infected gerbils. Genetically-modified mouse models, including transgenic and knockout mice, have also revealed the importance of p53, COX-2/prostaglandin, Wnt/β-catenin, proinflammatory cytokines, gastrin and type III mucin in the molecular mechanisms of gastric carcinogenesis. Microarray technology is available for comprehensive gene analysis in the gastric mucosa of mouse models, and epigenetics, such as DNA methylation, could be an alternative approach to correlate the observations in animal models with the etiology in humans.

  6. An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

    Science.gov (United States)

    Barajaz, Ashley M; Kliethermes, Christopher L

    2017-12-01

    Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Application of proteomics in the study of rodent models of cancer

    DEFF Research Database (Denmark)

    Terp, Mikkel Green; Ditzel, Henrik J

    2014-01-01

    The molecular and cellular mechanisms underlying the multistage processes of cancer progression and metastasis are complex and strictly depend on the interplay between tumor cells and surrounding tissues. Identification of protein aberrations in cancer pathophysiology requires a physiologically r......, and monitoring of cancer progression and treatment response. Central to such studies is the ability to ensure at an early stage that the identified proteins are of clinical relevance by examining relevant specimens from larger cohorts of cancer patients.......The molecular and cellular mechanisms underlying the multistage processes of cancer progression and metastasis are complex and strictly depend on the interplay between tumor cells and surrounding tissues. Identification of protein aberrations in cancer pathophysiology requires a physiologically...... relevant experimental model. The mouse offers such a model to identify protein changes associated with tumor initiation and progression, metastasis development, tumor/microenvironment interplay, and treatment responses. Furthermore, the mouse model offers the ability to collect samples at any stage...

  8. Effect of the new antiepileptic drug retigabine in a rodent model of mania

    DEFF Research Database (Denmark)

    Dencker, Ditte; Dias, Rebecca; Pedersen, Mette Lund

    2008-01-01

    Bipolar spectrum disorders are severe chronic mood disorders that are characterized by episodes of mania or hypomania and depression. Because patients with manic symptoms often experience clinical benefit from treatment with anticonvulsant drugs, it was hypothesized that retigabine, a novel...... compound with anticonvulsant efficacy, may also possess antimanic activity. The amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity model has been proposed as a suitable model for studying antimanic-like activity of novel compounds in mice and rats. The aims of the present study in rats were...

  9. "Asparagus Racemosus" Enhances Memory and Protects against Amnesia in Rodent Models

    Science.gov (United States)

    Ojha, Rakesh; Sahu, Alakh N.; Muruganandam, A. V.; Singh, Gireesh Kumar; Krishnamurthy, Sairam

    2010-01-01

    "Asparagus Racemosus" (AR) is an Ayurvedic rasayana possessing multiple neuropharmacological activities. The adpatogenic and antidepressant activity of AR is well documented. The present study was undertaken to assess nootropic and anti-amnesic activities of MAR in rats. The Morris water maze (MWM) and elevated plus maze (EPM) models were employed…

  10. Impact of the gut microbiota on rodent models of human disease.

    Science.gov (United States)

    Hansen, Axel Kornerup; Hansen, Camilla Hartmann Friis; Krych, Lukasz; Nielsen, Dennis Sandris

    2014-12-21

    Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 10(14) organisms dispersed on approximately 1000 different species. Today, diagnostics, in contrast to previous cultivation techniques, allow the identification of close to 100% of bacterial species. This has revealed that a range of animal models within different research areas, such as diabetes, obesity, cancer, allergy, behavior and colitis, are affected by their gut microbiota. Correlation studies may for some diseases show correlation between gut microbiota composition and disease parameters higher than 70%. Some disease phenotypes may be transferred when recolonizing germ free mice. The mechanistic aspects are not clear, but some examples on how gut bacteria stimulate receptors, metabolism, and immune responses are discussed. A more deeper understanding of the impact of microbiota has its origin in the overall composition of the microbiota and in some newly recognized species, such as Akkermansia muciniphila, Segmented filamentous bacteria and Faecalibacterium prausnitzii, which seem to have an impact on more or less severe disease in specific models. Thus, the impact of the microbiota on animal models is of a magnitude that cannot be ignored in future research. Therefore, either models with specific microbiota must be developed, or the microbiota must be characterized in individual studies and incorporated into data evaluation.

  11. Computer-assisted imaging algorithms facilitate histomorphometric quantification of kidney damage in rodent renal failure models

    Directory of Open Access Journals (Sweden)

    Marcin Klapczynski

    2012-01-01

    Full Text Available Introduction: Surgical 5/6 nephrectomy and adenine-induced kidney failure in rats are frequently used models of progressive renal failure. In both models, rats develop significant morphological changes in the kidneys and quantification of these changes can be used to measure the efficacy of prophylactic or therapeutic approaches. In this study, the Aperio Genie Pattern Recognition technology, along with the Positive Pixel Count, Nuclear and Rare Event algorithms were used to quantify histological changes in both rat renal failure models. Methods: Analysis was performed on digitized slides of whole kidney sagittal sections stained with either hematoxylin and eosin or immunohistochemistry with an anti-nestin antibody to identify glomeruli, regenerating tubular epithelium, and tubulointerstitial myofibroblasts. An anti-polymorphonuclear neutrophil (PMN antibody was also used to investigate neutrophil tissue infiltration. Results: Image analysis allowed for rapid and accurate quantification of relevant histopathologic changes such as increased cellularity and expansion of glomeruli, renal tubular dilatation, and degeneration, tissue inflammation, and mineral aggregation. The algorithms provided reliable and consistent results in both control and experimental groups and presented a quantifiable degree of damage associated with each model. Conclusion: These algorithms represent useful tools for the uniform and reproducible characterization of common histomorphologic features of renal injury in rats.

  12. Tachykinin-1 in the central nervous system regulates adiposity in rodents.

    Science.gov (United States)

    Trivedi, Chitrang; Shan, Xiaoye; Tung, Yi-Chun Loraine; Kabra, Dhiraj; Holland, Jenna; Amburgy, Sarah; Heppner, Kristy; Kirchner, Henriette; Yeo, Giles S H; Perez-Tilve, Diego

    2015-05-01

    Ghrelin is a circulating hormone that targets the central nervous system to regulate feeding and adiposity. The best-characterized neural system that mediates the effects of ghrelin on energy balance involves the activation of neuropeptide Y/agouti-related peptide neurons, expressed exclusively in the arcuate nucleus of the hypothalamus. However, ghrelin receptors are expressed in other neuronal populations involved in the control of energy balance. We combined laser capture microdissection of several nuclei of the central nervous system expressing the ghrelin receptor (GH secretagoge receptor) with microarray gene expression analysis to identify additional neuronal systems involved in the control of central nervous system-ghrelin action. We identified tachykinin-1 (Tac1) as a gene negatively regulated by ghrelin in the hypothalamus. Furthermore, we identified neuropeptide k as the TAC1-derived peptide with more prominent activity, inducing negative energy balance when delivered directly into the brain. Conversely, loss of Tac1 expression enhances the effectiveness of ghrelin promoting fat mass gain both in male and in female mice and increases the susceptibility to diet-induced obesity in ovariectomized mice. Taken together, our data demonstrate a role TAC1 in the control energy balance by regulating the levels of adiposity in response to ghrelin administration and to changes in the status of the gonadal function.

  13. The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection

    OpenAIRE

    Huijben, Silvie; Sim, Derek G.; Nelson, William, A.; Read, Andrew F.

    2011-01-01

    Malaria infections normally consist of more than one clonally-replicating lineage. Within-host interactions between sensitive and resistant parasites can have profound effects on the evolution of drug resistance. Here, using the Plasmodium chabaudi mouse malaria model, we ask whether the costs and benefits of resistance are affected by the number of co-infecting strains competing with a resistant clone. We found strong competitive suppression of resistant parasites in untreated infections and...

  14. Synergistic interactions between paracetamol and oxcarbazepine in somatic and visceral pain models in rodents.

    Science.gov (United States)

    Tomić, Maja A; Vucković, Sonja M; Stepanović-Petrović, Radica M; Ugresić, Nenad D; Prostran, Milica S; Bosković, Bogdan

    2010-04-01

    Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of coadministered paracetamol, a widely used non-opioid analgesic, and oxcarbazepine, a relatively novel anticonvulsant with analgesic properties, in a rat model of paw inflammatory hyperalgesia and in a mice model of visceral pain and determined the type of interaction between components. The effects of paracetamol, oxcarbazepine, and their combinations were examined in carrageenan-induced (0.1 mL, 1%) paw inflammatory hyperalgesia in rats and in an acetic acid-induced (10 mg/kg, 0.75%) writhing test in mice. In both models, drugs were coadministered in fixed-dose fractions of the 50% effective dose (ED(50)), and type of interaction was determined by isobolographic analysis. Paracetamol (50-200 mg/kg peroral), oxcarbazepine (40-160 mg/kg peroral), and their combination (1/8, 1/4, 1/3, and 1/2 of a single drug ED(50)) produced a significant, dose-dependent antihyperalgesia in carrageenan-injected rats. In the writhing test in mice, paracetamol (60-180 mg/kg peroral), oxcarbazepine (20-80 mg/kg peroral), and their combination (1/16, 1/8, 1/4, and 1/2 of a single drug ED(50)) significantly and dose dependently reduced the number of writhes. In both models, isobolographic analysis revealed a significant synergistic interaction between paracetamol and oxcarbazepine, with a >4-fold reduction of doses of both drugs in combination, compared with single drugs ED(50). The synergistic interaction between paracetamol and oxcarbazepine provides new information about combination pain treatment and should be explored further in patients, especially with somatic and/or visceral pain.

  15. In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models

    OpenAIRE

    Ogunlade, O.; Connell, J. J.; Huang, J. L.; Zhang, E.; Lythgoe, M. F.; Long, D. A.; Beard, P.

    2017-01-01

    Non-invasive imaging of the kidney vasculature in preclinical murine models is important for studying renal development, diseases and evaluating new therapies, but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualising the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optica...

  16. Effects of Simulated Smog Atmospheres in Rodent Models of Metabolic and Immunologic Dysfunction.

    Science.gov (United States)

    McGee Hargrove, Marie; Snow, Samantha J; Luebke, Robert W; Wood, Charles E; Krug, Jonathan D; Krantz, Q Todd; King, Charly; Copeland, Carey B; McCullough, Shaun D; Gowdy, Kymberly M; Kodavanti, Urmila P; Gilmour, M Ian; Gavett, Stephen H

    2018-03-06

    Air pollution is a diverse and dynamic mixture of gaseous and particulate matter, limiting our understanding of associated adverse health outcomes. The biological effects of two simulated smog atmospheres (SA) with different compositions but similar air quality health indexes were compared in a nonobese diabetic rat model (Goto-Kakizaki, GK) and three mouse immune models (house dust mite (HDM) allergy, antibody response to heat-killed pneumococcus, and resistance to influenza A infection). In GK rats, both SA-PM (high particulate matter) and SA-O 3 (high ozone) decreased cholesterol levels immediately after a 4-h exposure, whereas only SA-O 3 increased airflow limitation. Airway responsiveness to methacholine was increased in HDM-allergic mice compared with nonallergic mice, but exposure to SA-PM or SA-O 3 did not significantly alter responsiveness. Exposure to SA-PM did not affect the IgM response to pneumococcus, and SA-O 3 did not affect virus titers, although inflammatory cytokine levels were decreased in mice infected at the end of a 7-day exposure. Collectively, acute SA exposures produced limited health effects in animal models of metabolic and immune diseases. Effects of SA-O 3 tended to be greater than those of SA-PM, suggesting that gas-phase components in photochemically derived multipollutant mixtures may be of greater concern than secondary organic aerosol PM.

  17. Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade

    Directory of Open Access Journals (Sweden)

    Tope eLanre-Amos

    2010-09-01

    Full Text Available Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the basolateral amygdala which causes cell-type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity—theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala-hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments.

  18. Diurnal rodents as animal models of human central vision: characterisation of the retina of the sand rat Psammomys obsesus.

    Science.gov (United States)

    Saïdi, Tounès; Mbarek, Sihem; Chaouacha-Chekir, Rafika Ben; Hicks, David

    2011-07-01

    Cone photoreceptor-based central vision is of paramount importance in human eyesight, and the increasing numbers of persons affected by macular degeneration emphasizes the need for relevant and amenable animal models. Although laboratory mice and rats have provided valuable information on retinal diseases, they have inherent limitations for studies on macular pathology. In the present study, we extend our recent analyses of diurnal murid rodents to demonstrate that the sand rat Psammomys obesus has a remarkably cone-rich retina, and represents a useful adjunct to available animal models of central vision. Adult P. obesus were captured and transferred to animal facilities where they were maintained under standard light/dark cycles. Animals were euthanised and their eyes enucleated. Tissue was either fixed in paraformaldehyde and prepared for immunohistochemistry, or solubilized in lysis buffer and separated by SDS-PAGE and subjected to western blot analysis. Samples were labelled with a battery of antibodies against rod and cone photoreceptors, inner retinal neurones, and glia. P. obesus showed a high percentage of cones, 41% of total photoreceptor numbers in both central and peripheral retina. They expressed multiple cone-specific proteins, including short and medium-wavelength opsin and cone transducin. A second remarkable feature of the retina concerned the horizontal cells, which expressed high levels of glial fibrillar acidic protein and occludin, two proteins which are not seen in other species. The retina of P. obesus displays high numbers of morphologically and immunologically identifiable cones which will facilitate analysis of cone pathophysiology in this species. The unusual horizontal cell phenotype may be related to the cone distribution or to an alternative facet of the animals lifestyle.

  19. Clinical correlates to assist with chronic traumatic encephalopathy diagnosis: Insights from a novel rodent repeat concussion model.

    Science.gov (United States)

    Thomsen, Gretchen M; Ko, Ara; Harada, Megan Y; Ma, Annie; Wyss, Livia; Haro, Patricia; Vit, Jean-Philippe; Avalos, Pablo; Dhillon, Navpreet K; Cho, Noell; Shelest, Oksana; Ley, Eric J

    2017-06-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head injuries. Chronic traumatic encephalopathy symptoms include changes in mood, behavior, cognition, and motor function; however, CTE is currently diagnosed only postmortem. Using a rat model of recurrent traumatic brain injury (TBI), we demonstrate rodent deficits that predict the severity of CTE-like brain pathology. Bilateral, closed-skull, mild TBI was administered once per week to 35 wild-type rats; eight rats received two injuries (2×TBI), 27 rats received five injuries (5×TBI), and 13 rats were sham controls. To determine clinical correlates for CTE diagnosis, TBI rats were separated based on the severity of rotarod deficits and classified as "mild" or "severe" and further separated into "acute," "short," and "long" based on age at euthanasia (90, 144, and 235 days, respectively). Brain atrophy, phosphorylated tau, and inflammation were assessed. All eight 2×TBI cases had mild rotarod deficiency, 11 5×TBI cases had mild deficiency, and 16 cases had severe deficiency. In one cohort of rats, tested at approximately 235 days of age, balance, rearing, and grip strength were significantly worse in the severe group relative to both sham and mild groups. At the acute time period, cortical thinning, phosphorylated tau, and inflammation were not observed in either TBI group, whereas corpus callosum thinning was observed in both TBI groups. At later time points, atrophy, tau pathology, and inflammation were increased in mild and severe TBI groups in the cortex and corpus callosum, relative to sham controls. These injury effects were exacerbated over time in the severe TBI group in the corpus callosum. Our model of repeat mild TBI suggests that permanent deficits in specific motor function tests correlate with CTE-like brain pathology. Assessing balance and motor coordination over time may predict CTE diagnosis.

  20. Development of NMR imaging using CEST agents: application to brain tumor in a rodent model

    International Nuclear Information System (INIS)

    Flament, J.

    2012-01-01

    The study aimed at developing saturation transfer imaging of lipoCEST contrast agents for the detection of angiogenesis in a U87 mouse brain tumor model. A lipoCEST with a sensitivity threshold of 100 pM in vitro was optimized in order to make it compatible with CEST imaging in vivo. Thanks to the development of an experimental setup dedicated to CEST imaging, we evaluated lipoCEST to detect specifically tumor angiogenesis. We demonstrated for the first time that lipoCEST visualization was feasible in vivo in a mouse brain after intravenous injection. Moreover, the integrin α v β 3 over expressed during tumor angiogenesis can be specifically targeted using a functionalized lipoCEST with RGD peptide. The specific association between the RGD-lipoCEST and its target α v β 3 was confirmed by immunohistochemical data and fluorescence microscopy. Finally, in order to tend to a molecular imaging protocol by CEST-MRI, we developed a quantification tool of lipoCEST contrast agents. This tool is based on modeling of proton exchange processes in vivo. By taking into account both B0 and B1 fields inhomogeneities which can dramatically alter CEST contrast, we showed that the accuracy of our quantification tool was 300 pM in vitro. The tool was applied on in vivo data acquired on the U87 mouse model and the maximum concentration of RGD-lipoCEST linked to their molecular targets was evaluated to 1.8 nM. (author) [fr

  1. Peer pressures: Social instability stress in adolescence and social deficits in adulthood in a rodent model

    Directory of Open Access Journals (Sweden)

    Cheryl M. McCormick

    2015-02-01

    Full Text Available Studies in animal models generate and test hypotheses regarding developmental stage-specific vulnerability that might inform research questions about human development. In both rats and humans, peer relationships are qualitatively different in adolescence than at other stages of development, and social experiences in adolescence are considered important determinants of adult social function. This review describes our adolescent rat social instability stress model and the long-lasting effects social instability has on social behaviour in adulthood as well as the possible neural underpinnings. Effects of other adolescent social stress experiences in rats on social behaviours in adulthood also are reviewed. We discuss the role of hypothalamic–pituitary–adrenal (HPA function and glucocorticoid release in conferring differential susceptibility to social experiences in adolescents compared to adults. We propose that although differential perception of social experiences rather than immature HPA function may underlie the heightened vulnerability of adolescents to social instability, the changes in the trajectory of brain development and resultant social deficits likely are mediated by the heightened glucocorticoid release in response to repeated social stressors in adolescence compared to in adulthood.

  2. Translational relevance of rodent models of hypothalamic-pituitary-adrenal function and stressors in adolescence

    Directory of Open Access Journals (Sweden)

    Cheryl M. McCormick

    2017-02-01

    Full Text Available Elevations in glucocorticoids that result from environmental stressors can have programming effects on brain structure and function when the exposure occurs during sensitive periods that involve heightened neural development. In recent years, adolescence has gained increasing attention as another sensitive period of development, a period in which pubertal transitions may increase the vulnerability to stressors. There are similarities in physical and behavioural development between humans and rats, and rats have been used effectively as an animal model of adolescence and the unique plasticity of this period of ontogeny. This review focuses on benefits and challenges of rats as a model for translational research on hypothalamic-pituitary-adrenal (HPA function and stressors in adolescence, highlighting important parallels and contrasts between adolescent rats and humans, and we review the main stress procedures that are used in investigating HPA stress responses and their consequences in adolescence in rats. We conclude that a greater focus on timing of puberty as a factor in research in adolescent rats may increase the translational relevance of the findings.

  3. Translational Assays for Assessment of Cognition in Rodent Models of Alzheimer's Disease and Dementia.

    Science.gov (United States)

    Shepherd, A; Tyebji, S; Hannan, A J; Burrows, E L

    2016-11-01

    Cognitive dysfunction appears as a core feature of dementia, which includes its most prevalent form, Alzheimer's disease (AD), as well as vascular dementia, frontotemporal dementia, and other brain disorders. AD alone affects more than 45 million people worldwide, with growing prevalence in aging populations. There is no cure, and therapeutic options remain limited. Gene-edited and transgenic animal models, expressing disease-specific gene mutations, illuminate pathogenic mechanisms leading to cognitive decline in AD and other forms of dementia. To date, cognitive tests in AD mouse models have not been directly relevant to the clinical presentation of AD, providing challenges for translation of findings to the clinic. Touchscreen testing in mice has enabled the assessment of specific cognitive domains in mice that are directly relevant to impairments described in human AD patients. In this review, we provide context for how cognitive decline is measured in the clinic, describe traditional methods for assessing cognition in mice, and outline novel approaches, including the use of the touchscreen platform for cognitive testing. We highlight the limitations of traditional memory-testing paradigms in mice, particularly their capacity for direct translation into cognitive testing of patients. While it is not possible to expect direct translation in testing methodologies, we can aim to develop tests that engage similar neural substrates in both humans and mice. Ultimately, that would enable us to better predict efficacy across species and therefore improve the chances that a treatment that works in mice will also work in the clinic.

  4. Treatment of amblyopia in the adult: insights from a new rodent model of visual perceptual learning.

    Science.gov (United States)

    Bonaccorsi, Joyce; Berardi, Nicoletta; Sale, Alessandro

    2014-01-01

    Amblyopia is the most common form of impairment of visual function affecting one eye, with a prevalence of about 1-5% of the total world population. Amblyopia usually derives from conditions of early functional imbalance between the two eyes, owing to anisometropia, strabismus, or congenital cataract, and results in a pronounced reduction of visual acuity and severe deficits in contrast sensitivity and stereopsis. It is widely accepted that, due to a lack of sufficient plasticity in the adult brain, amblyopia becomes untreatable after the closure of the critical period in the primary visual cortex. However, recent results obtained both in animal models and in clinical trials have challenged this view, unmasking a previously unsuspected potential for promoting recovery even in adulthood. In this context, non invasive procedures based on visual perceptual learning, i.e., the improvement in visual performance on a variety of simple visual tasks following practice, emerge as particularly promising to rescue discrimination abilities in adult amblyopic subjects. This review will survey recent work regarding the impact of visual perceptual learning on amblyopia, with a special focus on a new experimental model of perceptual learning in the amblyopic rat.

  5. Treatment of amblyopia in the adult: insights from a new rodent model of visual perceptual learning

    Science.gov (United States)

    Bonaccorsi, Joyce; Berardi, Nicoletta; Sale, Alessandro

    2014-01-01

    Amblyopia is the most common form of impairment of visual function affecting one eye, with a prevalence of about 1–5% of the total world population. Amblyopia usually derives from conditions of early functional imbalance between the two eyes, owing to anisometropia, strabismus, or congenital cataract, and results in a pronounced reduction of visual acuity and severe deficits in contrast sensitivity and stereopsis. It is widely accepted that, due to a lack of sufficient plasticity in the adult brain, amblyopia becomes untreatable after the closure of the critical period in the primary visual cortex. However, recent results obtained both in animal models and in clinical trials have challenged this view, unmasking a previously unsuspected potential for promoting recovery even in adulthood. In this context, non invasive procedures based on visual perceptual learning, i.e., the improvement in visual performance on a variety of simple visual tasks following practice, emerge as particularly promising to rescue discrimination abilities in adult amblyopic subjects. This review will survey recent work regarding the impact of visual perceptual learning on amblyopia, with a special focus on a new experimental model of perceptual learning in the amblyopic rat. PMID:25076874

  6. Optogenetic delay of status epilepticus onset in an in vivo rodent epilepsy model.

    Directory of Open Access Journals (Sweden)

    Inna Sukhotinsky

    Full Text Available Epilepsy is a devastating disease, currently treated with medications, surgery or electrical stimulation. None of these approaches is totally effective and our ability to control seizures remains limited and complicated by frequent side effects. The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats. Hippocampal pyramidal neurons were transduced in vivo with a virus carrying an enhanced halorhodopsin (eNpHR, a yellow light activated chloride pump, and acute seizure progression was then monitored behaviorally and electrophysiologically in the presence and absence of illumination delivered via an optical fiber. Inhibition of those neurons with illumination prior to seizure onset significantly delayed electrographic and behavioral initiation of status epilepticus, and altered the dynamics of ictal activity development. These results reveal an essential role of hippocampal excitatory neurons in this model of ictogenesis and illustrate the power of optogenetic approaches for elucidation of seizure mechanisms. This early success in controlling seizures also suggests future therapeutic avenues.

  7. Examination of Gelatinase Isoforms in Rodent Models of Acute Neurodegenerative Diseases Using Two-Dimensional Zymography.

    Science.gov (United States)

    Chen, Shanyan; Meng, Fanjun; Chen, Zhenzhou; Qu, Zhe; Cui, Jiankun; Gu, Zezong

    2017-01-01

    Pathological activation of gelatinases (matrix metalloproteinase-2 and -9; MMP-2/-9) has been shown to cause a number of detrimental outcomes in neurodegenerative diseases. In gel gelatin zymography is a highly sensitive methodology commonly used in revealing levels of gelatinase activity and in separating the proform and active form of gelatinases, based on their different molecular weights. However, this methodology is inadequate in resolving complex enzyme isoforms, because gelatinase expression and activity can be regulated at transcriptional and/or post-translational levels under in vivo conditions resulting in alternation of their isoelectric focusing (IEF) points. In this chapter, we describe an advanced methodology, termed two-dimensional zymography, combining IEF with zymographic electrophoresis under non-reducing conditions to achieve significant improvement in separation of the gelatinase isoforms in both cell-based and in vivo models for acute brain injuries and neuroinflammation.

  8. Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia.

    Science.gov (United States)

    Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G; Grace, Anthony A

    2013-10-01

    Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.

  9. Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: A pilot study.

    Science.gov (United States)

    Mohan, Geetha; Magnitsky, Sergey; Melkus, Gerd; Subburaj, Karupppasamy; Kazakia, Galateia; Burghardt, Andrew J; Dang, Alexis; Lane, Nancy E; Majumdar, Sharmila

    2016-10-01

    Osteoarthritis (OA) is a major degenerative joint disease characterized by progressive loss of articular cartilage, synovitis, subchondral bone changes, and osteophyte formation. Currently there is no treatment for OA except temporary pain relief and end-stage joint replacement surgery. We performed a pilot study to determine the effect of kartogenin (KGN, a small molecule) on both cartilage and subchondral bone in a rat model of OA using multimodal imaging techniques. OA was induced in rats (OA and KGN treatment group) by anterior cruciate ligament transection (ACLT) surgery in the right knee joint. Sham surgery was performed on the right knee joint of control group rats. KGN group rats received weekly intra-articular injection of 125 μM KGN 1 week after surgery until week 12. All rats underwent in vivo magnetic resonance imaging (MRI) at 3, 6, and 12 weeks after surgery. Quantitative MR relaxation measures (T 1ρ and T 2 ) were determined to evaluate changes in articular cartilage. Cartilage and bone turnover markers (COMP and CTX-I) were determined at baseline, 3, 6, and 12 weeks. Animals were sacrificed at week 12 and the knee joints were removed for micro-computed tomography (micro-CT) and histology. KGN treatment significantly lowered the T 1ρ and T 2 relaxation times indicating decreased cartilage degradation. KGN treatment significantly decreased COMP and CTX-I levels indicating decreased cartilage and bone turnover rate. KGN treatment also prevented subchondral bone changes in the ACLT rat model of OA. Thus, kartogenin is a potential drug to prevent joint deterioration in post-traumatic OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1780-1789, 2016. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  10. Altered Right Ventricular Mechanical Properties Are Afterload Dependent in a Rodent Model of Bronchopulmonary Dysplasia

    Directory of Open Access Journals (Sweden)

    Jitandrakumar R. Patel

    2017-10-01

    Full Text Available Infants born premature are at increased risk for development of bronchopulmonary dysplasia (BPD, pulmonary hypertension (PH, and ultimately right ventricular (RV dysfunction, which together carry a high risk of neonatal mortality. However, the role alveolar simplification and abnormal pulmonary microvascular development in BPD affects RV contractile properties is unknown. We used a rat model of BPD to examine the effect of hyperoxia-induced PH on RV contractile properties. We measured in vivo RV pressure as well as passive force, maximum Ca2+ activated force, calcium sensitivity of force (pCa50 and rate of force redevelopment (ktr in RV skinned trabeculae isolated from hearts of 21-and 35-day old rats pre-exposed to 21% oxygen (normoxia or 85% oxygen (hyperoxia for 14 days after birth. Systolic and diastolic RV pressure were significantly higher at day 21 in hyperoxia exposed rats compared to normoxia control rats, but normalized by 35 days of age. Passive force, maximum Ca2+ activated force, and calcium sensitivity of force were elevated and cross-bridge cycling kinetics depressed in 21-day old hyperoxic trabeculae, whereas no differences between normoxic and hyperoxic trabeculae were seen at 35 days. Myofibrillar protein analysis revealed that 21-day old hyperoxic trabeculae had increased levels of beta-myosin heavy chain (β-MHC, atrial myosin light chain 1 (aMLC1; often referred to as essential light chain, and slow skeletal troponin I (ssTnI compared to age matched normoxic trabeculae. On the other hand, 35-day old normoxic and hyperoxic trabeculae expressed similar level of α- and β-MHC, ventricular MLC1 and predominantly cTnI. These results suggest that neonatal exposure to hyperoxia increases RV afterload and affect both the steady state and dynamic contractile properties of the RV, likely as a result of hyperoxia-induced expression of β-MHC, delayed transition of slow skeletal TnI to cardiac TnI, and expression of atrial MLC1. These

  11. Adrenomedulline improves ischemic left colonic anastomotic healing in an experimental rodent model

    Directory of Open Access Journals (Sweden)

    Oguzhan Karatepe

    2011-01-01

    Full Text Available BACKGROUND: Leakage from colonic anastomosis is a major complication causing increased mortality and morbidity. Ischemia is a well-known cause of this event. This study was designed to investigate the effects of adrenomedullin on the healing of ischemic colon anastomosis in a rat model. METHODS: Standardized left colon resection 3 cm above the peritoneal reflection and colonic anastomosis were performed in 40 Wistar rats that were divided into four groups. To mimic ischemia, the mesocolon was ligated 2 cm from either side of the anastomosis in all of the groups. The control groups (1 and 2 received no further treatment. The experimental groups (3 and 4 received adrenomedullin treatment. Adrenomedullin therapy was started in the perioperative period in group 3 and 4 rats (the therapeutic groups. Group 1 and group 3 rats were sacrificed on postoperative day 3. Group 2 and group 4 rats were sacrificed on postoperative day 7. After careful relaparotomy, bursting pressure, hydroxyproline, malondialdehyde, interleukin 6, nitric oxide, vascular endothelial growth factor, and tumor necrosis factor alpha levels were measured. Histopathological characteristics of the anastomosis were analyzed. RESULTS: The group 3 animals had a significantly higher bursting pressure than group 1 (p<0.05. Hydroxyproline levels in group 1 were significantly lower than in group 3 (p<0.05. The mean bursting pressure was significantly different between group 2 and group 4 (p<0.05. Hydroxyproline levels in groups 3 and 4 were significantly increased by adrenomedullin therapy relative to the control groups (p<0.05. When all groups were compared, malondialdehyde and nitric oxide were significantly lower in the control groups (p<0.05. When vascular endothelial growth factor levels were compared, no statistically significant difference between groups was observed. Interleukin 6 and tumor necrosis factor alpha were significantly decreased by adrenomedullin therapy (p<0.05. The

  12. Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy.

    Science.gov (United States)

    Dhanda, Saurabh; Sandhir, Rajat

    2015-06-01

    The present study was designed to evaluate the role of biogenic amines in behavioral alterations observed in rat model of hepatic encephalopathy (HE) following bile duct ligation (BDL). Male Wistar rats subjected to BDL developed biliary fibrosis after four weeks which was supported by altered liver function tests, increased ammonia levels and histological staining (Sirius red). Animals were assessed for their behavioral performance in terms of cognitive, anxiety and motor functions. The levels of dopamine (DA), serotonin (5-HT), epinephrine and norepinephrine (NE) were estimated in different regions of brain viz. cortex, hippocampus, striatum and cerebellum using HPLC along with activity of monoamine oxidase (MAO). Cognitive assessment of BDL rats revealed a progressive decline in learning, memory formation, retrieval, exploration of novel environment and spontaneous locomotor activity along with decrease in 5-HT and NE levels. This was accompanied by an increase in MAO activity. Motor functions of BDL rats were also altered which were evident from decrease in the time spent on the rotating rod and higher foot faults assessed using narrow beam walk task. A global decrease was observed in the DA content along with an increase in MAO activity. Histopathological studies using hematoxylin-eosin (H&E) and cresyl violet exhibited marked neuronal degeneration, wherein neurons appeared more pyknotic, condensed and damaged. The results reveal that dopaminergic and serotonergic pathways are disturbed in chronic liver failure post-BDL which may be responsible for behavioral impairments observed in HE. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

    Science.gov (United States)

    Wargo, A.R.; Huijben, S.; De Roode, J. C.; Shepherd, J.; Read, A.F.

    2007-01-01

    Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after pyrimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance. ?? 2007 by The National Academy of Sciences of the USA.

  14. Predictors of the nicotine reinforcement threshold, compensation, and elasticity of demand in a rodent model of nicotine reduction policy.

    Science.gov (United States)

    Grebenstein, Patricia E; Burroughs, Danielle; Roiko, Samuel A; Pentel, Paul R; LeSage, Mark G

    2015-06-01

    The FDA is considering reducing the nicotine content in tobacco products as a population-based strategy to reduce tobacco addiction. Research is needed to determine the threshold level of nicotine needed to maintain smoking and the extent of compensatory smoking that could occur during nicotine reduction. Sources of variability in these measures across sub-populations also need to be identified so that policies can take into account the risks and benefits of nicotine reduction in vulnerable populations. The present study examined these issues in a rodent nicotine self-administration model of nicotine reduction policy to characterize individual differences in nicotine reinforcement thresholds, degree of compensation, and elasticity of demand during progressive reduction of the unit nicotine dose. The ability of individual differences in baseline nicotine intake and nicotine pharmacokinetics to predict responses to dose reduction was also examined. Considerable variability in the reinforcement threshold, compensation, and elasticity of demand was evident. High baseline nicotine intake was not correlated with the reinforcement threshold, but predicted less compensation and less elastic demand. Higher nicotine clearance predicted low reinforcement thresholds, greater compensation, and less elastic demand. Less elastic demand also predicted lower reinforcement thresholds. These findings suggest that baseline nicotine intake, nicotine clearance, and the essential value of nicotine (i.e. elasticity of demand) moderate the effects of progressive nicotine reduction in rats and warrant further study in humans. They also suggest that smokers with fast nicotine metabolism may be more vulnerable to the risks of nicotine reduction. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Improvement of mesh recolonization in abdominal wall reconstruction with adipose vs. bone marrow mesenchymal stem cells in a rodent model.

    Science.gov (United States)

    van Steenberghe, M; Schubert, T; Guiot, Y; Goebbels, R M; Gianello, P

    2017-08-01

    Reconstruction of muscle defects remains a challenge. Our work assessed the potential of an engineered construct made of a human acellular collagen matrix (HACM) seeded with porcine mesenchymal stem cells (MSCs) to reconstruct abdominal wall muscle defects in a rodent model. This study compared 2 sources of MSCs (bone-marrow, BMSCs, and adipose, ASCs) in vitro and in vivo for parietal defect reconstruction. Cellular viability and growth factor release (VEGF, FGF-Beta, HGF, IGF-1, TGF-Beta) were investigated under normoxic/hypoxic culture conditions. Processed and recellularized HACMs were mechanically assessed. The construct was tested in vivo in full thickness abdominal wall defect treated with HACM alone vs. HACM+ASCs or BMSCs (n=14). Tissue remodeling was studied at day 30 for neo-angiogenesis and muscular reconstruction. A significantly lower secretion of IGF was observed with ASCs vs. BMSCs under hypoxic conditions (-97.6%, p<0.005) whereas significantly higher VEGF/FGF secretions were found with ASCs (+92%, p<0.001 and +72%, p<0.05, respectively). Processing and recellularization did not impair the mechanical properties of the HACM. In vivo, angiogenesis and muscle healing were significantly improved by the HACM+ASCs in comparison to BMSCs (p<0.05) at day 30. A composite graft made of an HACM seeded with ASCs can improve muscle repair by specific growth factor release in hypoxic conditions and by in vivo remodeling (neo-angiogenesis/graft integration) while maintaining mechanical properties. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Mapping of the brain hemodynamic responses to sensorimotor stimulation in a rodent model: A BOLD fMRI study.

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    Salem Boussida

    Full Text Available Blood Oxygenation Level Dependent functional MRI (BOLD fMRI during electrical paw stimulation has been widely used in studies aimed at the understanding of the somatosensory network in rats. However, despite the well-established anatomical connections between cortical and subcortical structures of the sensorimotor system, most of these functional studies have been concentrated on the cortical effects of sensory electrical stimulation. BOLD fMRI study of the integration of a sensorimotor input across the sensorimotor network requires an appropriate methodology to elicit functional activation in cortical and subcortical areas owing to the regional differences in both neuronal and vascular architectures between these brain regions. Here, using a combination of low level anesthesia, long pulse duration of the electrical stimulation along with improved spatial and temporal signal to noise ratios, we provide a functional description of the main cortical and subcortical structures of the sensorimotor rat brain. With this calibrated fMRI protocol, unilateral non-noxious sensorimotor electrical hindpaw stimulation resulted in robust positive activations in the contralateral sensorimotor cortex and bilaterally in the sensorimotor thalamus nuclei, whereas negative activations were observed bilaterally in the dorsolateral caudate-putamen. These results demonstrate that, once the experimental setup allowing necessary spatial and temporal signal to noise ratios is reached, hemodynamic changes related to neuronal activity, as preserved by the combination of a soft anesthesia with a soft muscle relaxation, can be measured within the sensorimotor network. Moreover, the observed responses suggest that increasing pulse duration of the electrical stimulus adds a proprioceptive component to the sensory input that activates sensorimotor network in the brain, and that these activation patterns are similar to those induced by digits paw's movements. These findings may

  17. Effects of Vitamin D Treatment on Skeletal Muscle Histology and Ultrastructural Changes in a Rodent Model

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    Sobhy M. Yakout

    2012-07-01

    Full Text Available Vitamin D is well known for its role in maintaining calcium and phosphorus homeostasis and in promoting bone mineralization; however, more of its pleiotropic effects have been described recently. The aim of the present investigation was to study the effect of vitamin D treatment on skeletal muscles changes under different dietary conditions using an animal model. Four groups of C57BL/6J mice (n = 11 each were maintained on either low fat diet (LFD or high fat diet ‎‎(HFD with and without 1α,25–dihydroxyvitamin D3 (calcitriol for 16 weeks. Animal weigh was recorded at baseline and then regular intervals, and at the end of the study, skeletal muscle tissues were harvested for the evaluation of the histopathological and ultrastructural changes. When control C57BL/6J mice were fed high-fat diet for 12 weeks, body weight gain was significantly increased compared with mice fed a LFD. (30.2% vs. 8.4%, p < 0.01. There was a significant gradual decrease in the weight of HFD fed mice that were treated with vitamin D as compared with a steady increase in the weights of controls (6.8% vs. 28.7%, p < 0.01. While the LFD group showed some ultrastructural changes, HDF fed on mice showed great muscle structural abnormalities. The whole sarcosome along with its membrane and cristae were severely damaged with scattered myocytes in HFD group. Furthermore, the mitochondria appeared weak and were on the verge of degenerations. The bands were diminished with loss of connections among myofibrils. These changes were attenuated in the HFD group treated with vitamin D with tissues have regained their normal structural appearance. The current findings indicate an important effect of vitamin D on skeletal muscle histology under HFD conditions.

  18. Sexually dimorphic effects of unpredictable early life adversity on visceral pain behavior in a rodent model.

    Science.gov (United States)

    Chaloner, Aaron; Greenwood-Van Meerveld, Beverley

    2013-03-01

    Visceral pain is the hallmark feature of irritable bowel syndrome (IBS), a gastrointestinal disorder, which is more commonly diagnosed in women. Female IBS patients frequently report a history of early life adversity (ELA); however, sex differences in ELA-induced visceral pain and the role of ovarian hormones have yet to be investigated. Therefore, we tested the hypothesis that ELA induces visceral hypersensitivity through a sexually dimorphic mechanism mediated via estradiol. As a model of ELA, neonatal rats were exposed to different pairings of an odor and shock to control for trauma predictability. In adulthood, visceral sensitivity was assessed via a visceromotor response to colorectal distension. Following ovariectomy and estradiol replacement in a separate group of rats, the visceral sensitivity was quantified. We found that females that received unpredictable odor-shock developed visceral hypersensitivity in adulthood. In contrast, visceral sensitivity was not significantly different following ELA in adult males. Ovariectomy reversed visceral hypersensitivity following unpredictable ELA, whereas estradiol replacement reestablished visceral hypersensitivity in the unpredictable group. This study is the first to show sex-related differences in visceral sensitivity following unpredictable ELA. Our data highlight the activational effect of estradiol as a pivotal mechanism in maintaining visceral hypersensitivity. This article directly implicates a critical role for ovarian hormones in maintaining visceral hypersensitivity following ELA, specifically identifying the activational effect of estradiol as a key modulator of visceral sensitivity. These data suggest that ELA induces persistent functional abdominal pain in female IBS patients through an estrogen-dependent mechanism. Copyright © 2013 American Pain Society. All rights reserved.

  19. Sustained release of milrinone delivered via microparticles in a rodent model of myocardial infarction.

    Science.gov (United States)

    Al Kindi, Hamood; Paul, Arghya; You, Zhipeng; Nepotchatykh, Oleg; Schwertani, Adel; Prakash, Satya; Shum-Tim, Dominique

    2014-11-01

    The aim of the present study was to construct a new drug delivery system for milrinone using microparticles. This novel technology enhances drug bioavailability and decreases toxicity, with future implications for the treatment of end-stage heart failure. Polylactic-co-glycolic acid microparticles (PLGA-MPs) loaded with milrinone were prepared using a double emulsion-solvent evaporation technique. In vitro release kinetics was evaluated at physiologic conditions. A total of 24 female Lewis rats underwent left coronary artery ligation. One week after ligation, all rats were randomized to 1 of 3 groups (n=8 per group). Group I received an intravenous injection of PLGA-MPs alone; group II, a bolus intravenous injection of milrinone; and group III an intravenous injection of milrinone-PLGA-MPs. All injections were administrated slowly by way of the tail vein over 10 minutes. Transthoracic echocardiography, noninvasive heart rate monitoring, and blood pressure measurements were performed at different predetermined intervals before and for 24 hours after the injection. All rats survived for 24 hours and were then killed by euthanasia. Serum plasma was taken for cytokine assays and determination of milrinone levels using high-performance liquid chromatography. Group III had a significantly greater left ventricular ejection fraction at 90 minutes and 3, 6, and 12 hours after treatment compared with the other groups. The milrinone plasma level was significantly greater in group III than in the other groups (group I, 0 ng/mL; group II, 1.7±2.4 ng/mL; group III, 9.1±2.2 ng/mL; Pmilrinone. We propose a new strategy for future drug delivery in patients with end-stage heart failure. Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  20. Glycoprotein 130 receptor signaling mediates α-cell dysfunction in a rodent model of type 2 diabetes

    DEFF Research Database (Denmark)

    Chow, Samuel Z; Speck, Madeleine; Yoganathan, Piriya

    2014-01-01

    Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated...

  1. A wireless power transmission system for implantable devices in freely moving rodents.

    Science.gov (United States)

    Eom, Kyungsik; Jeong, Joonsoo; Lee, Tae Hyung; Kim, Jinhyung; Kim, Junghoon; Lee, Sung Eun; Kim, Sung June

    2014-08-01

    Reliable wireless power delivery for implantable devices in animals is highly desired for safe and effective experimental use. Batteries require frequent replacement; wired connections are inconvenient and unsafe, and short-distance inductive coupling requires the attachment of an exterior transmitter to the animal's body. In this article, we propose a solution by which animals with implantable devices can move freely without attachments. Power is transmitted using coils attached to the animal's cage and is received by a receiver coil implanted in the animal. For a three-dimensionally uniform delivery of power, we designed a columnar dual-transmitter coil configuration. A resonator-based inductive link was adopted for efficient long-range power delivery, and we used a novel biocompatible liquid crystal polymer substrate as the implantable receiver device. Using this wireless power delivery system, we obtain an average power transfer efficiency of 15.2% (minimum efficiency of 10% and a standard deviation of 2.6) within a cage of 15×20×15 cm3.

  2. Behavioral and histological outcomes following neonatal HI injury in a preterm (P3) and term (P7) rodent model.

    Science.gov (United States)

    Alexander, M; Garbus, H; Smith, A L; Rosenkrantz, T S; Fitch, R H

    2014-02-01

    Hypoxia-ischemia (HI) occurs when blood and/or oxygen delivery to the brain is compromised. HI injuries can occur in infants born prematurely (HI populations, brain injury is associated with subsequent behavioral deficits. Neonatal HI injury can be modeled in rodents (e.g., the Rice-Vannucci method, via cautery of right carotid followed by hypoxia). When this injury is induced early in life (between postnatal day (P)1-5), neuropathologies typical of human preterm HI are modeled. When injury is induced later (P7-12), neuropathologies typical of those seen in HI term infants are modeled. The current study sought to characterize the similarities/differences between outcomes following early (P3) and late (P7) HI injury in rats. Male rats with HI injury on P3 or P7, as well as sham controls, were tested on a variety of behavioral tasks in both juvenile and adult periods. Results showed that P7 HI rats displayed deficits on motor learning, rapid auditory processing (RAP), and other learning/memory tasks, as well as a reduction in volume in various neuroanatomical structures. P3 HI animals showed only transient deficits on RAP tasks in the juvenile period (but not in adulthood), yet robust deficits on a visual attention task in adulthood. P3 HI animals did not show any significant reductions in brain volume that we could detect. These data suggest that: (1) behavioral deficits following neonatal HI are task-specific depending on timing of injury; (2) P3 HI rats showed transient deficits on RAP tasks; (3) the more pervasive behavioral deficits seen following P7 HI injury were associated with substantial global tissue loss; and (4) persistent deficits in attention in P3 HI subjects might be linked to neural connectivity disturbances rather than a global loss of brain volume, given that no such pathology was found. These combined findings can be applied to our understanding of differing long-term outcomes following neonatal HI injury in premature versus term infants

  3. Impact of anesthesia, analgesia, and euthanasia technique on the inflammatory cytokine profile in a rodent model of severe burn injury.

    Science.gov (United States)

    Al-Mousawi, Ahmed M; Kulp, Gabriela A; Branski, Ludwik K; Kraft, Robert; Mecott, Gabriel A; Williams, Felicia N; Herndon, David N; Jeschke, Marc G

    2010-09-01

    Anesthetics used in burn and trauma animal models may be influencing results by modulating inflammatory and acute-phase responses. Accordingly, we determined the effects of various anesthetics, analgesia, and euthanasia techniques in a rodent burn model. Isoflurane (ISO), ketamine-xylazine (KX), or pentobarbital (PEN) with or without buprenorphine were administered before scald-burn in 72 rats that were euthanized without anesthesia by decapitation after 24 h and compared with unburned shams. In a second experiment, 120 rats underwent the same scald-burn injury using KX, and 24 h later were euthanized under anesthesia or carbon dioxide (CO2). In addition, we compared euthanasia by exsanguination with that of decapitation. Serum cytokine levels were determined by an enzyme-linked immunosorbent assay. In the first experiment, ISO was associated with elevation of cytokine-induced neutrophil chemoattractant 2 (CINC-2) and monocyte chemotactic protein 1 (MCP-1), and KX and PEN was associated with elevation of CINC-1,CINC-2, IL-6, and MCP-1. Pentobarbital also decreased IL-1". IL-6 increased significantly when ISO or PEN were combined with buprenorphine. In the second experiment, euthanasia performed by exsanguination under ISO was associated with reduced levels of IL-1", CINC-1, CINC-2, and MCP-1, whereas KX reduced CINC-2 and increased IL-6 levels. Meanwhile, PEN reduced levels of IL-1" and MCP-1, and CO2 reduced CINC-2 and MCP-1. In addition,decapitation after KX, PEN, or CO2 decreased IL-1" and MCP-1, although we found no significant difference between ISO and controls. Euthanasia by exsanguination compared with decapitation using the same agent also led to modulation of several cytokines. Differential expression of inflammatory markers with the use of anesthetics and analgesics should be considered when designing animal studies and interpreting results because these seem to have a significant modulating impact. Our findings indicate that brief anesthesia with ISO

  4. Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.

    Science.gov (United States)

    O'Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

    2015-09-01

    Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of

  5. Systemic Administration of Glibenclamide Fails to Achieve Therapeutic Levels in the Brain and Cerebrospinal Fluid of Rodents.

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    Carolina Lahmann

    Full Text Available Activating mutations in the Kir6.2 (KCNJ11 subunit of the ATP-sensitive potassium channel cause neonatal diabetes (ND. Patients with severe mutations also suffer from neurological complications. Glibenclamide blocks the open KATP channels and is the treatment of choice for ND. However, although glibenclamide successfully restores normoglycaemia, it has a far more limited effect on the neurological problems. To assess the extent to which glibenclamide crosses the blood-brain barrier (BBB in vivo, we quantified glibenclamide concentrations in plasma, cerebrospinal fluid (CSF, and brain tissue of rats, control mice, and mice expressing a human neonatal diabetes mutation (Kir6.2-V59M selectively in neurones (nV59M mice. As only small sample volumes can be obtained from rodents, we developed a highly sensitive method of analysis, using liquid chromatography tandem mass spectrometry acquisition with pseudo-selected reaction monitoring, achieving a quantification limit of 10ng/ml (20nM glibenclamide in a 30μl sample. Glibenclamide was not detectable in the CSF or brain of rats after implantation with subcutaneous glibenclamide pellets, despite high plasma concentrations. Further, one hour after a suprapharmacological glibenclamide dose was administered directly into the lateral ventricle of the brain, the plasma concentration was twice that of the CSF. This suggests the drug is rapidly exported from the CSF. Elacridar, an inhibitor of P-glycoprotein and breast cancer resistance protein (major multidrug resistance transporters at the BBB, did not affect glibenclamide levels in CSF and brain tissue. We also identified a reduced sensitivity to volatile anaesthetics in nV59M mice and showed this was not reversed by systemic delivery of glibenclamide. Our results therefore suggest that little glibenclamide reaches the central nervous system when given systemically, that glibenclamide is rapidly removed across the BBB when given intracranioventricularly

  6. Beneficial Effects of Caloric Restriction on Chronic Kidney Disease in Rodent Models: A Meta-Analysis and Systematic Review.

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    Xiao-Meng Xu

    Full Text Available Numerous studies have demonstrated the life-extending effect of caloric restriction. It is generally accepted that caloric restriction has health benefits, such as prolonging lifespan and delaying the onset and progression of CKD in various species, especially in rodent models. Although many studies have tested the efficacy of caloric restriction, no complete quantitative analysis of the potential beneficial effects of reducing caloric intake on the development and progression of CKD has been published.All studies regarding the relationship between caloric restriction and chronic kidney diseases were searched in electronic databases, including PubMed/MEDLINE, EMBASE, Science Citation Index (SCI, OVID evidence-based medicine, Chinese Bio-medical Literature and Chinese science and technology periodicals (CNKI, VIP, and Wan Fang. The pooled odds ratios (OR and 95% confidence intervals (95% CI were calculated by using fixed- or random-effects models.The data from 27 of all the studies mentioned above was used in the Meta analysis. Through the meta-analysis, we found that the parameter of blood urea nitrogen, serum creatinine and urinary protein levels of the AL group was significant higher than that of the CR group, which are 4.11 mg/dl, 0.08mg/dl and 33.20mg/kg/24h, respectively. The incidence of the nephropathy in the caloric restriction (CR group was significantly lower than that in the ad libitum-fed (AL group. We further introduced the subgroup analysis and found that the effect of caloric restriction on the occurrence of kidney disease was only significant with prolonged intervention; the beneficial effects of CR on the 60%-caloric-restriction group were greater than on the less-than-60%-caloric-restriction group, and caloric restriction did not show obvious protective effects in genetically modified strains. Moreover, survival rate of the caloric restriction group is much higher than that of the ad libitum-fed (AL group.Our findings

  7. Long Non-Coding RNA Profiling in a Non-Alcoholic Fatty Liver Disease Rodent Model: New Insight into Pathogenesis

    Directory of Open Access Journals (Sweden)

    Yi Chen

    2017-01-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is one of the most prevalent chronic liver diseases worldwide with an unclear mechanism. Long non-coding RNAs (lncRNAs have recently emerged as important regulatory molecules. To better understand NAFLD pathogenesis, lncRNA and messenger RNA (mRNA microarrays were conducted in an NAFLD rodent model. Potential target genes of significantly changed lncRNA were predicted using cis/trans-regulatory algorithms. Gene Ontology (GO analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG pathway enrichment analysis were then performed to explore their function. In the current analysis, 89 upregulated and 177 downregulated mRNAs were identified, together with 291 deregulated lncRNAs. Bioinformatic analysis of these RNAs has categorized these RNAs into pathways including arachidonic acid metabolism, circadian rhythm, linoleic acid metabolism, peroxisome proliferator-activated receptor (PPAR signaling pathway, sphingolipid metabolism, steroid biosynthesis, tryptophan metabolism and tyrosine metabolism were compromised. Quantitative polymerase chain reaction (qPCR of representative nine mRNAs and eight lncRNAs (named fatty liver-related lncRNA, FLRL was conducted and this verified previous microarray results. Several lncRNAs, such as FLRL1, FLRL6 and FLRL2 demonstrated to be involved in circadian rhythm targeting period circadian clock 3 (Per3, Per2 and aryl hydrocarbon receptor nuclear translocator-like (Arntl, respectively. While FLRL8, FLRL3 and FLRL7 showed a potential role in PPAR signaling pathway through interaction with fatty acid binding protein 5 (Fabp5, lipoprotein lipase (Lpl and fatty acid desaturase 2 (Fads2. Functional experiments showed that interfering of lncRNA FLRL2 expression affected the expression of predicted target, circadian rhythm gene Arntl. Moreover, both FLRL2 and Arntl were downregulated in the NAFLD cellular model. The current study identified lncRNA and corresponding mRNA in NAFLD

  8. ℮-conome: an automated tissue counting platform of cone photoreceptors for rodent models of retinitis pigmentosa

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    Clérin Emmanuelle

    2011-12-01

    Full Text Available Abstract Background Retinitis pigmentosa is characterized by the sequential loss of rod and cone photoreceptors. The preservation of cones would prevent blindness due to their essential role in human vision. Rod-derived Cone Viability Factor is a thioredoxin-like protein that is secreted by rods and is involved in cone survival. To validate the activity of Rod-derived Cone Viability Factors (RdCVFs as therapeutic agents for treating retinitis Pigmentosa, we have developed e-conome, an automated cell counting platform for retinal flat mounts of rodent models of cone degeneration. This automated quantification method allows for faster data analysis thereby accelerating translational research. Methods An inverted fluorescent microscope, motorized and coupled to a CCD camera records images of cones labeled with fluorescent peanut agglutinin lectin on flat-mounted retinas. In an average of 300 fields per retina, nine Z-planes at magnification X40 are acquired after two-stage autofocus individually for each field. The projection of the stack of 9 images is subject to a threshold, filtered to exclude aberrant images based on preset variables. The cones are identified by treating the resulting image using 13 variables empirically determined. The cone density is calculated over the 300 fields. Results The method was validated by comparison to the conventional stereological counting. The decrease in cone density in rd1 mouse was found to be equivalent to the decrease determined by stereological counting. We also studied the spatiotemporal pattern of the degeneration of cones in the rd1 mouse and show that while the reduction in cone density starts in the central part of the retina, cone degeneration progresses at the same speed over the whole retinal surface. We finally show that for mice with an inactivation of the Nucleoredoxin-like genes Nxnl1 or Nxnl2 encoding RdCVFs, the loss of cones is more pronounced in the ventral retina. Conclusion The automated

  9. ℮-conome: an automated tissue counting platform of cone photoreceptors for rodent models of retinitis pigmentosa.

    Science.gov (United States)

    Clérin, Emmanuelle; Wicker, Nicolas; Mohand-Saïd, Saddek; Poch, Olivier; Sahel, José-Alain; Léveillard, Thierry

    2011-12-20

    Retinitis pigmentosa is characterized by the sequential loss of rod and cone photoreceptors. The preservation of cones would prevent blindness due to their essential role in human vision. Rod-derived Cone Viability Factor is a thioredoxin-like protein that is secreted by rods and is involved in cone survival. To validate the activity of Rod-derived Cone Viability Factors (RdCVFs) as therapeutic agents for treating retinitis Pigmentosa, we have developed e-conome, an automated cell counting platform for retinal flat mounts of rodent models of cone degeneration. This automated quantification method allows for faster data analysis thereby accelerating translational research. An inverted fluorescent microscope, motorized and coupled to a CCD camera records images of cones labeled with fluorescent peanut agglutinin lectin on flat-mounted retinas. In an average of 300 fields per retina, nine Z-planes at magnification X40 are acquired after two-stage autofocus individually for each field. The projection of the stack of 9 images is subject to a threshold, filtered to exclude aberrant images based on preset variables. The cones are identified by treating the resulting image using 13 variables empirically determined. The cone density is calculated over the 300 fields. The method was validated by comparison to the conventional stereological counting. The decrease in cone density in rd1 mouse was found to be equivalent to the decrease determined by stereological counting. We also studied the spatiotemporal pattern of the degeneration of cones in the rd1 mouse and show that while the reduction in cone density starts in the central part of the retina, cone degeneration progresses at the same speed over the whole retinal surface. We finally show that for mice with an inactivation of the Nucleoredoxin-like genes Nxnl1 or Nxnl2 encoding RdCVFs, the loss of cones is more pronounced in the ventral retina. The automated platform ℮-conome used here for retinal disease is a tool that

  10. Wild rodents as a model to discover genes and pathways underlying natural variation in infectious disease susceptibility.

    Science.gov (United States)

    Turner, A K; Paterson, S

    2013-11-01

    Individuals vary in their susceptibility to infectious disease, and it is now well established that host genetic factors form a major component of this variation. The discovery of genes underlying susceptibility has the potential to lead to improved disease control, through the identification and management of vulnerable individuals and the discovery of novel therapeutic targets. Laboratory rodents have proved invaluable for ascertaining the function of genes involved in immunity to infection. However, these captive animals experience conditions very different to the natural environment, lacking the genetic diversity and environmental pressures characteristic of natural populations, including those of humans. It has therefore often proved difficult to translate basic laboratory research to the real world. In order to further our understanding of the genetic basis of infectious disease resistance, and the evolutionary forces that drive variation in susceptibility, we propose that genetic research traditionally conducted on laboratory animals is expanded to the more ecologically valid arena of natural populations. In this article, we highlight the potential of using wild rodents as a new resource for biomedical research, to link the functional genetic knowledge gained from laboratory rodents with the variation in infectious disease susceptibility observed in humans and other natural populations. © 2013 John Wiley & Sons Ltd.

  11. Analgesic and Anti-Inflammatory Effects of 80% Methanol Extract of Leonotis ocymifolia (Burm.f. Iwarsson Leaves in Rodent Models

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    Asnakech Alemu

    2018-01-01

    Full Text Available Background. Pain and inflammation are the major health problems commonly treated with traditional remedies mainly using medicinal plants. Leonotis ocymifolia is one of such medicinal plants used in folkloric medicine of Ethiopia. However, the plant has not been scientifically evaluated. The aim of this study was to evaluate analgesic and anti-inflammatory effects of the 80% methanol leaves extract of Leonotis ocymifolia using rodent models. Method. The central and peripheral analgesic effect of the extract at 100, 200, and 400 mg/kg dose levels was evaluated using hot plate and acetic acid induced writhing rodent models, whereas carrageenan induced paw edema and cotton pellet granuloma methods were used to screen anti-inflammatory effect of the extract at the same dose levels. Acute toxicity test was also done. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test and p<0.05 was considered significant. Results. The extract did not produce mortality up to 2000 mg/kg. All tested doses of the extract showed significant analgesic effect with maximum latency response of 62.8% and inhibition of acetic acid induced writhing. Maximum anti-inflammatory effect was recorded at 6 h after induction, with 75.88% reduction in carrageenan induced paw edema. Moreover, all tested doses of extract significantly inhibited the formation of inflammatory exudates and granuloma formation (p<0.001. Conclusion. The study indicated that the extract was safe in mice and it has both analgesic and anti-inflammatory effect in rodent models.

  12. Rodent management: the man/environment interface

    International Nuclear Information System (INIS)

    Jackson, W.B.

    1978-01-01

    Rodents which interact with man generally are regarded as undesirable. Attempts at eliminating such rodents by increasing predation (including traps, microbiological agents, toxicants) have been relatively unsuccessful. Management by environmental manipulation must be basic. This then can be supplemented with predation at critical points where public health, use practices, or imperfections in the system demand. Society mores, practices, and economic considerations also have significant impact on the management system

  13. Tactile learning in rodents: Neurobiology and neuropharmacology.

    Science.gov (United States)

    Roohbakhsh, Ali; Shamsizadeh, Ali; Arababadi, Mohammad Kazemi; Ayoobi, Fateme; Fatemi, Iman; Allahtavakoli, Mohammad; Mohammad-Zadeh, Mohammad

    2016-02-15

    Animal models of learning and memory have been the subject of considerable research. Rodents such as mice and rats are nocturnal animals with poor vision, and their survival depends on their sense of touch. Recent reports have shown that whisker somatosensation is the main channel through which rodents collect and process environmental information. This review describes tactile learning in rodents from a neurobiological and neuropharmacological perspective, and how this is involved in memory-related processes. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Inhibition of COX1/2 alters the host response and reduces ECM scaffold mediated constructive tissue remodeling in a rodent model of skeletal muscle injury.

    Science.gov (United States)

    Dearth, Christopher L; Slivka, Peter F; Stewart, Scott A; Keane, Timothy J; Tay, Justin K; Londono, Ricardo; Goh, Qingnian; Pizza, Francis X; Badylak, Stephen F

    2016-02-01

    Extracellular matrix (ECM) has been used as a biologic scaffold material to both reinforce the surgical repair of soft tissue and serve as an inductive template to promote a constructive tissue remodeling response. Success of such an approach is dependent on macrophage-mediated degradation and remodeling of the biologic scaffold. Macrophage phenotype during these processes is a predictive factor of the eventual remodeling outcome. ECM scaffolds have been shown to promote an anti-inflammatory or M2-like macrophage phenotype in vitro that includes secretion of downstream products of cycolooxygenases 1 and 2 (COX1/2). The present study investigated the effect of a common COX1/2 inhibitor (Aspirin) on macrophage phenotype and tissue remodeling in a rodent model of ECM scaffold treated skeletal muscle injury. Inhibition of COX1/2 reduced the constructive remodeling response by hindering myogenesis and collagen deposition in the defect area. The inhibited response was correlated with a reduction in M2-like macrophages in the defect area. The effects of Aspirin on macrophage phenotype were corroborated using an established in vitro macrophage model which showed a reduction in both ECM induced prostaglandin secretion and expression of a marker of M2-like macrophages (CD206). These results raise questions regarding the common peri-surgical administration of COX1/2 inhibitors when biologic scaffold materials are used to facilitate muscle repair/regeneration. COX1/2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely administered post-surgically for analgesic purposes. While COX1/2 inhibitors are important in pain management, they have also been shown to delay or diminish the healing process, which calls to question their clinical use for treating musculotendinous injuries. The present study aimed to investigate the influence of a common NSAID, Aspirin, on the constructive remodeling response mediated by an ECM scaffold (UBM) in a rat skeletal

  15. Effects of parasitism on host reproductive investment in a rodent-flea system: host litter size matters.

    Science.gov (United States)

    Warburton, Elizabeth M; Khokhlova, Irina S; Dlugosz, Elizabeth M; Der Mescht, Luther Van; Krasnov, Boris R

    2017-02-01

    Parents may alter offspring phenotype depending on the type of environment they encounter. Parasitism is a common stressor; therefore, maternal reproductive investment could change in response to parasitic infection. However, few experiments have investigated the relationship between parasitism and maternal investment, whereas earlier field studies provided contradictory evidence. We investigated number, sex ratio, and growth of offspring in two rodent species, solitary altricial Meriones crassus and social precocial Acomys cahirinus, exposed to parasitism by fleas Xenopsylla ramesis and Parapulex chephrenis. No effect of treatment on litter size or sex ratio of a litter was found in either rodent species. Flea parasitism was found to affect pre-weaning body mass gain in M. crassus, but not in A. cahirinus pups. Furthermore, it appeared that female M. crassus invested resources into their offspring differently in dependence of litter size. In small litters (1-3 offspring), pups from infested females gained more body mass before weaning than pups from uninfested mothers. However, this trend was reversed in females with large litters indicating that parasitized females have a finite amount of resources with which to provision their young. Thus, M. crassus mothers parasitized by fleas seemed to receive some sort of external cues (e.g., stress caused by infestation) that prompted them to alter offspring provisioning, depending on species-specific possibilities and constraints. Therefore, parasites could be a mediator of environmentally induced maternal effects and offspring provisioning may have adaptive value against parasitism.

  16. Beneficial effects of chronic oxytocin administration and social co-housing in a rodent model of post-traumatic stress disorder.

    Science.gov (United States)

    Janezic, Eric M; Uppalapati, Swetha; Nagl, Stephanie; Contreras, Marco; French, Edward D; Fellous, Jean-Marc

    2016-12-01

    Post-traumatic stress disorder (PTSD) is in part due to a deficit in memory consolidation and extinction. Oxytocin (OXT) has anxiolytic effects and promotes prosocial behaviors in both rodents and humans, and evidence suggests that it plays a role in memory consolidation. We studied the effects of administered OXT and social co-housing in a rodent model of PTSD. Acute OXT yielded a short-term increase in the recall of the traumatic memory if administered immediately after trauma. Low doses of OXT delivered chronically had a cumulating anxiolytic effect that became apparent after 4 days and persisted. Repeated injections of OXT after short re-exposures to the trauma apparatus yielded a long-term reduction in anxiety. Co-housing with naive nonshocked animals decreased the memory of the traumatic context compared with single-housed animals. In the long term, these animals showed less thigmotaxis and increased interest in novel objects, and a low OXT plasma level. Co-housed PTSD animals showed an increase in risk-taking behavior. These results suggest beneficial effects of OXT if administered chronically through increases in memory consolidation after re-exposure to a safe trauma context. We also show differences between the benefits of social co-housing with naive rats and co-housing with other shocked animals on trauma-induced long-term anxiety.

  17. SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes

    DEFF Research Database (Denmark)

    Qi, Weier; Li, Qian; Liew, Chong Wee

    2017-01-01

    . However, the role of SHP-1 in intimal hyperplasia and restenosis has not been clarified in insulin resistance and diabetes. METHODS: We used a femoral artery wire injury mouse model, rodent models with insulin resistance and diabetes, and patients with type 2 diabetes. Further, we modulated SHP-1...... expression using a transgenic mouse that overexpresses SHP-1 in VSMCs (Shp-1-Tg). SHP-1 agonists were also employed to study the molecular mechanisms underlying the regulation of SHP-1 by oxidised lipids. RESULTS: Mice fed a high-fat diet (HFD) exhibited increased femoral artery intimal hyperplasia...... and decreased arterial SHP-1 expression compared with mice fed a regular diet. Arterial SHP-1 expression was also decreased in Zucker fatty rats, Zucker diabetic fatty rats and in patients with type 2 diabetes. In primary cultured VSMCs, oxidised LDL suppressed SHP-1 expression by activating Mek-1 (also known...

  18. Mapping CB1 cannabinoid receptors with [3H]OMAR in the Flinders rodent model of depression

    DEFF Research Database (Denmark)

    Nahimi, A.; Gjedde, A.; Wong, D. F.

    2012-01-01

    not significantly different. Conclusions: Although changes in CB1 receptor expression have been demonstrated in human suicide victims with depression and in animal models of depression, the present maps of [3H]OMAR binding revealed no difference between FSL and FRL rats. We used a single concentration of [3H......Background: The endocannabinoid system regulates cognitive and emotional processes and pathology of this system is implicated in psychiatric disorders, including depression and schizophrenia. The precise role of the endocannabinoid system in psychiatric disorders remains unclear, but changes...... in expression of CB1 receptors and subsequent altered modulation of monoamines is suggested in depression (Esteban & Garcia-Sevilla, 2011). CB1 receptor agonists, such as WIN55,212-2 and CP55,940 regulate synthesis and release of monoamines and are suggested as a novel therapy in the treatment of depression...

  19. Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

    Science.gov (United States)

    Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor; Lemire, Amanda M; Lehnen, Charles; Riddle, Megan J; Singh, Karnail; Panoskaltsis-Mortari, Angela; Vanhove, Bernard; Tolar, Jakub; Kean, Leslie S; Blazar, Bruce R

    2016-12-01

    Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical. We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents. Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known. Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.

  20. Dysregulated neuronal activity patterns implicate corticostriatal circuit dysfunction in multiple rodent models of Huntington’s disease

    Directory of Open Access Journals (Sweden)

    Benjamin R. Miller

    2011-05-01

    Full Text Available Huntington’s disease (HD is an autosomal dominant neurodegenerative disorder that targets the corticostriatal system and results in progressive deterioration of cognitive, emotional, and motor skills. Although cortical and striatal neurons are widely studied in animal models of HD, there is little information on neuronal function during expression of the HD behavioral phenotype. To address this knowledge gap, we used chronically implanted micro-wire bundles to record extracellular spikes and local field potentials (LFPs in truncated (R6/1 and R6/2 and full-length (knock-in, KI mouse models as well as in tgHD rats behaving in an open-field arena. Spike activity was recorded in the striatum of all models and in prefrontal cortex (PFC of R6/2 and KI mice, and in primary motor cortex (M1 of R6/2 mice. We also recorded LFP activity in R6/2 striatum. All HD models exhibited altered neuronal activity relative to wild-type (WT controls. Although there was no consistent effect on firing rate across models and brain areas, burst firing was reduced in striatum, PFC, and M1 of R6/2 mice, and in striatum of KI mice. Consistent with a decline in bursting, the interspike-interval coefficient of variation was reduced in all regions of all models, except PFC of KI mice and striatum of tgHD rats. Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2's. Preliminary analysis of striatal LFPs revealed aberrant behavior-related oscillations in the delta to theta range and in gamma activity. Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype. Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD

  1. Optimizing a Rodent Model of Parkinson's Disease for Exploring the Effects and Mechanisms of Deep Brain Stimulation

    Directory of Open Access Journals (Sweden)

    Karl Nowak

    2011-01-01

    instrumented rats carrying a backpack stimulator and implanted platinum/iridium electrodes. This model is suitable for (1 elucidating the electrochemical processes at the electrode/tissue interface, (2 analyzing the molecular, cellular and behavioral stimulation effects, (3 testing new target regions for DBS, (4 screening for potential neuroprotective DBS effects, and (5 improving the efficacy and safety of the method. An outlook is given on further developments of experimental DBS, including the use of transgenic animals and the testing of closed-loop systems for the direct on-demand application of electric stimulation.

  2. Uus Multiphonic Rodent

    Index Scriptorium Estoniae

    2009-01-01

    Tartus tegutsenud eksperimentaal-rock-duo Opium Flirt Eestisse jäänud liige Erki Hõbe (paarimees Ervin Trofimov tegutseb Ungaris) annab välja oma teise sooloalbumi nime all Multiphonic Rodent, heliplaadi "Astral Dance" esitluskontsert toimub 5. veebruaril Tallinnas baaris Juuksur

  3. Hantavirus Immunology of Rodent Reservoirs: Current Status and Future Directions

    Directory of Open Access Journals (Sweden)

    Tony Schountz

    2014-03-01

    Full Text Available Hantaviruses are hosted by rodents, insectivores and bats. Several rodent-borne hantaviruses cause two diseases that share many features in humans, hemorrhagic fever with renal syndrome in Eurasia or hantavirus cardiopulmonary syndrome in the Americas. It is thought that the immune response plays a significant contributory role in these diseases. However, in reservoir hosts that have been closely examined, little or no pathology occurs and infection is persistent despite evidence of adaptive immune responses. Because most hantavirus reservoirs are not model organisms, it is difficult to conduct meaningful experiments that might shed light on how the viruses evade sterilizing immune responses and why immunopathology does not occur. Despite these limitations, recent advances in instrumentation and bioinformatics will have a dramatic impact on understanding reservoir host responses to hantaviruses by employing a systems biology approach to identify important pathways that mediate virus/reservoir relationships.

  4. Vision in laboratory rodents-Tools to measure it and implications for behavioral research.

    Science.gov (United States)

    Leinonen, Henri; Tanila, Heikki

    2017-07-29

    Mice and rats are nocturnal mammals and their vision is specialized for detection of motion and contrast in dim light conditions. These species possess a large proportion of UV-sensitive cones in their retinas and the majority of their optic nerve axons target superior colliculus rather than visual cortex. Therefore, it was a widely held belief that laboratory rodents hardly utilize vision during day-time behavior. This dogma is being questioned as accumulating evidence suggests that laboratory rodents are able to perform complex visual functions, such as perceiving subjective contours, and that declined vision may affect their performance in many behavioral tasks. For instance, genetic engineering may have unexpected consequences on vision as mouse models of Alzheimer's and Huntington's diseases have declined visual function. Rodent vision can be tested in numerous ways using operant training or reflex-based behavioral tasks, or alternatively using electrophysiological recordings. In this article, we will first provide a summary of visual system and explain its characteristics unique to rodents. Then, we present well-established techniques to test rodent vision, with an emphasis on pattern vision: visual water test, optomotor reflex test, pattern electroretinography and pattern visual evoked potentials. Finally, we highlight the importance of visual phenotyping in rodents. As the number of genetically engineered rodent models and volume of behavioral testing increase simultaneously, the possibility of visual dysfunctions needs to be addressed. Neglect in this matter potentially leads to crude biases in the field of neuroscience and beyond. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Image-guided intraocular injection using multimodality optical coherence tomography and fluorescence confocal scanning laser ophthalmoscopy in rodent ophthalmological models

    Science.gov (United States)

    Terrones, Benjamin D.; Benavides, Oscar R.; Leeburg, Kelsey C.; Mehanathan, Sankarathi B.; Levine, Edward M.; Tao, Yuankai K.

    2018-02-01

    Intraocular injections are routinely performed for delivery of anti-VEGF and anti-inflammatory therapies in humans. While these injections are also performed in mice to develop novel models of ophthalmic diseases and screen novel therapeutics, the injection location and volume are not well-controlled and reproducible. We overcome limitations of conventional injections methods by developing a multimodality, long working distance, non-contact optical coherence tomography (OCT) and fluorescence confocal scanning laser ophthalmoscopy (cSLO) system for retinal imaging before and after injections. Our OCT+cSLO system combines a custom-built spectraldomain OCT engine (875+/-85 nm) with 125 kHz line-rate with a modified commercial cSLO with a maximum frame-rate of 30 fps (512 x 512 pix.). The system was designed for an overlapping OCT+cSLO field-of-view of 1.1 mm with a 7.76 mm working distance to the pupil. cSLO excitation light sources and filters were optimized for simultaneous GFP and tdTomato imaging. Lateral resolution was 3.02 µm for OCT and 2.74 μm for cSLO. Intravitreal injections of 5%, 10%, and 20% intralipid with Alex Fluor 488 were manually injected intraocularly in C57BL/6 mice. Post-injection imaging showed structural changes associated with retinal puncture, including the injection track, a retinal elevation, and detachment of the posterior hyaloid. OCT enables quantitative analysis of injection location and volumes whereas complementary cSLO improves specificity for identifying fluorescently labeled injected compounds and transgenic cells. The long working distance of our non-contact OCT+cSLO system is uniquely-suited for concurrent imaging with intraocular injections and may be applied for imaging of ophthalmic surgical dynamics and real-time image-guided injections.

  6. Visual Landmarks Facilitate Rodent Spatial Navigation in Virtual Reality Environments

    Science.gov (United States)

    Youngstrom, Isaac A.; Strowbridge, Ben W.

    2012-01-01

    Because many different sensory modalities contribute to spatial learning in rodents, it has been difficult to determine whether spatial navigation can be guided solely by visual cues. Rodents moving within physical environments with visual cues engage a variety of nonvisual sensory systems that cannot be easily inhibited without lesioning brain…

  7. Weight and Glucose Reduction Observed with a Combination of Nutritional Agents in Rodent Models Does Not Translate to Humans in a Randomized Clinical Trial with Healthy Volunteers and Subjects with Type 2 Diabetes.

    Directory of Open Access Journals (Sweden)

    Rebecca J Hodge

    Full Text Available Nutritional agents have modest efficacy in reducing weight and blood glucose in animal models and humans, but combinations are less well characterized. GSK2890457 (GSK457 is a combination of 4 nutritional agents, discovered by the systematic assessment of 16 potential components using the diet-induced obese mouse model, which was subsequently evaluated in a human study.In the diet-induced obese mouse model, GSK457 (15% w/w in chow given with a long-acting glucagon-like peptide -1 receptor agonist, exendin-4 AlbudAb, produced weight loss of 30.8% after 28 days of treatment. In db/db mice, a model of diabetes, GSK457 (10% w/w combined with the exendin-4 AlbudAb reduced glucose by 217 mg/dL and HbA1c by 1.2% after 14 days.GSK457 was evaluated in a 6 week randomized, placebo-controlled study that enrolled healthy subjects and subjects with type 2 diabetes to investigate changes in weight and glucose. In healthy subjects, GSK457 well tolerated when titrated up to 40 g/day, and it reduced systemic exposure of metformin by ~ 30%. In subjects with diabetes taking liraglutide 1.8 mg/day, GSK457 did not reduce weight, but it slightly decreased mean glucose by 0.356 mmol/L (95% CI: -1.409, 0.698 and HbAlc by 0.065% (95% CI: -0.495, 0.365, compared to placebo. In subjects with diabetes taking metformin, weight increased in the GSK457-treated group [adjusted mean % increase from baseline: 1.26% (95% CI: -0.24, 2.75], and mean glucose and HbA1c were decreased slightly compared to placebo [adjusted mean glucose change from baseline: -1.22 mmol/L (95% CI: -2.45, 0.01; adjusted mean HbA1c change from baseline: -0.219% (95% CI: -0.910, 0.472].Our data demonstrate remarkable effects of GSK457 in rodent models of obesity and diabetes, but a marked lack of translation to humans. Caution should be exercised with nutritional agents when predicting human efficacy from rodent models of obesity and diabetes.ClinicalTrials.gov NCT01725126.

  8. Anti-inflammatory effects and mechanisms of vagal nerve stimulation combined with electroacupuncture in a rodent model of TNBS-induced colitis.

    Science.gov (United States)

    Jin, Haifeng; Guo, Jie; Liu, Jiemin; Lyu, Bin; Foreman, Robert D; Yin, Jieyun; Shi, Zhaohong; Chen, Jiande D Z

    2017-09-01

    The purpose of this study was to determine the effects and mechanisms of vagal nerve stimulation (VNS) and additive effects of electroacupuncture (EA) on colonic inflammation in a rodent model of IBD. Chronic inflammation in rats was induced by intrarectal TNBS (2,4,6-trinitrobenzenesulfonic acid). The rats were then treated with sham ES (electrical stimulation), VNS, or VNS + EA for 3 wk. Inflammatory responses were assessed by disease activity index (DAI), macroscopic scores and histological scores of colonic tissues, plasma levels of TNFα, IL-1β, and IL-6, and myeloperoxidase (MPO) activity of colonic tissues. The autonomic function was assessed by the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. It was found that 1 ) the area under curve (AUC) of DAI was substantially decreased with VNS + EA and VNS, with VNS + EA being more effective than VNS ( P < 0.001); 2 ) the macroscopic score was 6.43 ± 0.61 in the sham ES group and reduced to 1.86 ± 0.26 with VNS ( P < 0.001) and 1.29 ± 0.18 with VNS + EA ( P < 0.001); 3 ) the histological score was 4.05 ± 0.58 in the sham ES group and reduced to 1.93 ± 0.37 with VNS ( P < 0.001) and 1.36 ± 0.20 with VNS + EA ( P < 0.001); 4 ) the plasma levels of TNFα, IL-1β, IL-6, and MPO were all significantly decreased with VNS and VNS + EA compared with the sham ES group; and 5 ) autonomically, both VNS + EA and VNS substantially increased vagal activity and decreased sympathetic activity compared with sham EA ( P < 0.001, P < 0.001, respectively). In conclusion, chronic VNS improves inflammation in TNBS-treated rats by inhibiting proinflammatory cytokines via the autonomic mechanism. Addition of noninvasive EA to VNS may enhance the anti-inflammatory effect of VNS. NEW & NOTEWORTHY This is the first study to address and compare the effects of vagal nerve stimulation (VNS), electrical acupuncture (EA) and VNS + EA on TNBS (2,4,6-trinitrobenzenesulfonic acid

  9. Lung function and airway inflammation in rats following exposure to combustion products of carbon-graphite/epoxy composite material: comparison to a rodent model of acute lung injury.

    Science.gov (United States)

    Whitehead, Gregory S; Grasman, Keith A; Kimmel, Edgar C

    2003-02-01

    Pulmonary function and inflammation in the lungs of rodents exposed by inhalation to carbon/graphite/epoxy advanced composite material (ACM) combustion products were compared to that of a rodent model of acute lung injury (ALI) produced by pneumotoxic paraquat dichloride. This investigation was undertaken to determine if short-term exposure to ACM smoke induces ALI; and to determine if smoke-related responses were similar to the pathogenic mechanisms of a model of lung vascular injury. We examined the time-course for mechanical lung function, infiltration of inflammatory cells into the lung, and the expression of three inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2) and interferon-gamma (IFN-gamma). Male Fischer-344 rats were either exposed to 26.8-29.8 g/m(3) nominal concentrations of smoke or were given i.p. injections of paraquat dichloride. Measurements were determined at 1, 2, 3, and 7 days post exposure. In the smoke-challenged rats, there were no changes in lung function indicative of ALI throughout the 7-day observation period, despite the acute lethality of the smoke atmosphere. However, the animals showed signs of pulmonary inflammation. The expression of TNF-alpha was significantly increased in the lavage fluid 1 day following exposure, which preceded the maximum leukocyte infiltration. MIP-2 levels were significantly increased in lavage fluid at days 2, 3, and 7. This followed the leukocyte infiltration. IFN-gamma was significantly increased in the lung tissue at day 7, which occurred during the resolution of the inflammatory response. The paraquat, which was also lethal to a small percentage of the animals, caused several physiologic changes characteristic of ALI, including significant decreases in lung compliance, lung volumes/capacities, distribution of ventilation, and gas exchange capacity. The expression of TNF-alpha and MIP-2 increased significantly in the lung tissue as well as in the

  10. Pig BMSCs Transfected with Human TFPI Combat Species Incompatibility and Regulate the Human TF Pathway in Vitro and in a Rodent Model

    Directory of Open Access Journals (Sweden)

    Hongchen Ji

    2015-05-01

    Full Text Available Background: The activation of tissue factor (TF is one of the major reasons for coagulation dysregulation after pig-to-primate xenotransplantation. Tissue factor pathway inhibitor (TFPI is the most important inhibitor of TF. Studies have demonstrated species incompatibility between pig TFPI and human TF. Methods: A pig-to-macaque heterotopic auxiliary liver transplantation model was established to determine the origin of activated TF. Chimeric proteins of human and pig TFPI were constructed to assess the role of Kunitz domains in species incompatibility. Immortalised pig bone marrow mesenchymal stem cells transfected with human TFPI were tested for their ability to inhibit clotting in vitro. Results: TF from recipient was activated early after liver xenotransplantation. Pig TFPI Kunitz domain 2 bound human FXa, but Kunitz domain 1 did not effectively inhibit human TF/FVIIa. Immortalised pig bone marrow mesenchymal cells (BMSCs transfected with human TFPI showed a prolonged recalcification time in vitro and in a rodent model. Conclusion: Recipient TF is relevant to dysregulated coagulation after xenotransplantation. Kunitz domain 1 plays the most important role in species incompatibility between pig TFPI and human TF, and clotting can be inhibited by human TFPI-transfected pig BMSCs. Our study shows a possible way to resolve the incompatibility of pig TFPI.

  11. Modeller af komplicerede systemer

    DEFF Research Database (Denmark)

    Mortensen, J.

    emphasizes their use in relation to technical systems. All the presented models, with the exception of the types presented in chapter 2, are non-theoretical non-formal conceptual network models. Two new model types are presented: 1) The System-Environment model, which describes the environments interaction...... with conceptual modeling in relation to process control. It´s purpose is to present classify and exemplify the use of a set of qualitative model types. Such model types are useful in the early phase of modeling, where no structured methods are at hand. Although the models are general in character, this thesis......This thesis, "Modeller af komplicerede systemer", represents part of the requirements for the Danish Ph.D.degree. Assisting professor John Nørgaard-Nielsen, M.Sc.E.E.Ph.D. has been principal supervisor and professor Morten Lind, M.Sc.E.E.Ph.D. has been assisting supervisor. The thesis is concerned...

  12. Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents

    International Nuclear Information System (INIS)

    Crowell, Susan Ritger; Amin, Shantu G.; Anderson, Kim A.; Krishnegowda, Gowdahalli; Sharma, Arun K.; Soelberg, Jolen J.; Williams, David E.; Corley, Richard A.

    2011-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude. Supported by Award Number P42 ES016465 from the National Institute of Environmental Health Sciences. -- Highlights: ► We present PBPK models for benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DBC). ► B[a]P model accurately predicts data from multiple sources over a wide dose range. ► DBC model was based on the B[a]P model as less chemical specific data is available. ► DBC model accurately predicted preliminary

  13. The systems integration modeling system

    International Nuclear Information System (INIS)

    Danker, W.J.; Williams, J.R.

    1990-01-01

    This paper discusses the systems integration modeling system (SIMS), an analysis tool for the detailed evaluation of the structure and related performance of the Federal Waste Management System (FWMS) and its interface with waste generators. It's use for evaluations in support of system-level decisions as to FWMS configurations, the allocation, sizing, balancing and integration of functions among elements, and the establishment of system-preferred waste selection and sequencing methods and other operating strategies is presented. SIMS includes major analysis submodels which quantify the detailed characteristics of individual waste items, loaded casks and waste packages, simulate the detailed logistics of handling and processing discrete waste items and packages, and perform detailed cost evaluations

  14. Dual action of high estradiol doses on MNU-induced prostate neoplasms in a rodent model with high serum testosterone: Protective effect and emergence of unstable epithelial microenvironment.

    Science.gov (United States)

    Gonçalves, Bianca F; de Campos, Silvana G P; Góes, Rejane M; Scarano, Wellerson R; Taboga, Sebastião R; Vilamaior, Patricia S L

    2017-06-01

    Estrogens are critical players in prostate growth and disease. Estrogen therapy has been the standard treatment for advanced prostate cancer for several decades; however, it has currently been replaced by alternative anti-androgenic therapies. Additionally, studies of its action on prostate biology, resulting from an association between carcinogens and estrogen, at different stages of life are scarce or inconclusive about its protective and beneficial role on induced-carcinogenesis. Thus, the aim of this study was to determine whether estradiol exerts a protective and/or stimulatory role on N-methyl-N-nitrosurea-induced prostate neoplasms. We adopted a rodent model that has been used to study induced-prostate carcinogenesis: the Mongolian gerbil. We investigated the occurrence of neoplasms, karyometric patterns, androgen and estrogen receptors, basal cells, and global methylation status in ventral and dorsolateral prostate tissues. Histopathological analysis showed that estrogen was able to slow tumor growth in both lobes after prolonged treatment. However, a true neoplastic regression was observed only in the dorsolateral prostate. In addition to the protective effects against neoplastic progression, estrogen treatment resulted in an epithelium that exhibited features distinctive from a normal prostate, including increased androgen-insensitive basal cells, high androgens and estrogen receptor positivity, and changes in DNA methylation patterns. Estrogen was able to slow tumor growth, but the epithelium exhibited features distinct from a normal prostatic epithelium, and this unstable microenvironment could trigger lesion recurrence over time. © 2017 Wiley Periodicals, Inc.

  15. Effects of L-arginine on anatomical and electrophysiological deterioration of the eye in a rodent model of nonarteritic ischemic optic neuropathy.

    Science.gov (United States)

    Chuman, Hideki; Maekubo, Tomoyuki; Osako, Takako; Ishiai, Michitaka; Kawano, Naoko; Nao-I, Nobuhisa

    2013-07-01

    The aims of this study were to clarify the effectiveness of L-arginine (1) for reducing the severity of anatomical changes in the eye and improving visual function in the acute stage of a rodent model of nonarteritic ischemic optic neuropathy (rNAION) and (2) in preventing those changes in anatomy and visual function. For the first aim, L-arginine was intravenously injected into rats 3 h after rNAION induction; for the second aim, rNAION was induced after the oral administration of L-arginine for 7 days. The inner retinal thickness was determined over time by optical coherence tomography, and the amplitude of the scotopic threshold response (STR) and the number of surviving retinal ganglion cells (RGCs) were measured. These data were compared with the baseline data from the control group. Both intravenous infusion of L-arginine after rNAION induction and oral pretreatment with L-arginine significantly decreased optic disc edema in the acute stage and thinning of the inner retina, reduced the decrease in STR amplitude, and reduced the decrease in the number of RGCs during rNAION. Based on these results, we conclude that L-arginine treatment is effective for reducing anatomical changes in the eye and improving visual function in the acute stage of rNAION and that pretreatment with L-arginine is an effective therapy to reduce the severity of the condition during recurrence in the other eye.

  16. Traumatic stress causes distinctive effects on fear circuit catecholamines and the fear extinction profile in a rodent model of posttraumatic stress disorder.

    Science.gov (United States)

    Lin, Chen-Cheng; Tung, Che-Se; Lin, Pin-Hsuan; Huang, Chuen-Lin; Liu, Yia-Ping

    2016-09-01

    Central catecholamines regulate fear memory across the medial prefrontal cortex (mPFC), amygdala (AMYG), and hippocampus (HPC). However, inadequate evidence exists to address the relationships among these fear circuit areas in terms of the fear symptoms of posttraumatic stress disorder (PTSD). By examining the behavioral profile in a Pavlovian fear conditioning paradigm together with tissue/efflux levels of dopamine (DA) and norepinephrine (NE) and their reuptake abilities across the fear circuit areas in rats that experienced single prolonged stress (SPS, a rodent model of PTSD), we demonstrated that SPS-impaired extinction retrieval was concomitant with the changes of central DA/NE in a dissociable manner. For tissue levels, diminished DA and increased NE were both observed in the mPFC and AMYG. DA efflux and synaptosomal DA transporter were consistently reduced in the AMYG/vHPC, whereas SPS reduced NE efflux in the infralimbic cortex and synaptosomal NE transporter in the mPFC. Furthermore, a lower expression of synaptosomal VMAT2 was observed in the mPFC, AMYG, and vHPC after SPS. Finally, negative correlations were observed between retrieval freezing and DA in the mPFC/AMYG; nevertheless, the phenomena became invalid after SPS. Our results suggest that central catecholamines are crucially involved in the retrieval of fear extinction in which DA and NE play distinctive roles across the fear circuit areas. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  17. Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia.

    Science.gov (United States)

    Ewing, Samuel G; Grace, Anthony A

    2013-02-01

    Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease.

    Science.gov (United States)

    Edrey, Yael H; Medina, David X; Gaczynska, Maria; Osmulski, Pawel A; Oddo, Salvatore; Caccamo, Antonella; Buffenstein, Rochelle

    2013-10-01

    Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Robot-Applied Resistance Augments the Effects of Body Weight-Supported Treadmill Training on Stepping and Synaptic Plasticity in a Rodent Model of Spinal Cord Injury.

    Science.gov (United States)

    Hinahon, Erika; Estrada, Christina; Tong, Lin; Won, Deborah S; de Leon, Ray D

    2017-08-01

    The application of resistive forces has been used during body weight-supported treadmill training (BWSTT) to improve walking function after spinal cord injury (SCI). Whether this form of training actually augments the effects of BWSTT is not yet known. To determine if robotic-applied resistance augments the effects of BWSTT using a controlled experimental design in a rodent model of SCI. Spinally contused rats were treadmill trained using robotic resistance against horizontal (n = 9) or vertical (n = 8) hind limb movements. Hind limb stepping was tested before and after 6 weeks of training. Two control groups, one receiving standard training (ie, without resistance; n = 9) and one untrained (n = 8), were also tested. At the terminal experiment, the spinal cords were prepared for immunohistochemical analysis of synaptophysin. Six weeks of training with horizontal resistance increased step length, whereas training with vertical resistance enhanced step height and movement velocity. None of these changes occurred in the group that received standard (ie, no resistance) training or in the untrained group. Only standard training increased the number of step cycles and shortened cycle period toward normal values. Synaptophysin expression in the ventral horn was highest in rats trained with horizontal resistance and in untrained rats and was positively correlated with step length. Adding robotic-applied resistance to BWSTT produced gains in locomotor function over BWSTT alone. The impact of resistive forces on spinal connections may depend on the nature of the resistive forces and the synaptic milieu that is present after SCI.

  20. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Zhoumeng [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079 (United States); Wang, Ran [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Institute of Food Safety, Jiangsu Academy of Agricultural Sciences, Nanjing 210014 (China); Ross, Matthew K. [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Filipov, Nikolay M., E-mail: filipov@uga.edu [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States)

    2013-11-15

    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data

  1. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    International Nuclear Information System (INIS)

    Lin, Zhoumeng; Fisher, Jeffrey W.; Wang, Ran; Ross, Matthew K.; Filipov, Nikolay M.

    2013-01-01

    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data.

  2. Is There a Canonical Cortical Circuit for the Cholinergic System? Anatomical Differences Across Common Model Systems.

    Science.gov (United States)

    Coppola, Jennifer J; Disney, Anita A

    2018-01-01

    Acetylcholine (ACh) is believed to act as a neuromodulator in cortical circuits that support cognition, specifically in processes including learning, memory consolidation, vigilance, arousal and attention. The cholinergic modulation of cortical processes is studied in many model systems including rodents, cats and primates. Further, these studies are performed in cortical areas ranging from the primary visual cortex to the prefrontal cortex and using diverse methodologies. The results of these studies have been combined into singular models of function-a practice based on an implicit assumption that the various model systems are equivalent and interchangeable. However, comparative anatomy both within and across species reveals important differences in the structure of the cholinergic system. Here, we will review anatomical data including innervation patterns, receptor expression, synthesis and release compared across species and cortical area with a focus on rodents and primates. We argue that these data suggest no canonical cortical model system exists for the cholinergic system. Further, we will argue that as a result, care must be taken both in combining data from studies across cortical areas and species, and in choosing the best model systems to improve our understanding and support of human health.

  3. Is There a Canonical Cortical Circuit for the Cholinergic System? Anatomical Differences Across Common Model Systems

    Directory of Open Access Journals (Sweden)

    Jennifer J. Coppola

    2018-01-01

    Full Text Available Acetylcholine (ACh is believed to act as a neuromodulator in cortical circuits that support cognition, specifically in processes including learning, memory consolidation, vigilance, arousal and attention. The cholinergic modulation of cortical processes is studied in many model systems including rodents, cats and primates. Further, these studies are performed in cortical areas ranging from the primary visual cortex to the prefrontal cortex and using diverse methodologies. The results of these studies have been combined into singular models of function—a practice based on an implicit assumption that the various model systems are equivalent and interchangeable. However, comparative anatomy both within and across species reveals important differences in the structure of the cholinergic system. Here, we will review anatomical data including innervation patterns, receptor expression, synthesis and release compared across species and cortical area with a focus on rodents and primates. We argue that these data suggest no canonical cortical model system exists for the cholinergic system. Further, we will argue that as a result, care must be taken both in combining data from studies across cortical areas and species, and in choosing the best model systems to improve our understanding and support of human health.

  4. The hippocampus, medial prefrontal cortex, and selective memory retrieval: evidence from a rodent model of the retrieval-induced forgetting effect.

    Science.gov (United States)

    Wu, Jade Q; Peters, Greg J; Rittner, Pedro; Cleland, Thomas A; Smith, David M

    2014-09-01

    Inhibition is an important component of many cognitive functions, including memory. For example, the retrieval-induced forgetting (RIF) effect occurs when extra practice with some items from a study list inhibits the retrieval of the nonpracticed items relative to a baseline condition that does not involve extra practice. Although counterintuitive, the RIF phenomenon may be important for resolving interference by inhibiting potentially competing retrieval targets. Neuroimaging studies suggest that the hippocampus and prefrontal cortex are involved in the RIF effect, but controlled lesion studies have not yet been performed. We developed a rodent model of the RIF training procedure and trained control rats and rats with temporary inactivation of the hippocampus or medial prefrontal cortex (mPFC). Rats were trained on a list of odor cues, presented in cups of digging medium with a buried reward, followed by additional practice trials with a subset of the cues. We then tested the rats' memories for the cues and their association with reward by presenting them with unbaited cups containing the test odorants and measuring how long they persisted in digging. Control rats exhibited a robust RIF effect in which memory for the nonpracticed odors was significantly inhibited. Thus, extra practice with some odor cues inhibited memory for the others, relative to a baseline condition that involved an identical amount of training. Inactivation of either the hippocampus or the mPFC blocked the RIF effect. We also constructed a computational model of a representational learning circuit to simulate the RIF effect. We show in this model that "sideband suppression" of similar memory representations can reproduce the RIF effect and that alteration of the suppression parameters and learning rate can reproduce the lesion effects seen in our rats. Our results suggest that the RIF effect is widespread and that inhibitory processes are an important feature of memory function. © 2014 Wiley

  5. A focus on reward in anorexia nervosa through the lens of the activity-based anorexia rodent model.

    Science.gov (United States)

    Foldi, C J; Milton, L K; Oldfield, B J

    2017-10-01

    Patients suffering anorexia nervosa (AN) become anhedonic, unable or unwilling to derive normal pleasures and tend to avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia model recapitulates many of the pathophysiological and behavioural hallmarks of the human condition, including a reduction in food intake, excessive exercise, dramatic weight loss, loss of reproductive cycles, hypothermia and anhedonia, and therefore it allows investigation into the underlying neurobiology of anorexia nervosa. The use of this model has directed attention to disruptions in central reward neurocircuitry, which may contribute to disease susceptibility. The purpose of this review is to demonstrate the utility of this unique model to provide insight into the mechanisms of reward relevant to feeding and weight loss, which may ultimately help to unravel the neurobiology of anorexia nervosa and, in a broader sense, the foundation of reward-based feeding. © 2017 British Society for Neuroendocrinology.

  6. Effects of glyphosate exposure on sperm concentration in rodents: A systematic review and meta-analysis.

    Science.gov (United States)

    Cai, Wenyan; Ji, Ying; Song, Xianping; Guo, Haoran; Han, Lei; Zhang, Feng; Liu, Xin; Zhang, Hengdong; Zhu, Baoli; Xu, Ming

    2017-10-01

    Correlation between exposure to glyphosate and sperm concentrations is important in reproductive toxicity risk assessment for male reproductive functions. Many studies have focused on reproductive toxicity on glyphosate, however, results are still controversial. We conducted a systematic review of epidemiological studies on the association between glyphosate exposure and sperm concentrations of rodents. The aim of this study is to explore the potential adverse effects of glyphosate on reproductive function of male rodents. Systematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Embase, WANFANG and CNKI databases with different combinations of glyphosate exposure and sperm concentration. 8 studies were eventually identified and random-effect model was conducted. Heterogeneity among study results was calculated via chi-square tests. Ten independent experimental datasets from these eight studies were acquired to synthesize the random-effect model. A decrease in sperm concentrations was found with mean difference of sperm concentrations(MDsperm)=-2.774×10 6 /sperm/g/testis(95%CI=-0.969 to -4.579) in random-effect model after glyphosate exposure. There was also a significant decrease after fitting the random-effect model: MDsperm=-1.632×10 6 /sperm/g/testis (95%CI=-0.662 to -2.601). The results of meta-analysis support the hypothesis that glyphosate exposure decreased sperm concentration in rodents. Therefore, we conclude that glyphosate is toxic to male rodent's reproductive system. Copyright © 2017. Published by Elsevier B.V.

  7. Positive end-expiratory pressure improves survival in a rodent model of cardiopulmonary resuscitation using high-dose epinephrine.

    LENUS (Irish Health Repository)

    McCaul, Conán

    2009-10-01

    Multiple interventions have been tested in models of cardiopulmonary resuscitation (CPR) to optimize drug use, chest compressions, and ventilation. None has studied the effects of positive end-expiratory pressure (PEEP) on outcome. We hypothesized that because PEEP can reverse pulmonary atelectasis, lower pulmonary vascular resistance, and potentially improve cardiac output, its use during CPR would increase survival.

  8. Protective Effects of Sodium (±-5-Bromo-2-(α-Hydroxypentyl Benzoate in a Rodent Model of Global Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Yuan Gao

    2017-09-01

    Full Text Available The aim of the current study was to explore the protective effects of sodium (±-5-bromo-2-(α-hydroxypentyl benzoate (brand name: brozopine, BZP in a rat model of global cerebral ischemia. The rat model was established using a modified Winocur’s method; close postoperative observation was conducted at all times. Neurological function was detected through prehensile traction and beam-walking test. BZP reduced mortality and prolonged the survival time of rats with global cerebral ischemia, within 24 h. There was a decreased survival rate (60% in the Model group, while the survival rate of the BZP (3 and 12 mg/kg remarkably increased the survival rate (to 80 and 90%, respectively, in a dose-dependent manner. Compared with the Model group (survival time: 18.50 h, the administration of BZP (0.75, 3, and 12 mg/kg prolonged the survival time (to 20.38, 21.85, and 23.90 h, respectively, particularly in BZP 12 mg/kg group (P < 0.05. Additionally, the BZP (12 mg/kg group exhibited an improvement in their motor function (P < 0.05. The BZP groups (0.75, 3, and 12 mg/kg displayed significantly reduced necrosis and the percentage of apoptotic cells (P < 0.05 and P < 0.01, respectively. Compared with Model group, BZP (0.75, 3, and 12 mg/kg increased the NeuN optical density values (P < 0.01. Rats with global ischemia had a high expression of Cyt-c, caspase-3, and the Bax/Bcl-2 ratio compared with sham group (P < 0.01. BZP (0.75, 3, and 12 mg/kg, however, reduced the expression of Cyt-c, caspase-3, and the Bax/Bcl-2 ratio, in a dose-dependent manner (P < 0.01. There was low expression of p-Akt and PI3K in Model group, compared with the sham group (P < 0.01. Meanwhile, BZP (0.75, 3, and 12 mg/kg increased the expression of p-Akt and PI3K in a dose-dependent manner (P < 0.01. We also found the expression of Cyt-c, caspase-3, Bax/Bcl-2 ratio, PI3K, p-Akt, and comprehensive score were directly related. In conclusion, BZP had therapeutic potential and prevented

  9. The bioeconomics of controlling an African rodent pest species

    DEFF Research Database (Denmark)

    Skonhoft, Anders; Leirs, Herwig; Andreassen, Harry P

    2006-01-01

    The paper treats the economy of controlling an African pest rodent, the multimammate rat, causing major damage in maize production. An ecological population model is presented and used as a basis for the economic analyses carried out at the village level using data from Tanzania. This model...... incorporates both density-dependent and density-independent (stochastic) factors. Rodents are controlled by applying poison, and the costs are made up of the cost of poison plus the damage to maize production. We analyse how the present-value costs of maize production are affected by various rodent control...

  10. Novel Therapeutic Approaches for the Treatment of Depression and Cognitive Deficits in a Rodent Model of Gulf War Veterans Illness

    Science.gov (United States)

    2015-10-01

    forced swim test. No two tests were carried out on the same day. Depression is a complex psychological phenomenon and as such is difficult to analyze...grant has also given both of us professional development opportunities. Our abstract has been accepted for presentation at American Epilepsy ...and neurologists at the 2015 American Epilepsy Society annual meeting. Our work on model development is currently under-review at “Neurotoxicology

  11. Anti-anxiety activity of hydro alcoholic extract of Scoparia dulcis Linn. assessed using different experimental anxiety models In rodents

    OpenAIRE

    Arasan Elayaraja; S. A. Rahaman; Prem kumar P.; Phani Kumar K.

    2015-01-01

    Scoparia dulcis belonging to the family Scrophulariaceae is an valuable medicinal herb, had showed antiviral, antimalarial, anticancer and antidiabetic activities. The present study was aimed to investigate the anti-anxiety activity of crude ethanolic extract of S.dulcis L by various behavioural models. Preliminary phytochemical investigation revealed the presence of  phenols and flavonoids. The extract at 100mg/kg and 200mg/kg was evaluated for anti anxiety activity by  Open-field test [OFT]...

  12. Modeling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species–pharmacokinetic and therapeutic implications

    OpenAIRE

    Boretti, Felicitas S.; Baek, Jin Hyen; Palmer, Andre F.; Schaer, Dominik J.; Buehler, Paul W.

    2014-01-01

    Background: Haptoglobin (Hp) prevents hemoglobin (Hb) extravasation and attenuates Hb induced tissue oxidation and vasoconstriction. Small animal models such as mouse, rat and guinea pig appear to demonstrate proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from humans in the clearance of Hb:Hp and demonstrate long persistence of circulating Hb:Hp complexes. Objective: The focus of this study is to understand Hb:Hp...

  13. Translation of Novel Serotonin 5-HT7 Agonist Drug Candidates in Rodent Models of Fragile X Syndrome

    Science.gov (United States)

    2016-09-01

    HT1A partial agonist for autism . 6th Cisbio HTRF symposium (Brewster, MA), September 14-17, 2015. Acknowledged DOD funding. Teaching Lectures . 10...grant is to synthesize 5-PAT-type 5HT7 receptor agonists and assess their effectiveness to correct FXS phenotypes in Fmr1-KO mice and other mouse models...President of DELSIA (Delivering Science Innovation for Autism ) and Vice President, Innovative Technologies at Autism Speaks, Daniel Smith, who

  14. The Earth System Model

    Science.gov (United States)

    Schoeberl, Mark; Rood, Richard B.; Hildebrand, Peter; Raymond, Carol

    2003-01-01

    The Earth System Model is the natural evolution of current climate models and will be the ultimate embodiment of our geophysical understanding of the planet. These models are constructed from components - atmosphere, ocean, ice, land, chemistry, solid earth, etc. models and merged together through a coupling program which is responsible for the exchange of data from the components. Climate models and future earth system models will have standardized modules, and these standards are now being developed by the ESMF project funded by NASA. The Earth System Model will have a variety of uses beyond climate prediction. The model can be used to build climate data records making it the core of an assimilation system, and it can be used in OSSE experiments to evaluate. The computing and storage requirements for the ESM appear to be daunting. However, the Japanese ES theoretical computing capability is already within 20% of the minimum requirements needed for some 2010 climate model applications. Thus it seems very possible that a focused effort to build an Earth System Model will achieve succcss.

  15. Oligodendrocyte death, neuroinflammation, and the effects of minocycline in a rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION).

    Science.gov (United States)

    Mehrabian, Zara; Guo, Yan; Weinreich, Daniel; Bernstein, Steven L

    2017-01-01

    Optic nerve (ON) damage following nonarteritic anterior ischemic optic neuropathy (NAION) and its models is associated with neurodegenerative inflammation. Minocycline is a tetracycline derivative antibiotic believed to exert a neuroprotective effect by selective alteration and activation of the neuroinflammatory response. We evaluated minocycline's post-induction ability to modify early and late post-ischemic inflammatory responses and its retinal ganglion cell (RGC)-neuroprotective ability. We used the rodent NAION (rNAION) model in male Sprague-Dawley rats. Animals received either vehicle or minocycline (33 mg/kg) daily intraperitoneally for 28 days. Early (3 days) ON-cytokine responses were evaluated, and oligodendrocyte death was temporally evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Cellular inflammation was evaluated with immunohistochemistry, and RGC preservation was compared with stereology of Brn3a-positive cells in flat mounted retinas. Post-rNAION, oligodendrocytes exhibit a delayed pattern of apoptosis extending over a month, with extrinsic monocyte infiltration occurring only in the primary rNAION lesion and progressive distal microglial activation. Post-induction minocycline failed to improve retinal ganglion cell survival compared with the vehicle treated (893.14 vs. 920.72; p>0.9). Cytokine analysis of the rNAION lesion 3 days post-induction revealed that minocycline exert general inflammatory suppression without selective upregulation of cytokines associated with the proposed alternative or neuroprotective M2 inflammatory pathway. The pattern of cytokine release, extended temporal window of oligodendrocyte death, and progressive microglial activation suggests that selective neuroimmunomodulation, rather than general inflammatory suppression, may be required for effective repair strategies in ischemic optic neuropathies.

  16. Comprehensive evaluation of peripheral nerve regeneration in the acute healing phase using tissue clearing and optical microscopy in a rodent model.

    Directory of Open Access Journals (Sweden)

    Yookyung Jung

    Full Text Available Peripheral nerve injury (PNI, a common injury in both the civilian and military arenas, is usually associated with high healthcare costs and with patients enduring slow recovery times, diminished quality of life, and potential long-term disability. Patients with PNI typically undergo complex interventions but the factors that govern optimal response are not fully characterized. A fundamental understanding of the cellular and tissue-level events in the immediate postoperative period is essential for improving treatment and optimizing repair. Here, we demonstrate a comprehensive imaging approach to evaluate peripheral nerve axonal regeneration in a rodent PNI model using a tissue clearing method to improve depth penetration while preserving neural architecture. Sciatic nerve transaction and end-to-end repair were performed in both wild type and thy-1 GFP rats. The nerves were harvested at time points after repair before undergoing whole mount immunofluorescence staining and tissue clearing. By increasing the optic depth penetration, tissue clearing allowed the visualization and evaluation of Wallerian degeneration and nerve regrowth throughout entire sciatic nerves with subcellular resolution. The tissue clearing protocol did not affect immunofluorescence labeling and no observable decrease in the fluorescence signal was observed. Large-area, high-resolution tissue volumes could be quantified to provide structural and connectivity information not available from current gold-standard approaches for evaluating axonal regeneration following PNI. The results are suggestive of observed behavioral recovery in vivo after neurorrhaphy, providing a method of evaluating axonal regeneration following repair that can serve as an adjunct to current standard outcomes measurements. This study demonstrates that tissue clearing following whole mount immunofluorescence staining enables the complete visualization and quantitative evaluation of axons throughout

  17. RSMASS system model development

    International Nuclear Information System (INIS)

    Marshall, A.C.; Gallup, D.R.

    1998-01-01

    RSMASS system mass models have been used for more than a decade to make rapid estimates of space reactor power system masses. This paper reviews the evolution of the RSMASS models and summarizes present capabilities. RSMASS has evolved from a simple model used to make rough estimates of space reactor and shield masses to a versatile space reactor power system model. RSMASS uses unique reactor and shield models that permit rapid mass optimization calculations for a variety of space reactor power and propulsion systems. The RSMASS-D upgrade of the original model includes algorithms for the balance of the power system, a number of reactor and shield modeling improvements, and an automatic mass optimization scheme. The RSMASS-D suite of codes cover a very broad range of reactor and power conversion system options as well as propulsion and bimodal reactor systems. Reactor choices include in-core and ex-core thermionic reactors, liquid metal cooled reactors, particle bed reactors, and prismatic configuration reactors. Power conversion options include thermoelectric, thermionic, Stirling, Brayton, and Rankine approaches. Program output includes all major component masses and dimensions, efficiencies, and a description of the design parameters for a mass optimized system. In the past, RSMASS has been used as an aid to identify and select promising concepts for space power applications. The RSMASS modeling approach has been demonstrated to be a valuable tool for guiding optimization of the power system design; consequently, the model is useful during system design and development as well as during the selection process. An improved in-core thermionic reactor system model RSMASS-T is now under development. The current development of the RSMASS-T code represents the next evolutionary stage of the RSMASS models. RSMASS-T includes many modeling improvements and is planned to be more user-friendly. RSMASS-T will be released as a fully documented, certified code at the end of

  18. Short and Long Term Behavioral and Pathological Changes in a Novel Rodent Model of Repetitive Mild Traumatic Brain Injury.

    Directory of Open Access Journals (Sweden)

    Kelly M McAteer

    Full Text Available A history of concussion, particularly repeated injury, has been linked to an increased risk for the development of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE. CTE is characterized by abnormal accumulation of hyperphosphorylated tau and deficits in learning and memory. As yet the mechanisms associated with the development of CTE are unknown. Accordingly, the aim of the current study was to develop and characterize a novel model of repetitive mTBI that accurately reproduces the key short and long-term functional and histopathological features seen clinically. Forty male Sprague-Dawley rats were randomly assigned to receive 0, 1 or 3x mTBI spaced five days apart using a modified version of the Marmarou impact-acceleration diffuse-TBI model to deliver 110G of linear force. Functional outcomes were assessed six and twelve weeks post-injury, with histopathology assessed twenty-four hours and twelve weeks post-injury. Repetitive mTBI resulted in mild spatial and recognition memory deficits as reflected by increased escape latency on the Barnes maze and decreased time spent in the novel arm of the Y maze. There was a trend towards increased anxiety-like behavior, with decreased time spent in the inner portion of the open field. At 24 hours and 12 weeks post injury, repetitive mTBI animals showed increased tau phosphorylation and microglial activation within the cortex. Increases in APP immunoreactivity were observed in repetitive mTBI animals at 12 weeks indicating long-term changes in axonal integrity. This novel model of repetitive mTBI with its persistent cognitive deficits, neuroinflammation, axonal injury and tau hyperphosphorylation, thus represents a clinically relevant experimental approach to further explore the underlying pathogenesis of CTE.

  19. Effects of amylin and bupropion/naltrexone on food intake and body weight are interactive in rodent models.

    Science.gov (United States)

    Clapper, Jason R; Athanacio, Jennifer; Wittmer, Carrie; Griffin, Pete S; D'Souza, Lawrence; Parkes, David G; Roth, Jonathan D

    2013-01-05

    Antagonism of opioid systems (e.g., with naltrexone) has been explored as an anti-obesity strategy, and is particularly effective when co-administered with dual inhibitors of dopamine and norepinephrine reuptake (e.g., bupropion). Previously, we demonstrated that amylin enhances the food intake lowering and weight loss effects of neurohormonal (e.g., leptin, cholecystokinin, melanocortins) and small molecule (e.g., phentermine, sibutramine) agents. Here, we sought to characterize the interaction of amylin with naltrexone/bupropion on energy balance. Wild-type and amylin knockout mice were similarly responsive to the food intake lowering effects of either naltrexone (1mg/kg, subcutaneous) or bupropion (50mg/kg, subcutaneous) suggesting that they act independently of amylinergic systems and could interact additively when given in combination with amylin. To test this, diet-induced obese rats were treated (for 11 days) with vehicle, rat amylin (50 μg/kg/d, infused subcutaneously), naltrexone/bupropion (1 and 20mg/kg, respectively by twice daily subcutaneous injection) or their combination. We found that amylin+naltrexone/bupropion combination therapy exerted additive effects to reduce cumulative food intake, body weight and fat mass. In a separate study, the effects of amylin and naltrexone/bupropion administered at the same doses (for 14 days) were compared to a pair-fed group. Although the combination and pair-fed groups lost a similar amount of body weight, rats treated with the combination lost 68% more fat and better maintained their lean mass. These findings support the strategy of combined amylin agonism with opioid and catecholaminergic signaling systems for the treatment of obesity. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Efficiency of lipofection combined with hyperthermia in Lewis lung carcinoma cells and a rodent pleural dissemination model of lung carcinoma.

    Science.gov (United States)

    Okita, Atsushi; Mushiake, Hiroyuki; Tsukuda, Kazunori; Aoe, Motoi; Murakami, Masakazu; Andou, Akio; Shimizu, Nobuyoshi

    2004-06-01

    We have previously reported that hyperthermia at 41 degrees C enhanced lipofection-mediated gene transduction into cultured cells. In this study, we adapted hyperthermia technique to novel cationic liposome (Lipofectamine 2000) mediated gene transfection into Lewis lung carcinoma cells in vitro and in vivo. In vitro, transfection efficiencies were 38.9+/-3.3% by lipofection alone and 52.1+/-2.6% by lipofection with hyperthermia for 30 min, and 62.5+/-5.5% and 81.4+/-3.2% for 1 h, respectively. Hyperthermia significantly enhanced gene transfection efficiency 1.2-1.4 times more than that with lipofection only. We also evaluated the effect of hyperthermia with a pleural dissemination model of lung carcinoma of mice. We developed a model which was well-tolerated with hyperthermia with lipofection by the mice. In spite of repeated treatments, transfection efficiencies were very low and we could not show the augmentation of gene transfection by hyperthermia. Though Lipofectamine 2000 showed strong gene transduction effect and hyperthermia augmented its effect in vitro, further evaluation is needed to adapt both techniques in vivo.

  1. The Cooccurrence of Obesity, Osteoporosis, and Sarcopenia in the Ovariectomized Rat: A Study for Modeling Osteosarcopenic Obesity in Rodents

    Directory of Open Access Journals (Sweden)

    Zahra Ezzat-Zadeh

    2017-01-01

    Full Text Available Background. Obesity, osteoporosis, and sarcopenia may individually occur due to age-related gradual alterations in body composition. This study investigates the cooccurrence of these age-related diseases in female animals with low levels of ovarian hormone in the absence of complex multifactorial process of chronological aging. Methods. Thirty-six 5- and 10-month-old female rats were chosen to model pre- and postmenopausal women, respectively. Rats were divided into three treatment groups in each age category—sham, ovariectomized (ovx, and ovx + E2 (17β-estradiol, 10 μg/kg—and were pair-fed. Volunteer wheel running activity, body composition, bone microstructure, serum C-telopeptides of type I collagen, bone specific alkaline phosphatase, E2, and gastrocnemius and soleus muscles were analyzed. Results. The cooccurrence of osteoporosis, sarcopenia, and obesity was observed in the older ovx rats associated with a significant (p<0.05 increased fat mass (30%, bone loss (9.6%, decreased normalized muscle mass-to-body-weight ratio (10.5%, and a significant decrease in physical activity (57%. The ratio of tibial bone mineral density to combined muscle mass was significantly decreased in both ovx age categories. Conclusion. Ovariectomized rat could be used as an experimental model to examine the effect of loss of ovarian hormones, while controlling for energy intake and expenditure, to conduct obesity and body composition translational research in females without the confounding effect of genetic background.

  2. A Theoretical and Experimental Investigation of Mechanical Damage to Rodent Sperm Generated by Microscale Ice Formation.

    Science.gov (United States)

    Han, X; Critser, J K

      BACKGROUND: Rodent sperm cryopreservation is of critical importance for the maintenance of lines or strains of genetically engineered mice and rats. However, rodent sperm are extremely mechanically sensitive due to their unusual morphology, and are severely damaged using current methods of cryopreservation. Those methods result in poor post thaw motility (PTM) for mouse. To investigate the mechanism of mechanical damage introduced to rodent sperm during freezing, a micro-mechanical model was established to analyze the sperm radial and axial thermal stresses generated by microscale extracellular ice formation. PTM of mouse sperm cryopreserved in capillaries of different radii (100, 200, 344, 526, 775µm) was measured using a standard computer-assisted sperm analysis system. The model predicts that when one of the inner dimensions of the containers (the inner diameter of plastic straws or straw capillaries) is on the same order of magnitude of sperm length, axial stress is significantly increased. The experimental results showed that the value of PTM was decreased from 38 ± 8 % in the larger (775µm) capillaries to 0 ± 0 % in the smaller (100 µm) ones. Theoretical analysis based on the established model were experimentally validated and can be used to guide the design of novel devices to improve the efficiency of rodent sperm cryopreservation.

  3. Systemic resilience model

    International Nuclear Information System (INIS)

    Lundberg, Jonas; Johansson, Björn JE

    2015-01-01

    It has been realized that resilience as a concept involves several contradictory definitions, both for instance resilience as agile adjustment and as robust resistance to situations. Our analysis of resilience concepts and models suggest that beyond simplistic definitions, it is possible to draw up a systemic resilience model (SyRes) that maintains these opposing characteristics without contradiction. We outline six functions in a systemic model, drawing primarily on resilience engineering, and disaster response: anticipation, monitoring, response, recovery, learning, and self-monitoring. The model consists of four areas: Event-based constraints, Functional Dependencies, Adaptive Capacity and Strategy. The paper describes dependencies between constraints, functions and strategies. We argue that models such as SyRes should be useful both for envisioning new resilience methods and metrics, as well as for engineering and evaluating resilient systems. - Highlights: • The SyRes model resolves contradictions between previous resilience definitions. • SyRes is a core model for envisioning and evaluating resilience metrics and models. • SyRes describes six functions in a systemic model. • They are anticipation, monitoring, response, recovery, learning, self-monitoring. • The model describes dependencies between constraints, functions and strategies

  4. The Cooccurrence of Obesity, Osteoporosis, and Sarcopenia in the Ovariectomized Rat: A Study for Modeling Osteosarcopenic Obesity in Rodents.

    Science.gov (United States)

    Ezzat-Zadeh, Zahra; Kim, Jeong-Su; Chase, P Bryant; Arjmandi, Bahram H

    2017-01-01

    Obesity, osteoporosis, and sarcopenia may individually occur due to age-related gradual alterations in body composition. This study investigates the cooccurrence of these age-related diseases in female animals with low levels of ovarian hormone in the absence of complex multifactorial process of chronological aging. Thirty-six 5- and 10-month-old female rats were chosen to model pre- and postmenopausal women, respectively. Rats were divided into three treatment groups in each age category-sham, ovariectomized (ovx), and ovx + E 2 (17 β -estradiol, 10  μ g/kg)-and were pair-fed. Volunteer wheel running activity, body composition, bone microstructure, serum C-telopeptides of type I collagen, bone specific alkaline phosphatase, E 2 , and gastrocnemius and soleus muscles were analyzed. The cooccurrence of osteoporosis, sarcopenia, and obesity was observed in the older ovx rats associated with a significant ( p obesity and body composition translational research in females without the confounding effect of genetic background.

  5. Predator odor avoidance as a rodent model of anxiety: learning-mediated consequences beyond the initial exposure.

    Science.gov (United States)

    Staples, Lauren G

    2010-11-01

    Prey animals such as rats display innate defensive responses when exposed to the odor of a predator, providing a valuable means of studying the neurobiology of anxiety. While the unconditioned behavioral and neural responses to a single predator odor exposure have been well documented, the paradigm can also be used to study learning-dependent adaptations that occur following repeated exposure to a stressor or associated stimuli. In developing preclinical models for human anxiety disorders this is advantageous, as anxiety disorders seldom involve a single acute experience of anxiety, but rather are chronic and/or recurring illnesses. Part 1 of this review summarizes current research on the three most commonly used predator-related odors: cat odor, ferret odor, and trimethylthiazoline (a component of fox odor). Part 2 reviews the learning-based behavioral and neural adaptations that underlie predator odor-induced context conditioning, one-trial tolerance, sensitization, habituation and dishabituation. Copyright © 2010 Elsevier Inc. All rights reserved.

  6. KDT501, a derivative from hops, normalizes glucose metabolism and body weight in rodent models of diabetes.

    Directory of Open Access Journals (Sweden)

    Veera R Konda

    Full Text Available AIMS/HYPOTHESIS: We developed KDT501, a novel substituted 1,3-cyclopentadione chemically derived from hop extracts, and evaluated it in various in vitro and in vivo models of diabetes and insulin sensitivity. METHODS: KDT501 was evaluated for anti-inflammatory effects in monocyte/macrophage cells; agonistic activity for peroxisome proliferator-activated receptors (PPAR; lipogenesis and gene expression profile in human subcutaneous adipocytes. Body composition, glucose, insulin sensitivity, and lipids were assessed in diet-induced obesity (DIO mice and Zucker Diabetic Fatty (ZDF rats after oral administration. RESULTS: KDT501 mediated lipogenesis in 3T3L1 and human subcutaneous adipocytes; however, the gene expression profile of KDT501 differed from that of the full PPARγ agonist rosiglitazone, suggesting that KDT501 has pleiotropic biological activities. In addition, KDT501 showed only modest, partial PPARγ agonist activity and exhibited anti-inflammatory effects in monocytes/macrophages that were not observed with rosiglitazone. In a DIO mouse model, oral administration of KDT501 significantly reduced fed blood glucose, glucose/insulin AUC following an oral glucose bolus, and body fat. In ZDF rats, oral administration of KDT501 significantly reduced fed glucose, fasting plasma glucose, and glucose AUC after an oral glucose bolus. Significant, dose-dependent reductions of plasma hemoglobin A1c, weight gain, total cholesterol, and triglycerides were also observed in animals receiving KDT501. CONCLUSION: These results indicate that KDT501 produces a unique anti-diabetic profile that is distinct in its spectrum of pharmacological effects and biological mechanism from both metformin and pioglitazone. KDT501 may thus constitute a novel therapeutic agent for the treatment of Type 2 diabetes and associated conditions.

  7. Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology.

    Science.gov (United States)

    Neill, Jo C; Grayson, Ben; Kiss, Béla; Gyertyán, István; Ferguson, Paul; Adham, Nika

    2016-01-01

    Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  8. Selected System Models

    Science.gov (United States)

    Schmidt-Eisenlohr, F.; Puñal, O.; Klagges, K.; Kirsche, M.

    Apart from the general issue of modeling the channel, the PHY and the MAC of wireless networks, there are specific modeling assumptions that are considered for different systems. In this chapter we consider three specific wireless standards and highlight modeling options for them. These are IEEE 802.11 (as example for wireless local area networks), IEEE 802.16 (as example for wireless metropolitan networks) and IEEE 802.15 (as example for body area networks). Each section on these three systems discusses also at the end a set of model implementations that are available today.

  9. Identification of prenatal toxic components of complex PAH mixtures derived from fossil fuel combustion employing rodent embryo culture systems

    International Nuclear Information System (INIS)

    Irvin, T.R.; Akgerman, A.

    1991-01-01

    Many adverse health effects caused by combustion-generated toxins have been recognized for some time. Acute pulmonary toxicity among urban populations has been repeatedly recorded during periods of high smoke, soot, and organo-particulate pollution. The combustion of coals and petroleum-derived fuels results in emission of particulate and organic vapor-phase components to the atmosphere. Isolation of these particle-absorbed compounds and subsequent toxicological testing has further indicated the importance of chronic, low-level exposure to airborne combustion-generated toxins in the etiology of many forms of human cancer; particulate phases of these emissions have been found to contain polycyclic aromatic hydrocarbons and heterocyclic organic compounds, absorbed onto the particle matrix, which possess potent carcinogenic and mutagenic properties. In this paper, the authors define a postimplantation rat embryo culture system constructed to identify prenatal toxic components of complex polycyclic aromatic hydrocarbon soots. Employing this culture system, we also describe its application to identify prenatal toxic components of diesel soot particulates

  10. A Rodent Model of Night-Shift Work Induces Short-Term and Enduring Sleep and Electroencephalographic Disturbances.

    Science.gov (United States)

    Grønli, Janne; Meerlo, Peter; Pedersen, Torhild T; Pallesen, Ståle; Skrede, Silje; Marti, Andrea R; Wisor, Jonathan P; Murison, Robert; Henriksen, Tone E G; Rempe, Michael J; Mrdalj, Jelena

    2017-02-01

    Millions of people worldwide are working at times that overlap with the normal time for sleep. Sleep problems related to the work schedule may mediate the well-established relationship between shift work and increased risk for disease, occupational errors and accidents. Yet, our understanding of causality and the underlying mechanisms that explain this relationship is limited. We aimed to assess the consequences of night-shift work for sleep and to examine whether night-shift work-induced sleep disturbances may yield electrophysiological markers of impaired maintenance of the waking brain state. An experimental model developed in rats simulated a 4-day protocol of night-work in humans. Two groups of rats underwent 8-h sessions of enforced ambulation, either at the circadian time when the animal was physiologically primed for wakefulness (active-workers, mimicking day-shift) or for sleep (rest-workers, mimicking night-shift). The 4-day rest-work schedule induced a pronounced redistribution of sleep to the endogenous active phase. Rest-work also led to higher electroencephalogram (EEG) slow-wave (1-4 Hz) energy in quiet wakefulness during work-sessions, suggesting a degraded waking state. After the daily work-sessions, being in their endogenous active phase, rest-workers slept less and had higher gamma (80-90 Hz) activity during wake than active-workers. Finally, rest-work induced an enduring shift in the main sleep period and attenuated the accumulation of slow-wave energy during NREM sleep. A comparison of recovery data from 12:12 LD and constant dark conditions suggests that reduced time in NREM sleep throughout the recorded 7-day recovery phase induced by rest-work may be modulated by circadian factors. Our data in rats show that enforced night-work-like activity during the normal resting phase has pronounced acute and persistent effects on sleep and waking behavior. The study also underscores the potential importance of animal models for future studies on the

  11. Anti-anxiety activity of hydro alcoholic extract of Scoparia dulcis Linn. assessed using different experimental anxiety models In rodents

    Directory of Open Access Journals (Sweden)

    Arasan Elayaraja

    2015-03-01

    Full Text Available Scoparia dulcis belonging to the family Scrophulariaceae is an valuable medicinal herb, had showed antiviral, antimalarial, anticancer and antidiabetic activities. The present study was aimed to investigate the anti-anxiety activity of crude ethanolic extract of S.dulcis L by various behavioural models. Preliminary phytochemical investigation revealed the presence of  phenols and flavonoids. The extract at 100mg/kg and 200mg/kg was evaluated for anti anxiety activity by  Open-field test [OFT], Elevated plus-maze test [EPM], Elevated Zero-maze test [EZM],, Social interaction test [SI] And  Novelty induced suppressed feeling latency test [FL]   and the results of behavioral tests indicated the dose dependent anti-anxiety activity of  Scoparia dulcis which is comparable to standard. It was concluded that crude ethanolic extract showed anti anxiety activity.Further studies are needed to identify the anxiolytic mechanism(s and the phytochemicals responsible for the observed anxiolytic effect  of the hydroalcoholic extract of Scoparia dulcis. 

  12. Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis

    Directory of Open Access Journals (Sweden)

    Valentina eWiescholleck

    2013-03-01

    Full Text Available Irreversible N-methyl-D-aspartate receptor (NMDAR antagonism is known to provoke symptoms of psychosis and schizophrenia in healthy humans. NMDAR hypofunction is believed to play a central role in the pathophysiology of both disorders and in an animal model of psychosis, that is based on irreversible antagonism of NMDARs, pronounced deficits in hippocampal synaptic plasticity have been reported shortly after antagonist treatment. Here, we examined the long-term consequences for long-term potentiation (LTP of a single acute treatment with an irreversible antagonist and investigated whether deficits are associated with memory impairments.The ability to express long-term potentiation (LTP at the perforant pathway – dentate gyrus synapse, as well as object recognition memory was assessed 1, 2, 3 and 4 weeks after a single -treatment of the antagonist, MK801. Here, LTP in freely behaving rats was significantly impaired at all time-points compared to control LTP before treatment. Object recognition memory was also significantly poorer in MK801-treated compared to vehicle-treated animals for several weeks after treatment. Histological analysis revealed no changes in brain tissue.Taken together, these data support that acute treatment with an irreversible NMDAR antagonist persistently impairs hippocampal functioning on behavioral, as well as synaptic levels. The long-term deficits in synaptic plasticity may underlie the cognitive impairments that are associated with schizophrenia-spectrum disorders.

  13. In vivo antitussive activity of Coccinia grandis against irritant aerosol and sulfur dioxide-induced cough model in rodents

    Directory of Open Access Journals (Sweden)

    Shakti Prasad Pattanayak and Priyashree Sunita

    2009-12-01

    Full Text Available Coccinia grandis (Cucurbitaceae has extensively used to get relief from asthma and cough by the indigenous people of India. The antitussive effect of aerosols of two different concentrations (2.5%, 5% w/v of methanol extract of C. grandis fruits were tested by counting the numbers of coughs produced due to aerosols of citric acid, 10 min after exposing the male guinea pigs to aerosols of test solutions for 7 min. In another set of experiment methanol extract was investigated for its therapeutic efficacy on a cough model induced by sulfur dioxide gas in mice. The results showed significant reduction of cough number obtained in the presence of both concentrations of methanol extract as that of the prototype antitussive agent codeine phosphate. Also, methanol extract exhibited significant antitussive effect at 100, 200 and 400 mg/kg, per orally by inhibiting the cough by 20.57, 33.73 and 56.71% within 90 min of performing the experiment respectively.

  14. The impact of postnatal leuprolide acetate treatment on reproductive characteristics in a rodent model of polycystic ovary syndrome.

    Science.gov (United States)

    Serrano Mujica, Lady Katerine; Bertolin, Kalyne; Bridi, Alessandra; Glanzner, Werner Giehl; Rissi, Vitor Braga; de Camargo, Flávia de Los Santos; Zanella, Renato; Prestes, Osmar Damian; Moresco, Rafael Noal; Antoniazzi, Alfredo Quites; Dias Gonçalves, Paulo Bayard; Premaor, Melissa Orlandin; Comim, Fabio Vasconcellos

    2017-02-15

    In this study, a GnRH agonist, leuprolide acetate (LA), was given as a single depot injection before 48 h of life to Wistar female rats allotted to prenatal (E16-18) and postnatal androgenization (day 5 of life) by the use of testosterone propionate, looking for reproductive endpoints. Remarkably, a single injection of LA increased the estrus cycles in the postnatal group (PostN) from 0% to 25% of the estrus cycles in the postnatal LA treated group (PostN L). LA also reduced the serum testosterone levels and cysts and atretic follicles in PostN L in contrast with rats (>100 days) from the PostN group (p = 0.04). Prenatally androgenized rats (PreN) exhibited significant modifications in the hypothalamic genes, such as Gnrh. To the best of our knowledge, this is the first study to show that blockage of the GnRH axis with leuprolide acetate depot prevented the development of typical features (anovulation, cysts, atretic follicles) in a postnatal testosterone propionate rat model of PCOS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Co-micronized palmitoylethanolamide/polydatin treatment causes endometriotic lesion regression in a rodent model of surgically-induced endometriosis

    Directory of Open Access Journals (Sweden)

    Rosanna Di Paola

    2016-10-01

    Full Text Available Endometriosis is a chronic, painful disease characterized by the presence of endometrial glands and stroma outside the uterine cavity. Palmitoylethanolamide (PEA, an endogenous fatty acid amide, has anti-inflammatory and neuroprotective effects. PEA lacks free radical scavenging activity, unlike polydatin (PLD, a natural precursor of resveratrol. The aim of this study was to investigate the effect of orally administered co-micronized PEA/polydatin (m(PEA/PLD in an autologous rat model of surgically-induced endometriosis. Endometriosis was induced in female Wistar albino rats by auto-transplantation of uterine squares (implants into the intestinal mesentery and peritoneal cavity. Rats were distributed into one control group and one treatment group (10 animals each: m(PEA/PLD 10 mg/kg/day. At 28 days after surgery the relative volume of the endometrioma was determined. Endometrial-like tissue was confirmed by histology: Masson trichrome and toluidine blue were used to detect fibrosis and mast cells, respectively. The treated group displayed a smaller cyst diameter, with improved fibrosis score and mast cell number decrease. m(PEA/PLD administration decreased angiogenesis (vascular endothelial growth factor, nerve growth factor, intercellular adhesion molecule, matrix metalloproteinase 9 expression and lymphocyte accumulation. m(PEA/PLD treatment also reduced peroxynitrite formation, (poly-ADPribose polymerase activation, IkBα phosphorylation and nuclear facor-kB traslocation in the nucleus. Our results suggested that m(PEA/PLD may be of use to inhibit development of endometriotic lesions in rats.

  16. Anti-Inflammatory Effect of Emblica officinalis in Rodent Models of Acute and Chronic Inflammation: Involvement of Possible Mechanisms

    Directory of Open Access Journals (Sweden)

    Mahaveer Golechha

    2014-01-01

    Full Text Available Emblica officinalis, commonly known as amla in Ayurveda, is unarguably the most important medicinal plant for prevention and treatment of various ailments. The present study investigated the anti-inflammatory activity of hydroalcoholic extract of Emblica officinalis (HAEEO. Acute inflammation in rats was induced by the subplantar injection of carrageenan, histamine, serotonin, and prostaglandin E2 and chronic inflammation was induced by the cotton pellet granuloma. Intraperitoneal (i.p. administration of HAEEO at all the tested doses (300, 500, and 700 mg/kg significantly (P<0.001 inhibited rat paw edema against all phlogistic agents and also reduced granuloma formation. However, at the dose of 700 mg/kg, HAEEO exhibited maximum anti-inflammatory activity in all experimental models, and the effects were comparable to that of the standard anti-inflammatory drugs. Additionally, in paw tissue the antioxidant activity of HAEEO was also measured and it was found that HAEEO significantly (P<0.001 increased glutathione, superoxide dismutase, and catalase activity and subsequently reduced lipid peroxidation evidenced by reduced malondialdehyde. Taken all together, the results indicated that HAEEO possessed potent anti-inflammatory activity and it may hold therapeutic promise in the management of acute and chronic inflammatory conditions.

  17. The bioeconomics of controlling an African rodent pest species

    OpenAIRE

    Skonhoft, Anders; Herwig, Leirs; Andreassen, Harry Peter; Mulungu, Loth S. A.; Stenseth, Nils Christian

    2006-01-01

    The paper treats the economy of controlling an African pest rodent, the multimammate rat, causing major damage in maize production. An ecological population model is presented and used as a basis for the economic analyses carried out at the village level using data from Tanzania. This model incorporates both density-dependent and density-independent (stochastic) factors. Rodents are controlled by applying poison, and the economic benefits depend on the income from maize production minus the c...

  18. Evaluation of optic nerve head blood flow in normal rats and a rodent model of non-arteritic ischemic optic neuropathy using laser speckle flowgraphy.

    Science.gov (United States)

    Takako, Hidaka; Hideki, Chuman; Nobuhisa, Nao-I

    2017-10-01

    To evaluate optic nerve head (ONH) blood flow in normal rats and a rodent model of non-arteritic ischemic optic neuropathy (rNAION) in vivo using laser speckle flowgraphy (LSFG). Rats were under general anesthesia; to induce NAION, Rose Bengal (RB) was injected into the tail vein. After the administration of RB, the left ONH was photoactivated using an argon green laser. We measured ONH blood flow in the normal rats and the rNAION group (at 1, 3, 7, 14, and 28 days after the induction of NAION) using an LSFG-Micro. We used the mean blur rate (MBR) of the vessel region (MV) and MBR of the tissue region (MT) as indicators of blood flow. We compared the MBR of the right and left eyes in both the normal rats and the rNAION group. In the normal rats, there were no significant differences in MV or MT between the right and left eyes. In the rNAION group, the MV and MT of the affected eyes were significantly lower than those of the unaffected eyes at all time points. There were significant differences between the left/right MV and MT ratios seen before the induction of NAION and those observed at 1, 3, 7, 14, and 28 days after the induction of NAION. However, there were no significant differences in these parameters among any of post-NAION induction time points. Our results indicated that the ONH blood flow of the rNAION rats fell in the acute and chronic phases.

  19. Three-dimensional quantification of orthodontic root resorption with time-lapsed imaging of micro-computed tomography in a rodent model.

    Science.gov (United States)

    Yang, Chongshi; Zhang, Yuanyuan; Zhang, Yan; Fan, Yubo; Deng, Feng

    2015-01-01

    Despite various X-ray approaches have been widely used to monitor root resorption after orthodontic treatment, a non-invasive and accurate method is highly desirable for long-term follow up. The aim of this study was to build a non-invasive method to quantify longitudinal orthodontic root resorption with time-lapsed images of micro-computed tomography (micro-CT) in a rodent model. Twenty male Sprague Dawley (SD) rats (aged 6-8 weeks, weighing 180-220 g) were used in this study. A 25 g orthodontic force generated by nickel-titanium coil spring was applied to the right maxillary first molar for each rat, while contralateral first molar was severed as a control. Micro-CT scan was performed at day 0 (before orthodontic load) and days 3, 7, 14, and 28 after orthodontic load. Resorption of mesial root of maxillary first molars at bilateral sides was calculated from micro-CT images with registration algorithm via reconstruction, superimposition and partition operations. Obvious resorption of mesial root of maxillary first molar can be detected at day 14 and day 28 at orthodontic side. Most of the resorption occurred in the apical region at distal side and cervical region at mesiolingual side. Desirable development of molar root of rats was identified from day 0 to day 28 at control side. The development of root concentrated on apical region. This non-invasive 3D quantification method with registration algorithm can be used in longitudinal study of root resorption. Obvious root resorption in rat molar can be observed three-dimensionally at day 14 and day 28 after orthodontic load. This indicates that registration algorithm combined with time-lapsed images provides clinic potential application in detection and quantification of root contour.

  20. Maternal protein restriction during lactation induces early and lasting plasma metabolomic and hepatic lipidomic signatures of the offspring in a rodent programming model.

    Science.gov (United States)

    Martin Agnoux, Aurore; El Ghaziri, Angélina; Moyon, Thomas; Pagniez, Anthony; David, Agnès; Simard, Gilles; Parnet, Patricia; Qannari, El Mostafa; Darmaun, Dominique; Antignac, Jean-Philippe; Alexandre-Gouabau, Marie-Cécile

    2018-05-01

    Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. However, the exact mechanisms underlying offspring metabolic adaptations are not yet fully understood. Specifically, it remains unclear whether the gestation or the lactation is the more vulnerable period to modify offspring metabolic flexibility. We investigated in a rodent model of intrauterine growth restriction (IUGR) induced by maternal protein restriction (R) during gestation which time window of maternal undernutrition (gestation, lactation or gestation-lactation) has more impact on the male offspring metabolomics phenotype. Plasma metabolome and hepatic lipidome of offspring were characterized through suckling period and at adulthood using liquid chromatography-high-resolution mass spectrometry. Multivariate analysis of these fingerprints highlighted a persistent metabolomics signature in rats suckled by R dams, with a clear-cut discrimination from offspring fed by control (C) dams. Pups submitted to a nutritional switch at birth presented a metabolomics signature clearly distinct from that of pups nursed by dams maintained on a consistent perinatal diet. Control rats suckled by R dams presented transiently higher branched-chain amino acid (BCAA) oxidation during lactation besides increased fatty acid (FA) β-oxidation, associated with preserved insulin sensitivity and lesser fat accretion that persisted throughout their life. In contrast, IUGR rats displayed permanently impaired β-oxidation, associated to increased glucose or BCAA oxidation at adulthood, depending on the fact that pups experienced slow postnatal or catch-up growth, as suckled by R or C dams, respectively. Taken together, these findings provide evidence for a significant contribution of the lactation period in metabolic programming. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Neuroprotection of a novel cyclopeptide C*HSDGIC* from the cyclization of PACAP (1-5 in cellular and rodent models of retinal ganglion cell apoptosis.

    Directory of Open Access Journals (Sweden)

    Huanhuan Cheng

    Full Text Available To investigate the protective effects of a novel cyclopeptide C*HSDGIC* (CHC from the cyclization of Pituitary adenylate cyclase-activating polypeptide (PACAP (1-5 in cellular and rodent models of retinal ganglion cell apoptosis.Double-labeling immunohistochemistry was used to detect the expression of Thy-1 and PACAP receptor type 1 in a retinal ganglion cell line RGC-5. The apoptosis of RGC-5 cells was induced by 0.02 J/cm(2 Ultraviolet B irradiation. MTT assay, flow cytometry, fluorescence microscopy were used to investigate the viability, the level of reactive oxygen species (ROS and apoptosis of RGC-5 cells respectively. CHC attenuated apoptotic cell death induced by Ultraviolet B irradiation and inhibited the excessive generation of ROS. Moreover, CHC treatment resulted in decreased expression of Bax and concomitant increase of Bcl-2, as was revealed by western-blot analysis. The in vivo apoptosis of retinal ganglion cells was induced by injecting 50 mM N-methyl-D-aspartate (NMDA (100 nmol in a 2 µL saline solution intravitreally, and different dosages of CHC were administered. At day 7, rats in CHC+ NMDA-treated groups showed obvious aversion to light when compared to NMDA rats. Electroretinogram recordings revealed a marked decrease in the amplitudes of a-wave, b-wave, and photopic negative response due to NMDA damage. In retina receiving intravitreal NMDA and CHC co-treatment, these values were significantly increased. CHC treatment also resulted in less NMDA-induced cell loss and a decrease in the proportion of dUTP end-labeling-positive cells in ganglion cell line.C*HSDGIC*, a novel cyclopeptide from PACAP (1-5 attenuates apoptosis in RGC-5 cells and inhibits NMDA-induced retinal neuronal death. The beneficial effects may occur via the mitochondria pathway. PACAP derivatives like CHC may serve as a promising candidate for neuroprotection in glaucoma.

  2. Conspecific Interactions in Adult Laboratory Rodents: Friends or Foes?

    Science.gov (United States)

    Lukas, Michael; de Jong, Trynke R

    2017-01-01

    Interactions between adult conspecifics, including sexual behaviors, affiliation, and aggression are crucial for the well-being, survival, and reproduction of mammals. This holds true for any mammalian species, but certainly for humans: An inability to optimally navigate the social system can have a strong negative impact on physical and mental health. Translational rodent models have been used for decades to unravel the neural pathways and substrates involved in normal and abnormal conspecific interactions. Researchers in the field of translational social neuroscience face a double challenge: Not only do they need to pay considerable attention to the behavioral ecology of their model species or their ancestors, they also have to expect a relatively large variability in behavior and adjust their experimental design accordingly. In this chapter, we will lay out traditional and novel rodent models and paradigms to study sexual, affiliative, and aggressive interactions among adult conspecifics. We will discuss the merits and main findings and briefly consider the most promising novel directions. Finally, we review the modulatory involvement of two major players in mammal social interaction: the central oxytocin and vasopressin system.

  3. Associations between parenting behavior and anxiety in a rodent model and a clinical sample: relationship to peripheral BDNF levels

    Science.gov (United States)

    Dalle Molle, R; Portella, A K; Goldani, M Z; Kapczinski, F P; Leistner-Segala, S; Salum, G A; Manfro, G G; Silveira, P P

    2012-01-01

    Adverse early-life environment is associated with anxiety-like behaviors and disorders. Brain-derived neurotrophic factor (BDNF) is sensitive to this environment and could be a marker of underlying brain changes. We aimed at evaluating the development of anxiety-like behaviors in a rat model of early adversity, as well as the possible association with BDNF levels. Similar associations were investigated in a sample of adolescent humans. For the rat study, Wistar rat litters were divided into: early-life stress (ELS, limited access to nesting material) and control groups. Maternal behavior was observed from days 1 to 9 of life and, as adults, rats were subjected to behavioral testing and BDNF measurements in plasma, hippocampus, amygdala and periaqueductal gray. For the human study, 129 adolescents were evaluated for anxiety symptoms and perceived parental care. Serum BDNF levels and the Val66Met polymorphism of the BDNF gene were investigated. We found that ELS dams showed more pure contact, that is, contact with low care and high control, toward pups, and their adult offspring demonstrated higher anxiety-like behaviors and plasma BDNF. Also the pure contact correlated positively with adult peripheral BDNF. Similarly in humans, there was a positive correlation between maternal overprotection and serum BDNF only in Met carriers. We also found negative correlations between maternal warmth and separation anxiety, social phobia and school phobia. Finally, our translational approach revealed that ELS, mediated through variations in maternal care, is associated with anxiety in both rats and humans and increased peripheral BDNF may be marking these phenomena. PMID:23168995

  4. Ascending central canal dilation and progressive ependymal disruption in a contusion model of rodent chronic spinal cord injury

    Directory of Open Access Journals (Sweden)

    Keirstead Hans S

    2007-09-01

    Full Text Available Abstract Background Chronic spinal cord injury (SCI can lead to an insidious decline in motor and sensory function in individuals even years after the initial injury and is accompanied by a slow and progressive cytoarchitectural destruction. At present, no pathological mechanisms satisfactorily explain the ongoing degeneration. Methods Adult female Sprague-Dawley rats were anesthetized laminectomized at T10 and received spinal cord contusion injuries with a force of 250 kilodynes using an Infinite Horizon Impactor. Animals were randomly distributed into 5 groups and killed 1 (n = 4, 28 (n = 4, 120 (n = 4, 450 (n = 5, or 540 (n = 5 days after injury. Morphometric and immunohistochemical studies were then performed on 1 mm block sections, 6 mm cranial and 6 mm caudal to the lesion epicenter. The SPSS 11.5 t test was used to determine differences between quantitative measures. Results Here, we document the first report of an ascending central canal dilation and progressive ependymal disruption cranial to the epicenter of injury in a contusion model of chronic SCI, which was characterized by extensive dural fibrosis and intraparenchymal cystic cavitation. Expansion of the central canal lumen beyond a critical diameter corresponded with ependymal cell ciliary loss, an empirically predictable thinning of the ependymal region, and a decrease in cell proliferation in the ependymal region. Large, aneurysmal dilations of the central canal were accompanied by disruptions in the ependymal layer, periependymal edema and gliosis, and destruction of the adjacent neuropil. Conclusion Cells of the ependymal region play an important role in CSF homeostasis, cellular signaling and wound repair in the spinal cord. The possible effects of this ascending pathology on ependymal function are discussed. Our studies suggest central canal dilation and ependymal region disruption as steps in the pathogenesis of chronic SCI, identify central canal dilation as a marker of

  5. Perinatal administration of aromatase inhibitors in rodents as animal models of human male homosexuality: similarities and differences.

    Science.gov (United States)

    Olvera-Hernández, Sandra; Fernández-Guasti, Alonso

    2015-01-01

    In this chapter we briefly review the evidence supporting the existence of biological influences on sexual orientation. We focus on basic research studies that have affected the estrogen synthesis during the critical periods of brain sexual differentiation in male rat offspring with the use of aromatase inhibitors, such as 1,4,6-androstatriene-3,17 (ATD) and letrozole. The results after prenatal and/or postnatal treatment with ATD reveal that these animals, when adults, show female sexual responses, such as lordosis or proceptive behaviors, but retain their ability to display male sexual activity with a receptive female. Interestingly, the preference and sexual behavior of these rats vary depending upon the circadian rhythm.Recently, we have established that the treatment with low doses of letrozole during the second half of pregnancy produces male rat offspring, that when adults spend more time in the company of a sexually active male than with a receptive female in a preference test. In addition, they display female sexual behavior when forced to interact with a sexually experienced male and some typical male sexual behavior when faced with a sexually receptive female. Interestingly, these males displayed both sexual behavior patterns spontaneously, i.e., in absence of exogenous steroid hormone treatment. Most of these features correspond with those found in human male homosexuals; however, the "bisexual" behavior shown by the letrozole-treated rats may be related to a particular human population. All these data, taken together, permit to propose letrozole prenatal treatment as a suitable animal model to study human male homosexuality and reinforce the hypothesis that human sexual orientation is underlied by changes in the endocrine milieu during early development.

  6. High-intensity interval and endurance training are associated with divergent skeletal muscle adaptations in a rodent model of hypertension.

    Science.gov (United States)

    Holloway, Tanya M; Bloemberg, Darin; da Silva, Mayne L; Quadrilatero, Joe; Spriet, Lawrence L

    2015-06-01

    Skeletal muscle is extremely adaptable to a variety of metabolic challenges, as both traditional moderate-intensity endurance (ET) and high-intensity interval training (HIIT) increases oxidative potential in a coordinated manner. Although these responses have been clearly demonstrated in healthy individuals, it remains to be determined whether both produce similar responses in the context of hypertension, one of the most prevalent and costly diseases worldwide. Therefore, in the current study, we used the Dahl sodium-sensitive rat, a model of hypertension, to determine the molecular responses to 4 wk of either ET or HIIT in the red (RG) and white gastrocnemius (WG) muscles. In the RG, both ET and HIIT increased the content of electron transport chain proteins and increased succinate dehydrogenase (SDH) content in type I fibers. Although both intensities of exercise shifted fiber type in RG (increased IIA, decreased IIX), only HIIT was associated with a reduction in endothelial nitric oxide synthase and an increase in HIF-1α proteins. In the WG, both ET and HIIT increased markers of the electron transport chain; however, HIIT decreased SDH content in a fiber-specific manner. ET increased type IIA, decreased IIB fibers, and increased capillarization, while, in contrast, HIIT increased the percentage of IIB fibers, decreased capillary-to-fiber ratios, decreased endothelial nitric oxide synthase, and increased hypoxia inducible factor-1α (HIF-1α) protein. Altogether, these data show that unlike in healthy animals, ET and HIIT have divergent effects in the skeletal muscle of hypertensive rats. This suggests ET may be optimal at improving the oxidative capacity of skeletal muscle in animals with hypertension. Copyright © 2015 the American Physiological Society.

  7. The effects of nicotine in the neonatal quinpirole rodent model of psychosis: Neural plasticity mechanisms and nicotinic receptor changes.

    Science.gov (United States)

    Peterson, Daniel J; Gill, W Drew; Dose, John M; Hoover, Donald B; Pauly, James R; Cummins, Elizabeth D; Burgess, Katherine C; Brown, Russell W

    2017-05-15

    Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 receptor sensitivity persistent throughout the animal's lifetime. In Experiment 1, we analyzed the role of α7 and α4β2 nicotinic receptors (nAChRs) in nicotine behavioral sensitization and on the brain-derived neurotrophic factor (BDNF) response to nicotine in NQ- and neonatally saline (NS)-treated rats. In Experiment 2, we analyzed changes in α7 and α4β2 nAChR density in the nucleus accumbens (NAcc) and dorsal striatum in NQ and NS animals sensitized to nicotine. Male and female Sprague-Dawley rats were neonatally treated with quinpirole (1mg/kg) or saline from postnatal days (P)1-21. Animals were given ip injections of either saline or nicotine (0.5mg/kg free base) every second day from P33 to P49 and tested on behavioral sensitization. Before each injection, animals were ip administered the α7 nAChR antagonist methyllycaconitine (MLA; 2 or 4mg/kg) or the α4β2 nAChR antagonist dihydro beta erythroidine (DhβE; 1 or 3mg/kg). Results revealed NQ enhanced nicotine sensitization that was blocked by DhβE. MLA blocked the enhanced nicotine sensitization in NQ animals, but did not block nicotine sensitization. NQ enhanced the NAcc BDNF response to nicotine which was blocked by both antagonists. In Experiment 2, NQ enhanced nicotine sensitization and enhanced α4β2, but not α7, nAChR upregulation in the NAcc. These results suggest a relationship between accumbal BDNF and α4β2 nAChRs and their role in the behavioral response to nicotine in the NQ model which has relevance to schizophrenia, a behavioral disorder with high rates of tobacco smoking. Copyright © 2017. Published by Elsevier B.V.

  8. Enhancement of the efficacy of x-irradiation by pentobarbital in a rodent brain-tumor model

    International Nuclear Information System (INIS)

    Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H.

    1990-01-01

    Radiation therapy is an important component of brain tumor treatment, but its efficacy is limited by its toxicity to the surrounding normal tissue. Pentobarbital acts as a cerebral radioprotectant, but the selectivity of its protection for the central nervous system has not been demonstrated. To determine if pentobarbital also protects tumor against ionizing radiation, five groups of Fischer 344 rats were observed after exposure to varying combinations of the presence or absence of implanted tumor, pentobarbital, and radiation treatment. The first three groups underwent cerebral implantations of a suspension of 9L gliosarcoma cells. Group 1 was left untreated and served as tumor-bearing controls. Group 2 received 30 Gy of whole-brain x-irradiation without anesthesia 8 days after tumor implantation. Group 3 received the same radiation treatment 15 minutes after pretreatment with 60 mg/kg of pentobarbital intraperitoneally. Groups 4 and 5 served as radiation controls, receiving 30 Gy of x-irradiation while awake and 30 Gy of x-irradiation after pentobarbital administration, respectively. Survival was calculated from the death of the last tumor-bearing rat. The mean survival time in tumor-bearing control rats was 20.8 +/- 2.6 days (+/- standard deviation). X-irradiation alone significantly enhanced the period of survival in rats implanted with the 9L tumor (29.7 +/- 5.6 days, p less than 0.03). Further significant prolongation of survival was seen with the addition of pentobarbital to the treatment regimen (39.9 +/- 13.5 days, p less than 0.01). Nontumor-bearing rats irradiated while awake (Group 4) survived 30.9 +/- 2.3 days. All of their pentobarbital-anesthetized counterparts in Group 5 survived. If pentobarbital had offered radioprotection to the tumor, then Group 3 would have had a shorter survival period than Group 2

  9. Modeling cellular systems

    CERN Document Server

    Matthäus, Franziska; Pahle, Jürgen

    2017-01-01

    This contributed volume comprises research articles and reviews on topics connected to the mathematical modeling of cellular systems. These contributions cover signaling pathways, stochastic effects, cell motility and mechanics, pattern formation processes, as well as multi-scale approaches. All authors attended the workshop on "Modeling Cellular Systems" which took place in Heidelberg in October 2014. The target audience primarily comprises researchers and experts in the field, but the book may also be beneficial for graduate students.

  10. Assessment of symptomatic and neuroprotective efficacy of Mucuna pruriens seed extract in rodent model of Parkinson's disease.

    Science.gov (United States)

    Kasture, Sanjay; Pontis, Silvia; Pinna, Annalisa; Schintu, Nicoletta; Spina, Liliana; Longoni, Rosanna; Simola, Nicola; Ballero, Mauro; Morelli, Micaela

    2009-02-01

    , indicating the lack of components characterized by rewarding effects in the extract. Finally, in a subchronic mice model of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine hydrochloride (MPTP)-induced dopamine neuron degeneration, MP extract did not prove capable of preventing either tyrosine hydroxylase decrease induced by MPTP or astroglial or microglial activation as assessed by means of GFAP and CD11b immunohistochemistry, supporting the absence of neuroprotective effects by MP. Characterization MP extract strongly supports its antiparkinsonian activity.

  11. Astrogliosis has Different Dynamics after Cell Transplantation and Mechanical Impact in the Rodent Model of Parkinson‘s Disease

    Directory of Open Access Journals (Sweden)

    Nikola Tomov

    2018-03-01

    Full Text Available Background: Transplantation of fetal mesencephalic tissue is a well-established concept for functional reinnervation of the dopamine-depleted rat striatum. However, there is no extensive description of the glial response of the host brain following this procedure. Aims: The present study aimed to quantitatively and qualitatively analyse astrogliosis surrounding intrastriatal grafts and compare it to the reaction to mechanical injury with the transplantation instrument only. Study Design: Animal experimentation. Methods: The standard 6-hydroxydopamine-induced unilateral model of Parkinson's disease was used. The experimental animals received transplantation of a single-cell suspension of E14 ventral mesencephalic tissue. Control animals (sham-transplanted were subjected to injury by the transplantation cannula, without injection of a cell suspension. Histological analyses were carried out 7 and 28 days following the procedure by immunohistochemistry assays for tyrosine hydroxylase and glial fibrillary acidic protein. To evaluate astrogliosis, the cell density and immunopositive area were measured in distinct zones within and surrounding the grafts or the cannula tract. Results: Statistical analysis revealed that astrogliosis in the grafted striatum increased from day 7 to day 28, as shown by a significant change in both cell density and the immunopositive area. The cell density increased from 816.7±370.6 to 1403±272.1 cells/mm2 (p<0.0001 аnd from 523±245.9 to 1164±304.8 cells/mm2 (p<0.0001 in the two zones in the graft core, and from 1151±218.6 to 1485±210.6 cells/mm2 (p<0.05 for the zone in the striatum immediately adjacent to the graft. The glial fibrillary acidic protein-expressing area increased from 0.3109±0.1843 to 0.7949±0.1910 (p<0.0001 and from 0.1449±0.1240 to 0.702±0.2558 (p<0.0001 for the same zones in the graft core, and from 0.5277±0.1502 to 0.6969±0.1223 (p<0.0001 for the same area adjacent to the graft zone. However

  12. Astrogliosis has Different Dynamics after Cell Transplantation and Mechanical Impact in the Rodent Model of Parkinson‘s Disease

    Directory of Open Access Journals (Sweden)

    Nikola Tomov

    2018-03-01

    Full Text Available Background: Transplantation of fetal mesencephalic tissue is a well-established concept for functional reinnervation of the dopamine-depleted rat striatum. However, there is no extensive description of the glial response of the host brain following this procedure. Aims: The present study aimed to quantitatively and qualitatively analyse astrogliosis surrounding intrastriatal grafts and compare it to the reaction to mechanical injury with the transplantation instrument only. Study Design: Animal experimentation. Methods: The standard 6-hydroxydopamine-induced unilateral model of Parkinson’s disease was used. The experimental animals received transplantation of a single-cell suspension of E14 ventral mesencephalic tissue. Control animals (sham-transplanted were subjected to injury by the transplantation cannula, without injection of a cell suspension. Histological analyses were carried out 7 and 28 days following the procedure by immunohistochemistry assays for tyrosine hydroxylase and glial fibrillary acidic protein. To evaluate astrogliosis, the cell density and immunopositive area were measured in distinct zones within and surrounding the grafts or the cannula tract. Results: Statistical analysis revealed that astrogliosis in the grafted striatum increased from day 7 to day 28, as shown by a significant change in both cell density and the immunopositive area. The cell density increased from 816.7±370.6 to 1403±272.1 cells/mm2 (p<0.0001 аnd from 523±245.9 to 1164±304.8 cells/mm2 (p<0.0001 in the two zones in the graft core, and from 1151±218.6 to 1485±210.6 cells/mm2 (p<0.05 for the zone in the striatum immediately adjacent to the graft. The glial fibrillary acidic protein-expressing area increased from 0.3109±0.1843 to 0.7949±0.1910 (p<0.0001 and from 0.1449±0.1240 to 0.702±0.2558 (p<0.0001 for the same zones in the graft core, and from 0.5277±0.1502 to 0.6969±0.1223 (p<0.0001 for the same area adjacent to the graft zone. However

  13. Network Analysis of Rodent Transcriptomes in Spaceflight

    Science.gov (United States)

    Ramachandran, Maya; Fogle, Homer; Costes, Sylvain

    2017-01-01

    Network analysis methods leverage prior knowledge of cellular systems and the statistical and conceptual relationships between analyte measurements to determine gene connectivity. Correlation and conditional metrics are used to infer a network topology and provide a systems-level context for cellular responses. Integration across multiple experimental conditions and omics domains can reveal the regulatory mechanisms that underlie gene expression. GeneLab has assembled rich multi-omic (transcriptomics, proteomics, epigenomics, and epitranscriptomics) datasets for multiple murine tissues from the Rodent Research 1 (RR-1) experiment. RR-1 assesses the impact of 37 days of spaceflight on gene expression across a variety of tissue types, such as adrenal glands, quadriceps, gastrocnemius, tibalius anterior, extensor digitorum longus, soleus, eye, and kidney. Network analysis is particularly useful for RR-1 -omics datasets because it reinforces subtle relationships that may be overlooked in isolated analyses and subdues confounding factors. Our objective is to use network analysis to determine potential target nodes for therapeutic intervention and identify similarities with existing disease models. Multiple network algorithms are used for a higher confidence consensus.

  14. The rodent ultrasound production mechanism.

    Science.gov (United States)

    Roberts, L H

    1975-03-01

    Rodents produce two types of sounds, audible and ultrasonic, that differ markedly in physical structure. Studies of sound production in light gases show that whereas the audible cries appear to be produced, as in the case of most other mammals, by vibrating structures in the larynx, the ultrasonic cries are produced by a different mechanism, probably a whistle. 'Bird-call' whistles are shown to have all the properties of rodent ultrasonic cries and to mimic them in almost every detail. Thus it is concluded that rodents have two distinct sound production mechanisms, one for audible cries and one for ultrasonic cries.

  15. Modeling Sustainable Food Systems.

    Science.gov (United States)

    Allen, Thomas; Prosperi, Paolo

    2016-05-01

    The processes underlying environmental, economic, and social unsustainability derive in part from the food system. Building sustainable food systems has become a predominating endeavor aiming to redirect our food systems and policies towards better-adjusted goals and improved societal welfare. Food systems are complex social-ecological systems involving multiple interactions between human and natural components. Policy needs to encourage public perception of humanity and nature as interdependent and interacting. The systemic nature of these interdependencies and interactions calls for systems approaches and integrated assessment tools. Identifying and modeling the intrinsic properties of the food system that will ensure its essential outcomes are maintained or enhanced over time and across generations, will help organizations and governmental institutions to track progress towards sustainability, and set policies that encourage positive transformations. This paper proposes a conceptual model that articulates crucial vulnerability and resilience factors to global environmental and socio-economic changes, postulating specific food and nutrition security issues as priority outcomes of food systems. By acknowledging the systemic nature of sustainability, this approach allows consideration of causal factor dynamics. In a stepwise approach, a logical application is schematized for three Mediterranean countries, namely Spain, France, and Italy.

  16. Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-ι

    Science.gov (United States)

    Sajan, Mini P.; Nimal, Sonali; Mastorides, Stephen; Acevedo-Duncan, Mildred; Kahn, C. Ronald; Fields, Alan P.; Braun, Ursula; Leitges, Michael; Farese, Robert V.

    2013-01-01

    Excessive activity of hepatic atypical protein kinase (aPKC) is proposed to play a critical role in mediating lipid and carbohydrate abnormalities in obesity, the metabolic syndrome, and type 2 diabetes mellitus. In previous studies of rodent models of obesity and type 2 diabetes mellitus, adenoviral-mediated expression of kinase-inactive aPKC rapidly reversed or markedly improved most if not all metabolic abnormalities. Here, we examined effects of 2 newly developed small-molecule PKC-ι/λ inhibitors. We used the mouse model of heterozygous muscle-specific knockout of PKC-λ, in which partial deficiency of muscle PKC-λ impairs glucose transport in muscle and thereby causes glucose intolerance and hyperinsulinemia, which, via hepatic aPKC activation, leads to abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. One inhibitor, 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)], binds to the substrate-binding site of PKC-λ/ι, but not other PKCs. The other inhibitor, aurothiomalate, binds to cysteine residues in the PBl-binding domains of aPKC-λ/ι/ζ and inhibits scaffolding. Treatment with either inhibitor for 7 days inhibited aPKC, but not Akt, in liver and concomitantly improved insulin signaling to Akt and aPKC in muscle and adipocytes. Moreover, both inhibitors diminished excessive expression of hepatic, aPKC-dependent lipogenic, proinflammatory, and gluconeogenic factors; and this was accompanied by reversal or marked improvements in hyperglycemia, hyperinsulinemia, abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. Our findings highlight the pathogenetic importance of insulin signaling to hepatic PKC-ι in obesity, the metabolic syndrome, and type 2 diabetes mellitus and suggest that 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)] and aurothiomalate or similar agents that

  17. Immunogenicity and Protective Efficacy of Brugia malayi Heavy Chain Myosin as Homologous DNA, Protein and Heterologous DNA/Protein Prime Boost Vaccine in Rodent Model.

    Directory of Open Access Journals (Sweden)

    Jyoti Gupta

    Full Text Available We earlier demonstrated the immunoprophylactic efficacy of recombinant heavy chain myosin (Bm-Myo of Brugia malayi (B. malayi in rodent models. In the current study, further attempts have been made to improve this efficacy by employing alternate approaches such as homologous DNA (pcD-Myo and heterologous DNA/protein prime boost (pcD-Myo+Bm-Myo in BALB/c mouse model. The gene bm-myo was cloned in a mammalian expression vector pcDNA 3.1(+ and protein expression was confirmed in mammalian Vero cell line. A significant degree of protection (79.2%±2.32 against L3 challenge in pcD-Myo+Bm-Myo immunized group was observed which was much higher than that exerted by Bm-Myo (66.6%±2.23 and pcD-Myo (41.6%±2.45. In the heterologous immunized group, the percentage of peritoneal leukocytes such as macrophages, neutrophils, B cells and T cells marginally increased and their population augmented further significantly following L3 challenge. pcD-Myo+Bm-Myo immunization elicited robust cellular and humoral immune responses as compared to pcD-Myo and Bm-Myo groups as evidenced by an increased accumulation of CD4+, CD8+ T cells and CD19+ B cells in the mouse spleen and activation of peritoneal macrophages. Though immunized animals produced antigen-specific IgG antibodies and isotypes, sera of mice receiving pcD-Myo+Bm-Myo or Bm-Myo developed much higher antibody levels than other groups and there was profound antibody-dependent cellular adhesion and cytotoxicity (ADCC to B. malayi infective larvae (L3. pcD-Myo+Bm-Myo as well as Bm-Myo mice generated a mixed T helper cell phenotype as evidenced by the production of both pro-inflammatory (IL-2, IFN-γ and anti-inflammatory (IL-4, IL-10 cytokines. Mice receiving pcD-Myo on contrary displayed a polarized pro-inflammatory immune response. The findings suggest that the priming of animals with DNA followed by protein booster generates heightened and mixed pro- and anti-inflammatory immune responses that are capable of

  18. Modeling Complex Systems

    CERN Document Server

    Boccara, Nino

    2010-01-01

    Modeling Complex Systems, 2nd Edition, explores the process of modeling complex systems, providing examples from such diverse fields as ecology, epidemiology, sociology, seismology, and economics. It illustrates how models of complex systems are built and provides indispensable mathematical tools for studying their dynamics. This vital introductory text is useful for advanced undergraduate students in various scientific disciplines, and serves as an important reference book for graduate students and young researchers. This enhanced second edition includes: . -recent research results and bibliographic references -extra footnotes which provide biographical information on cited scientists who have made significant contributions to the field -new and improved worked-out examples to aid a student’s comprehension of the content -exercises to challenge the reader and complement the material Nino Boccara is also the author of Essentials of Mathematica: With Applications to Mathematics and Physics (Springer, 2007).

  19. Using Geographic Information System-based Ecologic Niche Models to Forecast the Risk of Hantavirus Infection in Shandong Province, China

    Science.gov (United States)

    Wei, Lan; Qian, Quan; Wang, Zhi-Qiang; Glass, Gregory E.; Song, Shao-Xia; Zhang, Wen-Yi; Li, Xiu-Jun; Yang, Hong; Wang, Xian-Jun; Fang, Li-Qun; Cao, Wu-Chun

    2011-01-01

    Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in Shandong Province, China. In this study, we combined ecologic niche modeling with geographic information systems (GIS) and remote sensing techniques to identify the risk factors and affected areas of hantavirus infections in rodent hosts. Land cover and elevation were found to be closely associated with the presence of hantavirus-infected rodent hosts. The averaged area under the receiver operating characteristic curve was 0.864, implying good performance. The predicted risk maps based on the model were validated both by the hantavirus-infected rodents' distribution and HFRS human case localities with a good fit. These findings have the applications for targeting control and prevention efforts. PMID:21363991

  20. Modeling Complex Systems

    International Nuclear Information System (INIS)

    Schreckenberg, M

    2004-01-01

    This book by Nino Boccara presents a compilation of model systems commonly termed as 'complex'. It starts with a definition of the systems under consideration and how to build up a model to describe the complex dynamics. The subsequent chapters are devoted to various categories of mean-field type models (differential and recurrence equations, chaos) and of agent-based models (cellular automata, networks and power-law distributions). Each chapter is supplemented by a number of exercises and their solutions. The table of contents looks a little arbitrary but the author took the most prominent model systems investigated over the years (and up until now there has been no unified theory covering the various aspects of complex dynamics). The model systems are explained by looking at a number of applications in various fields. The book is written as a textbook for interested students as well as serving as a comprehensive reference for experts. It is an ideal source for topics to be presented in a lecture on dynamics of complex systems. This is the first book on this 'wide' topic and I have long awaited such a book (in fact I planned to write it myself but this is much better than I could ever have written it!). Only section 6 on cellular automata is a little too limited to the author's point of view and one would have expected more about the famous Domany-Kinzel model (and more accurate citation!). In my opinion this is one of the best textbooks published during the last decade and even experts can learn a lot from it. Hopefully there will be an actualization after, say, five years since this field is growing so quickly. The price is too high for students but this, unfortunately, is the normal case today. Nevertheless I think it will be a great success! (book review)

  1. Modeling the earth system

    Energy Technology Data Exchange (ETDEWEB)

    Ojima, D. [ed.

    1992-12-31

    The 1990 Global Change Institute (GCI) on Earth System Modeling is the third of a series organized by the Office for Interdisciplinary Earth Studies to look in depth at particular issues critical to developing a better understanding of the earth system. The 1990 GCI on Earth System Modeling was organized around three themes: defining critical gaps in the knowledge of the earth system, developing simplified working models, and validating comprehensive system models. This book is divided into three sections that reflect these themes. Each section begins with a set of background papers offering a brief tutorial on the subject, followed by working group reports developed during the institute. These reports summarize the joint ideas and recommendations of the participants and bring to bear the interdisciplinary perspective that imbued the institute. Since the conclusion of the 1990 Global Change Institute, research programs, nationally and internationally, have moved forward to implement a number of the recommendations made at the institute, and many of the participants have maintained collegial interactions to develop research projects addressing the needs identified during the two weeks in Snowmass.

  2. Sex differences in behavioral outcome following neonatal hypoxia ischemia: insights from a clinical meta-analysis and a rodent model of induced hypoxic ischemic brain injury.

    Science.gov (United States)

    Smith, Amanda L; Alexander, Michelle; Rosenkrantz, Ted S; Sadek, Mona Lisa; Fitch, R Holly

    2014-04-01

    Hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) is one of the most common injuries among preterm infants and term infants with birth complications. Both populations show cognitive/behavioral deficits, including impairments in sensory, learning/memory, and attention domains. Clinical data suggests a sex difference in HI outcomes, with males exhibiting more severe cognitive/behavioral deficits relative to matched females. Our laboratory has also reported more severe behavioral deficits among male rats with induced HI relative to females with comparable injury (Hill et al., 2011a,b). The current study initially examined published clinical studies from the past 20years where long-term IQ outcome scores for matched groups of male and female premature infants were reported separately (IQ being the most common outcome measure). A meta-analysis revealed a female "advantage," as indicated by significantly better scores on performance and full scale IQ (but not verbal IQ) for premature females. We then utilized a rodent model of neonatal HI injury to assess sham and postnatal day 7 (P7) HI male and female rats on a battery of behavioral tasks. Results showed expected deficits in HI male rats, but also showed task-dependent sex differences, with HI males having significantly larger deficits than HI females on some tasks but equivalent deficits on other tasks. In contrast to behavioral results, post mortem neuropathology associated with HI was comparable across sex. These findings suggest: 1) neonatal female "protection" in some behavioral domains, as indexed by superior outcome following early injury relative to males; and 2) female protection may entail sex-specific plasticity or compensation, rather than a reduction in gross neuropathology. Further exploration of the mechanisms underlying this sex effect could aid in neuroprotection efforts for at-risk neonates in general, and males in particular. Moreover, our current report of comparable anatomical

  3. Effects of rodent community diversity and composition on prevalence of an endemic bacterial pathogen - Bartonella

    Science.gov (United States)

    Bai, Y.; Kosoy, M.Y.; Calisher, C.H.; Cully, J.F.; Collinge, S.K.

    2009-01-01

    By studying Bartonella prevalence in rodent communities from 23 geographic sites in the western United States and one site in northern Mexico, the present study focused on the effects of rodent community diversity (measured by richness and Shannon index) and composition on prevalence of Bartonella infections. The analysis showed negative correlations of Bartonella prevalence with rodent richness and Shannon index. Further, Bartonella prevalence varied among rodent genera/species. Three models were applied to explain the observations. (1) Within-species/genus transmission: Bartonella strains usually are host-specific and adding non-host species would decrease Bartonella prevalence in its principal host through reduction of host contact (encounter reduction); (2) Frequency-dependence: Adding hosts would decrease the proportion of all infected individuals in the community, resulting in a reduction in the number of contacts between susceptible and infected individuals that usually leads to transmission (transmission reduction); and (3) Dominant species effect: Dominant species, if not susceptible to Bartonellae, can constrain the abundance of susceptible hosts (susceptible host regulation). These mechanisms work in concert; and the level of Bartonella prevalence is an outcome of regulation of all of these mechanisms on the entire system.

  4. System equivalent model mixing

    Science.gov (United States)

    Klaassen, Steven W. B.; van der Seijs, Maarten V.; de Klerk, Dennis

    2018-05-01

    This paper introduces SEMM: a method based on Frequency Based Substructuring (FBS) techniques that enables the construction of hybrid dynamic models. With System Equivalent Model Mixing (SEMM) frequency based models, either of numerical or experimental nature, can be mixed to form a hybrid model. This model follows the dynamic behaviour of a predefined weighted master model. A large variety of applications can be thought of, such as the DoF-space expansion of relatively small experimental models using numerical models, or the blending of different models in the frequency spectrum. SEMM is outlined, both mathematically and conceptually, based on a notation commonly used in FBS. A critical physical interpretation of the theory is provided next, along with a comparison to similar techniques; namely DoF expansion techniques. SEMM's concept is further illustrated by means of a numerical example. It will become apparent that the basic method of SEMM has some shortcomings which warrant a few extensions to the method. One of the main applications is tested in a practical case, performed on a validated benchmark structure; it will emphasize the practicality of the method.

  5. Bone morphology of the hind limbs in two caviomorph rodents.

    Science.gov (United States)

    de Araújo, F A P; Sesoko, N F; Rahal, S C; Teixeira, C R; Müller, T R; Machado, M R F

    2013-04-01

    In order to evaluate the hind limbs of caviomorph rodents a descriptive analysis of the Cuniculus paca (Linnaeus, 1766) and Hydrochoerus hydrochaeris (Linnaeus, 1766) was performed using anatomical specimens, radiography, computed tomography (CT) and full-coloured prototype models to generate bone anatomy data. The appendicular skeleton of the two largest rodents of Neotropical America was compared with the previously reported anatomical features of Rattus norvegicus (Berkenhout, 1769) and domestic Cavia porcellus (Linnaeus, 1758). The structures were analyzed macroscopically and particular findings of each species reported. Features including the presence of articular fibular projection and lunulae were observed in the stifle joint of all rodents. Imaging aided in anatomical description and, specifically in the identification of bone structures in Cuniculus paca and Hydrochoerus hydrochaeris. The imaging findings were correlated with the anatomical structures observed. The data may be used in future studies comparing these animals to other rodents and mammalian species. © 2012 Blackwell Verlag GmbH.

  6. Mechanical Systems, Classical Models

    CERN Document Server

    Teodorescu, Petre P

    2009-01-01

    This third volume completes the Work Mechanical Systems, Classical Models. The first two volumes dealt with particle dynamics and with discrete and continuous mechanical systems. The present volume studies analytical mechanics. Topics like Lagrangian and Hamiltonian mechanics, the Hamilton-Jacobi method, and a study of systems with separate variables are thoroughly discussed. Also included are variational principles and canonical transformations, integral invariants and exterior differential calculus, and particular attention is given to non-holonomic mechanical systems. The author explains in detail all important aspects of the science of mechanics, regarded as a natural science, and shows how they are useful in understanding important natural phenomena and solving problems of interest in applied and engineering sciences. Professor Teodorescu has spent more than fifty years as a Professor of Mechanics at the University of Bucharest and this book relies on the extensive literature on the subject as well as th...

  7. Obesidade induzida por consumo de dieta: modelo em roedores para o estudo dos distúrbios relacionados com a obesidade Diet-induced obesity: rodent model for the study of obesity-related disorders

    Directory of Open Access Journals (Sweden)

    Tiago Campos Rosini

    2012-06-01

    mostly to genetic mutations, but this model is far from that found in humans. The use of hypercaloric or hyperlipidemic diets has been used as a model of obesity induction in animals, because of its similarity to the genesis and metabolic responses caused by obesity in humans. The objective of this review is to show the different types of diets used to induce obesity in rodents, the induced metabolic alterations, and to identify some points that should be taken into account so that the model can be effective for the study of obesity-related complications. A search was performed in the PubMed database using the following keywords: 1- "hypercaloric diet" AND "rodent", 2- "hyperlipidic diet" AND "rodent", selecting those considered the most relevant according to the following criteria: date of publication (1995-2011; the use of wild-type animals; detailed description of the diet used and analysis of biochemical and vascular parameters of interest. References were included to introduce subjects such as the increased prevalence of obesity and questions related to the genesis of obesity in humans. The model of diet-induced obesity in rodents can be considered effective when the objective is the study of the physiopathology of metabolic and vascular complications associated with obesity.

  8. Synaptic Vesicle Endocytosis in Different Model Systems

    Directory of Open Access Journals (Sweden)

    Quan Gan

    2018-06-01

    Full Text Available Neurotransmission in complex animals depends on a choir of functionally distinct synapses releasing neurotransmitters in a highly coordinated manner. During synaptic signaling, vesicles fuse with the plasma membrane to release their contents. The rate of vesicle fusion is high and can exceed the rate at which synaptic vesicles can be re-supplied by distant sources. Thus, local compensatory endocytosis is needed to replenish the synaptic vesicle pools. Over the last four decades, various experimental methods and model systems have been used to study the cellular and molecular mechanisms underlying synaptic vesicle cycle. Clathrin-mediated endocytosis is thought to be the predominant mechanism for synaptic vesicle recycling. However, recent studies suggest significant contribution from other modes of endocytosis, including fast compensatory endocytosis, activity-dependent bulk endocytosis, ultrafast endocytosis, as well as kiss-and-run. Currently, it is not clear whether a universal model of vesicle recycling exist for all types of synapses. It is possible that each synapse type employs a particular mode of endocytosis. Alternatively, multiple modes of endocytosis operate at the same synapse, and the synapse toggles between different modes depending on its activity level. Here we compile review and research articles based on well-characterized model systems: frog neuromuscular junctions, C. elegans neuromuscular junctions, Drosophila neuromuscular junctions, lamprey reticulospinal giant axons, goldfish retinal ribbon synapses, the calyx of Held, and rodent hippocampal synapses. We will compare these systems in terms of their known modes and kinetics of synaptic vesicle endocytosis, as well as the underlying molecular machineries. We will also provide the future development of this field.

  9. Modeling dental radiographic systems

    International Nuclear Information System (INIS)

    Webber, R.L.

    1980-01-01

    The Bureau of Radiological Health has been actively collaborating with the Clinical Investigations Branch, NIDR, in applied research involving diagnostic use of ionizing radiation in dentistry. This work has centered on the search for alternatives to conventional radiographic systems in an attempt to improve diagnostic performance while reducing the required exposure. The basic approach involves analysis of factors limiting performance of properly defined diagnostic tasks and the modeling alternative systems with an eye toward increasing objective measures of performance. Previous collaborative work involved using a nonlinear model to compare various x-ray spectra. The data were expressed as brightness-contrast versus exposure for simulated tasks of clinical interest. This report supplements these findings by extending the number of parameters under investigation and modifying the mode of data display so that an actual radiographic image can be simulated on a television screen

  10. Modeling Novo Nordisk Production Systems

    DEFF Research Database (Denmark)

    Miller, Thomas Dedenroth

    1997-01-01

    This report describes attributes of models and systems, and how models can be used for description of production systems. There are special attention on the 'Theory of Domains'.......This report describes attributes of models and systems, and how models can be used for description of production systems. There are special attention on the 'Theory of Domains'....

  11. Template based rodent brain extraction and atlas mapping.

    Science.gov (United States)

    Weimin Huang; Jiaqi Zhang; Zhiping Lin; Su Huang; Yuping Duan; Zhongkang Lu

    2016-08-01

    Accurate rodent brain extraction is the basic step for many translational studies using MR imaging. This paper presents a template based approach with multi-expert refinement to automatic rodent brain extraction. We first build the brain appearance model based on the learning exemplars. Together with the template matching, we encode the rodent brain position into the search space to reliably locate the rodent brain and estimate the rough segmentation. With the initial mask, a level-set segmentation and a mask-based template learning are implemented further to the brain region. The multi-expert fusion is used to generate a new mask. We finally combine the region growing based on the histogram distribution learning to delineate the final brain mask. A high-resolution rodent atlas is used to illustrate that the segmented low resolution anatomic image can be well mapped to the atlas. Tested on a public data set, all brains are located reliably and we achieve the mean Jaccard similarity score at 94.99% for brain segmentation, which is a statistically significant improvement compared to two other rodent brain extraction methods.

  12. Dendrimer-driven neurotrophin expression differs in temporal patterns between rodent and human stem cells.

    Science.gov (United States)

    Shakhbazau, Antos; Shcharbin, Dzmitry; Seviaryn, Ihar; Goncharova, Natalya; Kosmacheva, Svetlana; Potapnev, Mihail; Bryszewska, Maria; Kumar, Ranjan; Biernaskie, Jeffrey; Midha, Rajiv

    2012-05-07

    This study reports the use of a nonviral expression system based on polyamidoamine dendrimers for time-restricted neurotrophin overproduction in mesenchymal stem cells and skin precursor-derived Schwann cells. The dendrimers were used to deliver plasmids for brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) expression in both rodent and human stem cells, and the timelines of expression were studied. We have found that, despite the fact that transfection efficiencies and protein expression levels were comparable, dendrimer-driven expression in human mesenchymal stem cells was characterized by a more rapid decline compared to rodent cells. Transient expression systems can be beneficial for some neurotrophins, which were earlier reported to cause unwanted side effects in virus-based long-term expression models. Nonviral neurotrophin expression is a biologically safe and accessible alternative to increase the therapeutic potential of autologous adult stem cells and stem cell-derived functional differentiated cells.

  13. The Need for Speed in Rodent Locomotion Analyses

    Science.gov (United States)

    Batka, Richard J.; Brown, Todd J.; Mcmillan, Kathryn P.; Meadows, Rena M.; Jones, Kathryn J.; Haulcomb, Melissa M.

    2016-01-01

    Locomotion analysis is now widely used across many animal species to understand the motor defects in disease, functional recovery following neural injury, and the effectiveness of various treatments. More recently, rodent locomotion analysis has become an increasingly popular method in a diverse range of research. Speed is an inseparable aspect of locomotion that is still not fully understood, and its effects are often not properly incorporated while analyzing data. In this hybrid manuscript, we accomplish three things: (1) review the interaction between speed and locomotion variables in rodent studies, (2) comprehensively analyze the relationship between speed and 162 locomotion variables in a group of 16 wild-type mice using the CatWalk gait analysis system, and (3) develop and test a statistical method in which locomotion variables are analyzed and reported in the context of speed. Notable results include the following: (1) over 90% of variables, reported by CatWalk, were dependent on speed with an average R2 value of 0.624, (2) most variables were related to speed in a nonlinear manner, (3) current methods of controlling for speed are insufficient, and (4) the linear mixed model is an appropriate and effective statistical method for locomotion analyses that is inclusive of speed-dependent relationships. Given the pervasive dependency of locomotion variables on speed, we maintain that valid conclusions from locomotion analyses cannot be made unless they are analyzed and reported within the context of speed. PMID:24890845

  14. Screening of nanoparticulate delivery systems for the photodetection of cancer in a simple and cost-effective model.

    Science.gov (United States)

    Zeisser-Labouèbe, Magali; Delie, Florence; Gurny, Robert; Lange, Norbert

    2009-02-01

    In urology, fluorescence-based imaging methods have been proven to significantly improve the detection of small, barely visible tumors and reduce the recurrence rate. Under ethical and economical pressure, new effective screening systems have to be developed to exploit and assess novel strategies for fluorescence photodetection in other areas. For this purpose, the chorioallantoic membrane (CAM) of the developing chick embryo is an attractive alternative model to the mammalian models. Hypericin encapsulated into nanoparticles for the photodetection of ovarian metastases was evaluated in the CAM model with respect to vascular extravazation and tumor targeting and compared with free drug following intravenous administration. To validate the CAM model as a valuable screening system for photodetection of cancer, we drew a comparison with results obtained on a conventional rodent model. Rodent and CAM models led to the same conclusion regarding the benefits of nanoencapsulation to improve selective accumulation of drug in ovarian micrometastases.

  15. Prospective Preliminary In Vitro Investigation of a Magnetic Iron Oxide Nanoparticle Conjugated with Ligand CD80 and VEGF Antibody As a Targeted Drug Delivery System for the Induction of Cell Death in Rodent Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Anne Marie Kay Kovach

    2016-10-01

    Full Text Available Target drug deliveries using nanotechnology are a novel consideration in the treatment of cancer. We present herein an in vitro mouse model for the preliminary investigation of the efficacy of an iron oxide nanoparticle complex conjugated to vascular endothelial growth factor (VEGF antibody and ligand cluster of differentiation 80 (CD80 for the purpose of eventual translational applications in the treatment of human osteosarcoma (OSA. The 35 nm diameter iron oxide magnetic nanoparticles are functionalized with an n-hydroxysuccinimide biocompatible coating and are conjugated on the surface to proteins VEGF antibody and ligand CD80. Combined, these proteins have the ability to target OSA cells and induce apoptosis. The proposed system was tested on a cancerous rodent osteoblast cell line (ATCCTMNPO CRL-2836 at four different concentrations (0.1, 1.0, 10.0, and 100.0 μg/mL of ligand CD80 alone, VEGF antibody alone, and a combination thereof (CD80+VEGF. Systems were implemented every 24 h over different sequential treatment timelines: 24, 48, and 72 h, to find the optimal protein concentration required for a reduction in cell proliferation. Results demonstrated that a combination of ligand CD80 and VEGF antibody was consistently most effective at reducing aberrant osteoblastic proliferation for both the 24- and 72-h timelines. At 48 h, however, an increase in cell proliferation was documented for the 0.1 and 1 μg/mL groups. For the 24- and 72-h tests, concentrations of 1.0 μg/mL of CD80+VEGF and 0.1 μg/mL of VEGF antibody were most effective. Concentrations of 10.0 and 100.0 μg/mL of CD80+VEGF reduced cell proliferation, but not as remarkably as the 1.0 μg/mL concentration. In addition, cell proliferation data showed that multiple treatments (72-h test induced cell death in the osteoblasts better than a single treatment. Future targeted drug delivery system research includes trials in OSA cell lines from greater phylum

  16. Noninvasive near-infrared live imaging of human adult mesenchymal stem cells transplanted in a rodent model of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Bossolasco P

    2012-01-01

    Full Text Available P Bossolasco1,*, L Cova2,*, G Levandis3, V Diana2, S Cerri3, G Lambertenghi Deliliers1, E Polli1, V Silani2,4, F Blandini3, MT Armentero31Fondazione Matarelli, Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Milan, 2Department of Neurology and Laboratory of Neuroscience-IRCCS Istituto Auxologico Italiano, Cusano Milanino, 3Laboratory of Functional Neurochemistry, Interdepartmental Research Centre for Parkinson’s Disease, IRCCS National Institute of Neurology “C Mondino”, Pavia, 4Department of Neurology and Laboratory of Neuroscience, Centro “Dino Ferrari” Università degli Studi di Milano-IRCCS Istituto Auxologico Italiano, Milan, Italy *These authors contributed equally to this workBackground: We have previously shown that human mesenchymal stem cells (hMSCs can reduce toxin-induced neurodegeneration in a well characterized rodent model of Parkinson’s disease. However, the precise mechanisms, optimal cell concentration required for neuroprotection, and detailed cell tracking need to be defined. We exploited a near-infrared imaging platform to perform noninvasive tracing following transplantation of tagged hMSCs in live parkinsonian rats.Methods: hMSCs were labeled both with a membrane intercalating dye, emitting in the near-infrared 815 nm spectrum, and the nuclear counterstain, Hoechst 33258. Effects of near-infrared dye on cell metabolism and proliferation were extensively evaluated in vitro. Tagged hMSCs were then administered to parkinsonian rats bearing a 6-hydroxydopamine-induced lesion of the nigrostriatal pathway, via two alternative routes, ie, intrastriatal or intranasal, and the cells were tracked in vivo and ex vivo using near-infrared technology.Results: In vitro, NIR815 staining was stable in long-term hMSC cultures and did not interfere with cell metabolism or proliferation. A significant near-infrared signal was detectable in vivo, confined around the injection

  17. Forecasting rodent outbreaks in Africa

    DEFF Research Database (Denmark)

    Leirs, Herwig; Verhagen, Ron; Verheyen, Walter

    1996-01-01

    1. Rainfall data were collated for years preceding historical outbreaks of Mastomys rats in East Africa in order to test the hypothesis that such outbreaks occur after long dry periods. 2. Rodent outbreaks were generally not preceded by long dry periods. 3. Population dynamics of Mastomys...... natalensis rats in Tanzania are significantly affected by the distribution of rainfall during the rainy season. 4. All previous rodent outbreaks in Tanzania were preceded by abundant rainfall early in the rainy season, i.e, towards the end of the year. 5. A flow chart is constructed to assess the likelihood...

  18. Convergent and Divergent Adaptations of Subterranean Rodents

    DEFF Research Database (Denmark)

    Fang, Xiaodong

    Subterranean rodents comprise approximately 250 species that spend their entire lives in underground, unventilated tunnels, distributed along all continents except Australia and Antarctica. Subterranean rodents escape from predators and extreme climatic fluctuations in their underground habitats,...

  19. The water economy of South American desert rodents: from integrative to molecular physiological ecology.

    Science.gov (United States)

    Bozinovic, Francisco; Gallardo, Pedro

    2006-01-01

    Rodents from arid and semi-arid habitats live under conditions where the spatial and temporal availability of free water is limited, or scarce, thus forcing these rodents to deal with the problem of water conservation. The response of rodents to unproductive desert environments and water deficits has been intensively investigated in many deserts of the world. However, current understanding of the cellular, systemic and organismal physiology of water economy relies heavily on short-term, laboratory-oriented experiments, which usually focus on responses at isolated levels of biological organization. In addition, studies in small South American mammals are scarce. Indeed xeric habitats have existed in South America for a long time and it is intriguing why present day South American desert rodents do not show the wide array of adaptive traits to desert life observed for rodents on other continents. Several authors have pointed out that South American desert rodents lack physiological and energetic specialization for energy and water conservation, hypothesizing that their success is based more on behavioral and ecological strategies. We review phenotypic flexibility and physiological diversity in water flux rate, urine osmolality, and expression of water channels in South American desert-dwelling rodents. As far as we know, this is the first review of integrative studies at cellular, systemic and organismal levels. Our main conclusion is that South American desert rodents possess structural as well as physiological systems for water conservation, which are as remarkable as those found in "classical" rodents inhabiting other desert areas of the world.

  20. Guide to Commensal Rodent Control

    Science.gov (United States)

    1991-12-01

    in many detergents also fluoresce. For positive identification, place the suspect material on Urease Siom lhymol Blue test paper, moisten with water...are applied in a thin layer in protected rat and mouse r’unways, baitboxes, or tubes along walls. The powder is picked up by the rodents on their feet

  1. The Ethics of Rodent Control

    NARCIS (Netherlands)

    Meerburg, B.G.; Brom, F.W.A.; Kijlstra, A.

    2008-01-01

    Because western societies generally see animals as objects of moral concern, demands have been made on the way they are treated, e.g. during animal experimentation. In the case of rodent pests, however, inhumane control methods are often applied. This inconsistency in the human-animal relationship

  2. A biometric approach to laboratory rodent identification.

    Science.gov (United States)

    Cameron, Jens; Jacobson, Christina; Nilsson, Kenneth; Rögnvaldsson, Thorsteinn

    2007-03-01

    Individual identification of laboratory rodents typically involves invasive methods, such as tattoos, ear clips, and implanted transponders. Beyond the ethical dilemmas they may present, these methods may cause pain or distress that confounds research results. The authors describe a prototype device for biometric identification of laboratory rodents that would allow researchers to identify rodents without the complications of other methods. The device, which uses the rodent's ear blood vessel pattern as the identifier, is fast, automatic, noninvasive, and painless.

  3. 21 CFR 1250.96 - Rodent control.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Rodent control. 1250.96 Section 1250.96 Food and... SANITATION Sanitation Facilities and Conditions on Vessels § 1250.96 Rodent control. Vessels shall be... of rodent control. ...

  4. Central nervous system radiation injury in small animal models

    International Nuclear Information System (INIS)

    Kogel, A.J. van der

    1991-01-01

    Experimental studies on radiation injury in the central nervous system have been carried out in many species ranging from mouse to monkey. This review is restricted to studies in rodents irradiated with low linear energy transfer (LET) radiation. In this paper, the various rodent models of brain and spinal cord injury are described with particular emphasis on the pathology of different types of lesions and theories of their pathogenesis. Many of the initial studies were limited to relatively high single doses, but in later work more clinically relevant fractionated irradiation schemes were employed. This has led to the recognition of various types of early and late delayed injury that are analogous to the syndromes observed in humans. Two main pathways have been suggested for the pathogenesis, one involving predominantly the progressive loss of glial cells and the other involving vascular injury. The relative importance of both mechanisms will be discussed with respect to treatment conditions and to dose level in particular. An hypothesis is presented concerning the possible role of different cell types in the development of specific syndromes

  5. In vivo microCT imaging of rodent cerebral vasculature

    International Nuclear Information System (INIS)

    Seo, Youngho; Hasegawa, Bruce H; Hashimoto, Tomoki; Nuki, Yoshitsugu

    2008-01-01

    Computed tomography (CT) remains a critical diagnostic tool for evaluating patients with cerebrovascular disease, and the advent of specialized systems for imaging rodents has extended these techniques to small animal models of these diseases. We therefore have evaluated in vivo methods of imaging rat models of hemorrhagic stroke using a high resolution compact computed tomography ('microCT') system (FLEX(tm) X-O(tm), Gamma Medica-Ideas, Northridge, CA). For all in vivo studies, the head of the anesthetized rat was secured in a custom immobilization device for microCT imaging with 512 projections over 2 min at 60 kVp and 0.530 mA (I tube x t/rotation = 63.6 mAs). First, imaging without iodinated contrast was performed (a) to differentiate the effect of contrast agent in contrast-enhanced CT and (b) to examine the effectiveness of the immobilization device between two time points of CT acquisitions. Then, contrast-enhanced CT was performed with continuous administration of iopromide (300 mgI ml -1 at 1.2 ml min -1 ) to visualize aneurysms and other vascular formations in the carotid and cerebral arteries that may precede subarachnoid hemorrhage. The accuracy of registration between the noncontrast and contrast-enhanced CT images with the immobilization device was compared against the images aligned with normalized mutual information using FMRIB's linear image registration tool (FLIRT). Translations and rotations were examined between the FLIRT-aligned noncontrast CT image and the nonaligned noncontrast CT image. These two data sets demonstrated translational and rotational differences of less than 0.5 voxel (∼85 μm) and 0.5 deg., respectively. Noncontrast CT demonstrated a very small volume (0.1 ml) of femoral arterial blood introduced surgically into the rodent brain. Continuous administration of iopromide during the CT acquisition produced consistent vascular contrast in the reconstructed CT images. As a result, carotid arteries and major cerebral blood vessels

  6. In vivo microCT imaging of rodent cerebral vasculature

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Youngho; Hasegawa, Bruce H [Center for Molecular and Functional Imaging, Department of Radiology, University of California, San Francisco, CA 94143 (United States); Hashimoto, Tomoki; Nuki, Yoshitsugu [Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143 (United States)], E-mail: youngho.seo@radiology.ucsf.edu

    2008-04-07

    Computed tomography (CT) remains a critical diagnostic tool for evaluating patients with cerebrovascular disease, and the advent of specialized systems for imaging rodents has extended these techniques to small animal models of these diseases. We therefore have evaluated in vivo methods of imaging rat models of hemorrhagic stroke using a high resolution compact computed tomography ('microCT') system (FLEX(tm) X-O(tm), Gamma Medica-Ideas, Northridge, CA). For all in vivo studies, the head of the anesthetized rat was secured in a custom immobilization device for microCT imaging with 512 projections over 2 min at 60 kVp and 0.530 mA (I{sub tube} x t/rotation = 63.6 mAs). First, imaging without iodinated contrast was performed (a) to differentiate the effect of contrast agent in contrast-enhanced CT and (b) to examine the effectiveness of the immobilization device between two time points of CT acquisitions. Then, contrast-enhanced CT was performed with continuous administration of iopromide (300 mgI ml{sup -1} at 1.2 ml min{sup -1}) to visualize aneurysms and other vascular formations in the carotid and cerebral arteries that may precede subarachnoid hemorrhage. The accuracy of registration between the noncontrast and contrast-enhanced CT images with the immobilization device was compared against the images aligned with normalized mutual information using FMRIB's linear image registration tool (FLIRT). Translations and rotations were examined between the FLIRT-aligned noncontrast CT image and the nonaligned noncontrast CT image. These two data sets demonstrated translational and rotational differences of less than 0.5 voxel ({approx}85 {mu}m) and 0.5 deg., respectively. Noncontrast CT demonstrated a very small volume (0.1 ml) of femoral arterial blood introduced surgically into the rodent brain. Continuous administration of iopromide during the CT acquisition produced consistent vascular contrast in the reconstructed CT images. As a result, carotid

  7. Effects of Climate and Rodent Factors on Hemorrhagic Fever with Renal Syndrome in Chongqing, China, 1997-2008.

    Directory of Open Access Journals (Sweden)

    Yuntao Bai

    Full Text Available China has the highest global incidence of hemorrhagic fever with renal syndrome (HFRS, constituting 90% of the cases in the world. Chongqing, located in the Three Gorges Reservoir Region, has been experiencing differences in the occurrence of HFRS from 1997 to 2008. The current study was designed to explore the effects of climate and rodent factors on the transmission of HFRS in Chongqing. Data on monthly HFRS cases, rodent strains, and climatic factors were collected from 1997 to 2008. Spatio-temporal analysis indicated that most HFRS cases were clustered in central Chongqing and that the incidence of HFRS decreased from 1997 to 2008. Poisson regression models showed that temperature (with lagged months of 0 and 5 and rainfall (with 2 lagged months were key climatic factors contributing to the transmission of HFRS. A zero-inflated negative binomial model revealed that rodent density was also significantly associated with the occurrence of HFRS in the Changshou district. The monthly trend in HFRS incidence was positively associated with rodent density and rainfall and negatively associated with temperature. Possible mechanisms are proposed through which construction of the dam influenced the incidence of HFRS in Chongqing. The findings of this study may contribute to the development of early warning systems for the control and prevention of HFRS in the Three Gorges Reservoir Region.

  8. Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

    Science.gov (United States)

    Lisieski, Michael J.; Eagle, Andrew L.; Conti, Alana C.; Liberzon, Israel; Perrine, Shane A.

    2018-01-01

    Post-traumatic stress disorder (PTSD) is a common, costly, and often debilitating psychiatric condition. However, the biological mechanisms underlying this disease are still largely unknown or poorly understood. Considerable evidence indicates that PTSD results from dysfunction in highly-conserved brain systems involved in stress, anxiety, fear, and reward. Pre-clinical models of traumatic stress exposure are critical in defining the neurobiological mechanisms of PTSD, which will ultimately aid in the development of new treatments for PTSD. Single prolonged stress (SPS) is a pre-clinical model that displays behavioral, molecular, and physiological alterations that recapitulate many of the same alterations observed in PTSD, illustrating its validity and giving it utility as a model for investigating post-traumatic adaptations and pre-trauma risk and protective factors. In this manuscript, we review the present state of research using the SPS model, with the goals of (1) describing the utility of the SPS model as a tool for investigating post-trauma adaptations, (2) relating findings using the SPS model to findings in patients with PTSD, and (3) indicating research gaps and strategies to address them in order to improve our understanding of the pathophysiology of PTSD. PMID:29867615

  9. On Modelling an Immune System

    OpenAIRE

    Monroy, Raúl; Saab, Rosa; Godínez, Fernando

    2004-01-01

    Immune systems of live forms have been an abundant source of inspiration to contemporary computer scientists. Problem solving strategies, stemming from known immune system phenomena, have been successfully applied to challenging problems of modern computing. However, research in artificial immune systems has overlooked establishing a coherent model of known immune system behaviour. This paper aims reports on an preliminary computer model of an immune system, where each immune system component...

  10. Neurobiology of rodent self-grooming and its value for translational neuroscience.

    Science.gov (United States)

    Kalueff, Allan V; Stewart, Adam Michael; Song, Cai; Berridge, Kent C; Graybiel, Ann M; Fentress, John C

    2016-01-01

    Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders--including models of autism spectrum disorder and obsessive compulsive disorder--that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.

  11. Allometric disparity in rodent evolution

    OpenAIRE

    Wilson LAB

    2013-01-01

    In this study, allometric trajectories for 51 rodent species, comprising equal representatives from each of the major clades (Ctenohystrica, Muroidea, Sciuridae), are compared in a multivariate morphospace (=allometric space) to quantify magnitudes of disparity in cranial growth. Variability in allometric trajectory patterns was compared to measures of adult disparity in each clade, and dietary habit among the examined species, which together encapsulated an ecomorphological breadth. Results ...

  12. Pembangunan Model Restaurant Management System

    OpenAIRE

    Fredy Jingga; Natalia Limantara

    2014-01-01

    Model design for Restaurant Management System aims to help in restaurant business process, where Restaurant Management System (RMS) help the waitress and chef could interact each other without paper limitation.  This Restaurant Management System Model develop using Agile Methodology and developed based on PHP Programming Langguage. The database management system is using MySQL. This web-based application model will enable the waitress and the chef to interact in realtime, from the time they a...

  13. Modelling of wastewater systems

    DEFF Research Database (Denmark)

    Bechmann, Henrik

    to analyze and quantify the effect of the Aeration Tank Settling (ATS) operating mode, which is used during rain events. Furthermore, the model is used to propose a control algorithm for the phase lengths during ATS operation. The models are mainly formulated as state space model in continuous time......In this thesis, models of pollution fluxes in the inlet to 2 Danish wastewater treatment plants (WWTPs) as well as of suspended solids (SS) concentrations in the aeration tanks of an alternating WWTP and in the effluent from the aeration tanks are developed. The latter model is furthermore used...... at modelling the fluxes in terms of the multiple correlation coefficient R2. The model of the SS concentrations in the aeration tanks of an alternating WWTP as well as in the effluent from the aeration tanks is a mass balance model based on measurements of SS in one aeration tank and in the common outlet...

  14. Magnetic resonance imaging after radiofrequency ablation in a rodent model of liver tumor: tissue characterization using a novel necrosis-avid contrast agent

    International Nuclear Information System (INIS)

    Ni, Yicheng; Yu, Jie; Marchal, Guy; Chen, Feng; Mulier, Stefaan; Sun, Xihe; Landuyt, Willy; Verbruggen, Alfons

    2006-01-01

    We exploited a necrosis-avid contrast agent ECIV-7 for magnetic resonance imaging (MRI) in rodent liver tumors after radiofrequency ablation (RFA). Rats bearing liver rhabdomyosarcoma (R1) were randomly allocated to three groups: group I, complete RFA, group II, incomplete RFA, and group III, sham ablation. Within 24 h after RFA, T1-weighted (T1-w) MRI was performed before and after injection of ECIV-7 at 0.05 mmol/kg and followed up from 6-24 h. Signal intensities (SIs) were measured with relative enhancement (RE) and contrast ratio (CR) calculated. The MRI findings were verified histomorphologically. On plain T1-w MRI the contrasts between normal liver, RFA lesion, residual and/or intact tumor were vague. Early after administration of ECIV-7, the liver SI was strongly enhanced (RE=40-50%), leaving the RFA lesion as a hypointense region in groups I and II. At delayed phase, two striking peri-ablational enhancement patterns appeared (RE=90% and CR=1.89%), i.e., ''O'' type of hyperintense rim in group I and ''C'' type of incomplete rim in group II. These MRI manifestations could be proven histologically. In this study, tissue components after RFA could be characterized with discernable contrasts by necrosis-avid contrast agent (NACA)-enhanced MRI, especially at delayed phase. This approach may prove useful for defining the ablated area and identifying residual tumor after RFA. (orig.)

  15. Modeling and estimating system availability

    International Nuclear Information System (INIS)

    Gaver, D.P.; Chu, B.B.

    1976-11-01

    Mathematical models to infer the availability of various types of more or less complicated systems are described. The analyses presented are probabilistic in nature and consist of three parts: a presentation of various analytic models for availability; a means of deriving approximate probability limits on system availability; and a means of statistical inference of system availability from sparse data, using a jackknife procedure. Various low-order redundant systems are used as examples, but extension to more complex systems is not difficult

  16. Techniques and evaluation from a cross-platform imaging comparison of quantitative ultrasound parameters in an in vivo rodent fibroadenoma model.

    Science.gov (United States)

    Wirtzfeld, Lauren A; Nam, Kibo; Labyed, Yassin; Ghoshal, Goutam; Haak, Alexander; Sen-Gupta, Ellora; He, Zhi; Hirtz, Nathaniel R; Miller, Rita J; Sarwate, Sandhya; Simpson, Douglas G; Zagzebski, James A; Bigelow, Timothy A; Oelze, Michael; Hall, Timothy J; O'Brien, William D

    2013-07-01

    This contribution demonstrates that quantitative ultrasound (QUS) capabilities are platform independent, using an in vivo model. Frequency-dependent attenuation estimates, backscatter coefficient, and effective scatterer diameter estimates are shown to be comparable across four different ultrasound imaging systems with varied processing techniques. The backscatter coefficient (BSC) is a fundamental material property from which several QUS parameters are estimated; therefore, consistent BSC estimates among different systems must be demonstrated. This study is an intercomparison of BSC estimates acquired by three research groups (UIUC, UW, ISU) from four in vivo spontaneous rat mammary fibroadenomas using three clinical array systems and a single-element laboratory scanner system. Because of their highly variable backscatter properties, fibroadenomas provided an extreme test case for BSC analysis, and the comparison is across systems for each tumor, not across the highly heterogeneous tumors. RF echo data spanning the 1 to 12 MHz frequency range were acquired in three dimensions from all animals using each system. Each research group processed their RF data independently, and the resulting attenuation, BSC, and effective scatterer diameter (ESD) estimates were compared. The attenuation estimates across all systems showed the same trends and consistently fit the power-law dependence on frequency. BSCs varied among the multiple slices of data acquired by each transducer, with variations between transducers being of a similar magnitude as those from slice to slice. Variation between BSC estimates was assessed via functional signal-to-noise ratios derived from backscatter data. These functional signal-to-noise ratios indicated that BSC versus frequency variations between systems ranged from negligible compared with the noise level to roughly twice the noise level. The corresponding functional analysis of variance (fANOVA) indicated statistically significant differences

  17. Calorie restriction in rodents: Caveats to consider.

    Science.gov (United States)

    Ingram, Donald K; de Cabo, Rafael

    2017-10-01

    The calorie restriction paradigm has provided one of the most widely used and most useful tools for investigating mechanisms of aging and longevity. By far, rodent models have been employed most often in these endeavors. Over decades of investigation, claims have been made that the paradigm produces the most robust demonstration that aging is malleable. In the current review of the rodent literature, we present arguments that question the robustness of the paradigm to increase lifespan and healthspan. Specifically, there are several questions to consider as follows: (1) At what age does CR no longer produce benefits? (2) Does CR attenuate cognitive decline? (3) Are there negative effects of CR, including effects on bone health, wound healing, and response to infection? (4) How important is schedule of feeding? (5) How long does CR need to be imposed to be effective? (6) How do genotype and gender influence CR? (7) What role does dietary composition play? Consideration of these questions produce many caveats that should guide future investigations to move the field forward. Published by Elsevier B.V.

  18. Modeling soft interface dominated systems

    NARCIS (Netherlands)

    Lamorgese, A.; Mauri, R.; Sagis, L.M.C.

    2017-01-01

    The two main continuum frameworks used for modeling the dynamics of soft multiphase systems are the Gibbs dividing surface model, and the diffuse interface model. In the former the interface is modeled as a two dimensional surface, and excess properties such as a surface density, or surface energy

  19. Optimizing the phenotyping of rodent ASD models: enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2012-02-01

    in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD.

  20. Gene transfer in rodents and primates as a new tool for modeling diseases in animals and assessing functions by in vivo imaging

    Energy Technology Data Exchange (ETDEWEB)

    Deglon, N. [Atomic Energy Commission (CEA), Dept. of Medical Research and MIRCen Program, 91 - Orsay (France)

    2006-07-01

    The identification of disease-causing genes in familial forms of neuro-degenerative disorders and the development of genetic models closely replicating human CNS pathologies have drastically changed our understanding of the molecular events leading to neuronal cell death. If these achievements open new opportunities of therapeutic interventions efficient delivery systems taking into account the specificity of the central nervous system are required to administer therapeutic candidates. In addition, there is a need to develop 1) genetic models in large animals that replicate late stages of the diseases and 2) imaging techniques suitable for longitudinal, quantitative and non-invasive evaluation of disease progression and the evaluation of new therapeutic strategies. Over the last few years, we have investigated the potential of lentiviral vectors as tool to model and treat CNS disorders. The use of lentiviral vectors to create animal model of these pathologies holds various advantages compared to classical transgenic approaches. Viral vectors are versatile, highly flexible tools to perform in vivo studies. Multiple genetic models can be created in a short period of time. High transduction efficiencies as well as robust and sustained trans-gene expression lead to the rapid appearance of functional and behavioral abnormalities and severe neuro-degeneration. Targeted injections in different brain areas can be used to investigate the regional specificity of the neuro-pathology and eliminate potential side effects associated with a widespread over-expression of the trans-gene. Finally, models can be established in different mammalian species including non-human primates, thereby providing an opportunity to assess complex behavioral changes and perform longitudinal follow-up of neuro-pathological alterations by imaging. We have demonstrated the proof of principle of this approach for Huntington's disease. We have shown that the intratriatal injection of lentiviral

  1. Gene transfer in rodents and primates as a new tool for modeling diseases in animals and assessing functions by in vivo imaging

    International Nuclear Information System (INIS)

    Deglon, N.

    2006-01-01

    The identification of disease-causing genes in familial forms of neuro-degenerative disorders and the development of genetic models closely replicating human CNS pathologies have drastically changed our understanding of the molecular events leading to neuronal cell death. If these achievements open new opportunities of therapeutic interventions efficient delivery systems taking into account the specificity of the central nervous system are required to administer therapeutic candidates. In addition, there is a need to develop 1) genetic models in large animals that replicate late stages of the diseases and 2) imaging techniques suitable for longitudinal, quantitative and non-invasive evaluation of disease progression and the evaluation of new therapeutic strategies. Over the last few years, we have investigated the potential of lentiviral vectors as tool to model and treat CNS disorders. The use of lentiviral vectors to create animal model of these pathologies holds various advantages compared to classical transgenic approaches. Viral vectors are versatile, highly flexible tools to perform in vivo studies. Multiple genetic models can be created in a short period of time. High transduction efficiencies as well as robust and sustained trans-gene expression lead to the rapid appearance of functional and behavioral abnormalities and severe neuro-degeneration. Targeted injections in different brain areas can be used to investigate the regional specificity of the neuro-pathology and eliminate potential side effects associated with a widespread over-expression of the trans-gene. Finally, models can be established in different mammalian species including non-human primates, thereby providing an opportunity to assess complex behavioral changes and perform longitudinal follow-up of neuro-pathological alterations by imaging. We have demonstrated the proof of principle of this approach for Huntington's disease. We have shown that the intratriatal injection of lentiviral vector

  2. Safeguards system effectiveness modeling

    International Nuclear Information System (INIS)

    Bennett, H.A.; Boozer, D.D.; Chapman, L.D.; Daniel, S.L.; Engi, D.; Hulme, B.L.; Varnado, G.B.

    1976-01-01

    A general methodology for the comparative evaluation of physical protection system effectiveness at nuclear facilities is presently under development. The approach is applicable to problems of sabotage or theft at fuel cycle facilities. The overall methodology and the primary analytic techniques used to assess system effectiveness are briefly outlined

  3. Safeguards system effectiveness modeling

    International Nuclear Information System (INIS)

    Boozer, D.D.; Hulme, B.L.; Daniel, S.L.; Varnado, G.B.; Bennett, H.A.; Chapman, L.D.; Engi, D.

    1976-09-01

    A general methodology for the comparative evaluation of physical protection system effectiveness at nuclear facilities is presently under development. The approach is applicable to problems of sabotage or theft at fuel cycle facilities. In this paper, the overall methodology and the primary analytic techniques used to assess system effectiveness are briefly outlined

  4. Safeguards system effectiveness modeling

    International Nuclear Information System (INIS)

    Bennett, H.A.; Boozer, D.D.; Chapman, L.D.; Daniel, S.L.; Engi, D.; Hulme, B.L.; Varnado, G.B.

    1976-01-01

    A general methodology for the comparative evaluation of physical protection system effectiveness at nuclear facilities is presently under development. The approach is applicable to problems of sabotage or theft at fuel cycle facilities. In this paper, the overall methodology and the primary analytic techniques used to assess system effectiveness are briefly outlined

  5. ECONOMIC MODELING STOCKS CONTROL SYSTEM: SIMULATION MODEL

    OpenAIRE

    Климак, М.С.; Войтко, С.В.

    2016-01-01

    Considered theoretical and applied aspects of the development of simulation models to predictthe optimal development and production systems that create tangible products andservices. It isproved that theprocessof inventory control needs of economicandmathematical modeling in viewof thecomplexity of theoretical studies. A simulation model of stocks control that allows make managementdecisions with production logistics

  6. Synanthropic rodents as possible reservoirs of shigatoxigenic Escherichia coli strains

    Directory of Open Access Journals (Sweden)

    Ximena eBlanco Crivelli

    2012-11-01

    Full Text Available Shigatoxigenic Escherichia coli (STEC strains are worldwide zoonotic pathogen responsible for different cases of human disease including hemolytic uremic syndrome (HUS. Transmission of STEC to humans occurs through the consumption of food and water contaminated by faeces of carriers and by person-to-person contact.The objective of this study was twofold: (a to investigate whether synanthropic rodents are possible reservoirs of STEC in the urban area and (b whether a particular genus out of synanthropic rodent is the principal carrier of STEC.One hundred forty-five rodents were captured in Buenos Aires City. Screening for stx1/stx2 and rfbO157 was done by PCR from the confluence zone. STEC isolates were further characterized with biochemical tests by standard methods. Additional virulence factors (eae, ehxA and saa were also determined by PCR. Forty-one of the rodents were necropsied and sample of kidney and small and large intestine were taken for histopathological diagnosis. The samples sections were stained with hematoxylin-eosin, and observed by light microscopy to evaluate the systemic involvement of these species in natural infections. STEC was isolated from seven out of twenty seven suspect animals at screening. The following genotypes were found in the STEC strains: stx1/stx2/ehxA (1, stx2 (4, stx2/ehxA (1, stx2/ehxA/eae (1. Neither gross nor microscopic lesions compatible with those produced by Shiga toxin were observed in the studied organs of necropsied rodents.The bivariate analysis including the hundred forty-five rodents data showed that the isolation of STEC is associated positively to Rattus genus. This synanthropic species may play a role in the transmissibility of the agent thus being a risk to the susceptible population. Their control should be included specifically in actions to dismiss the contamination of food and water by STEC in the urban area, as additional strategies for epidemiological control.

  7. Multiple infections of rodents with zoonotic pathogens in Austria.

    Science.gov (United States)

    Schmidt, Sabrina; Essbauer, Sandra S; Mayer-Scholl, Anne; Poppert, Sven; Schmidt-Chanasit, Jonas; Klempa, Boris; Henning, Klaus; Schares, Gereon; Groschup, Martin H; Spitzenberger, Friederike; Richter, Dania; Heckel, Gerald; Ulrich, Rainer G

    2014-07-01

    Rodents are important reservoirs for a large number of zoonotic pathogens. We examined the occurrence of 11 viral, bacterial, and parasitic agents in rodent populations in Austria, including three different hantaviruses, lymphocytic choriomeningitis virus, orthopox virus, Leptospira spp., Borrelia spp., Rickettsia spp., Bartonella spp., Coxiella burnetii, and Toxoplasma gondii. In 2008, 110 rodents of four species (40 Clethrionomys glareolus, 29 Apodemus flavicollis, 26 Apodemus sylvaticus, and 15 Microtus arvalis) were trapped at two rural sites in Lower Austria. Chest cavity fluid and samples of lung, spleen, kidney, liver, brain, and ear pinna skin were collected. We screened selected tissue samples for hantaviruses, lymphocytic choriomeningitis virus, orthopox viruses, Leptospira, Borrelia, Rickettsia, Bartonella spp., C. burnetii, and T. gondii by RT-PCR/PCR and detected nucleic acids of Tula hantavirus, Leptospira spp., Borrelia afzelii, Rickettsia spp., and different Bartonella species. Serological investigations were performed for hantaviruses, lymphocytic choriomeningitis virus, orthopox viruses, and Rickettsia spp. Here, Dobrava-Belgrade hantavirus-, Tula hantavirus-, lymphocytic choriomeningitis virus-, orthopox virus-, and rickettsia-specific antibodies were demonstrated. Puumala hantavirus, C. burnetii, and T. gondii were neither detected by RT-PCR/PCR nor by serological methods. In addition, multiple infections with up to three pathogens were shown in nine animals of three rodent species from different trapping sites. In conclusion, these results show that rodents in Austria may host multiple zoonotic pathogens. Our observation raises important questions regarding the interactions of different pathogens in the host, the countermeasures of the host's immune system, the impact of the host-pathogen interaction on the fitness of the host, and the spread of infectious agents among wild rodents and from those to other animals or humans.

  8. Utah optrode array customization using stereotactic brain atlases and 3-D CAD modeling for optogenetic neocortical interrogation in small rodents and nonhuman primates.

    Science.gov (United States)

    Boutte, Ronald W; Merlin, Sam; Yona, Guy; Griffiths, Brandon; Angelucci, Alessandra; Kahn, Itamar; Shoham, Shy; Blair, Steve

    2017-10-01

    As the optogenetic field expands, the need for precise targeting of neocortical circuits only grows more crucial. This work demonstrates a technique for using Solidworks ® computer-aided design (CAD) and readily available stereotactic brain atlases to create a three-dimensional (3-D) model of the dorsal region of area visual cortex 4 (V4D) of the macaque monkey ( Macaca fascicularis ) visual cortex. The 3-D CAD model of the brain was used to customize an [Formula: see text] Utah optrode array (UOA) after it was determined that a high-density ([Formula: see text]) UOA caused extensive damage to marmoset ( Callithrix jacchus ) primary visual cortex as assessed by electrophysiological recording of spiking activity through a 1.5-mm-diameter through glass via. The [Formula: see text] UOA was customized for optrode length ([Formula: see text]), optrode width ([Formula: see text]), optrode pitch ([Formula: see text]), backplane thickness ([Formula: see text]), and overall form factor ([Formula: see text]). Two [Formula: see text] UOAs were inserted into layer VI of macaque V4D cortices with minimal damage as assessed in fixed tissue cytochrome oxidase staining in nonrecoverable surgeries. Additionally, two [Formula: see text] arrays were implanted in mice ( Mus musculus ) motor cortices, providing early evidence for long-term tolerability (over 6 months), and for the ability to integrate the UOA with a Holobundle light delivery system toward patterned optogenetic stimulation of cortical networks.

  9. Transformation of the rodent malaria parasite Plasmodium chabaudi and generation of a stable fluorescent line PcGFPCON

    Directory of Open Access Journals (Sweden)

    Reece Sarah E

    2008-09-01

    Full Text Available Abstract Background The rodent malaria parasite Plasmodium chabaudi has proven of great value in the analysis of fundamental aspects of host-parasite-vector interactions implicated in disease pathology and parasite evolutionary ecology. However, the lack of gene modification technologies for this model has precluded more direct functional studies. Methods The development of in vitro culture methods to yield P. chabaudi schizonts for transfection and conditions for genetic modification of this rodent malaria model are reported. Results Independent P. chabaudi gene-integrant lines that constitutively express high levels of green fluorescent protein throughout their life cycle have been generated. Conclusion Genetic modification of P. chabaudi is now possible. The production of genetically distinct reference lines offers substantial advances to our understanding of malaria parasite biology, especially interactions with the immune system during chronic infection.

  10. The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension-induced visceral pain models in Rodents.

    Science.gov (United States)

    Sakin, Y S; Dogrul, A; Ilkaya, F; Seyrek, M; Ulas, U H; Gulsen, M; Bagci, S

    2015-07-01

    Recent studies showed that the pharmacological inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) elicit promising analgesic effects in a variety of nociceptive models without serious side effects. However, the full spectrum of activities is not observed upon inhibition of either FAAH or MAGL enzymes alone and thus dual FAAH and MAGL inhibitors have been described. Visceral pain is strongly associated with inflammation and distension of the gut. Thus, we explored the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on inflammatory and mechanically evoked visceral pain models. Visceral inflammatory and distension-induced pain were assessed with the 0.6% acetic acid writhing test in mice and colorectal distension (CRD) test in rats, respectively. The selective FAAH inhibitor PF 3845, MAGL inhibitor JZL 184, dual inhibitor JZL 195, and the cannabis analog CP 55,940 were given systemically 30 min prior to nociceptive testing. PF 3845 (5, 10, and 20 mg/kg), JZL 184 (5, 10, and 20 mg/kg), and JZL 195 (5, 10, and 20 mg/kg) elicit dose-dependent antinociceptive in the acetic acid writhing test. In the CRD model, while JZL 195 (5, 10, or 20 mg/kg) and PF3845 (10, 20, and 40 mg/kg) produced dose-dependent antinociceptive effects comparable to those of CP 55,940 (0.1, 0.3, or 1 mg/kg), JZL 184 (10, 20, and 40 mg/kg) alone did not alter the visceromotor response (VMR). The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension-induced, visceral pain. © 2015 John Wiley & Sons Ltd.

  11. The Revised Neurobehavioral Severity Scale (NSS-R) for Rodents.

    Science.gov (United States)

    Yarnell, Angela M; Barry, Erin S; Mountney, Andrea; Shear, Deborah; Tortella, Frank; Grunberg, Neil E

    2016-04-08

    Motor and sensory deficits are common following traumatic brain injury (TBI). Although rodent models provide valuable insight into the biological and functional outcomes of TBI, the success of translational research is critically dependent upon proper selection of sensitive, reliable, and reproducible assessments. Published literature includes various observational scales designed to evaluate post-injury functionality; however, the heterogeneity in TBI location, severity, and symptomology can complicate behavioral assessments. The importance of choosing behavioral outcomes that can be reliably and objectively quantified in an efficient manner is becoming increasingly important. The Revised Neurobehavioral Severity Scale (NSS-R) is a continuous series of specific, sensitive, and standardized observational tests that evaluate balance, motor coordination, and sensorimotor reflexes in rodents. The tasks follow a specific order designed to minimize interference: balance, landing, tail raise, dragging, righting reflex, ear reflex, eye reflex, sound reflex, tail pinch, and hindpaw pinch. The NSS-R has proven to be a reliable method differentiating brain-injured rodents from non-brain-injured rodents across many brain injury models. Copyright © 2016 John Wiley & Sons, Inc.

  12. Urban resident attitudes toward rodents, rodent control products, and environmental effects

    Science.gov (United States)

    Rodent control in urban areas can result in the inadvertent mortality of non-target species (e.g., bobcats). However, there is little detailed information about rodent control practices of urban residents. Our objective was to evaluate urban rodent control behaviors in two area...

  13. ASN reputation system model

    Science.gov (United States)

    Hutchinson, Steve; Erbacher, Robert F.

    2015-05-01

    Network security monitoring is currently challenged by its reliance on human analysts and the inability for tools to generate indications and warnings for previously unknown attacks. We propose a reputation system based on IP address set membership within the Autonomous System Number (ASN) system. Essentially, a metric generated based on the historic behavior, or misbehavior, of nodes within a given ASN can be used to predict future behavior and provide a mechanism to locate network activity requiring inspection. This will provide reinforcement of notifications and warnings and lead to inspection for ASNs known to be problematic even if initial inspection leads to interpretation of the event as innocuous. We developed proof of concept capabilities to generate the IP address to ASN set membership and analyze the impact of the results. These results clearly show that while some ASNs are one-offs with individual or small numbers of misbehaving IP addresses, there are definitive ASNs with a history of long term and wide spread misbehaving IP addresses. These ASNs with long histories are what we are especially interested in and will provide an additional correlation metric for the human analyst and lead to new tools to aid remediation of these IP address blocks.

  14. Semi-Autonomous Rodent Habitat for Deep Space Exploration

    Science.gov (United States)

    Alwood, J. S.; Shirazi-Fard, Y.; Pletcher, D.; Globus, R.

    2018-01-01

    NASA has flown animals to space as part of trailblazing missions and to understand the biological responses to spaceflight. Mice traveled in the Lunar Module with the Apollo 17 astronauts and now mice are frequent research subjects in LEO on the ISS. The ISS rodent missions have focused on unravelling biological mechanisms, better understanding risks to astronaut health, and testing candidate countermeasures. A critical barrier for longer-duration animal missions is the need for humans-in-the-loop to perform animal husbandry and perform routine tasks during a mission. Using autonomous or telerobotic systems to alleviate some of these tasks would enable longer-duration missions to be performed at the Deep Space Gateway. Rodent missions performed using the Gateway as a platform could address a number of critical risks identified by the Human Research Program (HRP), as well as Space Biology Program questions identified by NRC Decadal Survey on Biological and Physical Sciences in Space, (2011). HRP risk areas of potentially greatest relevance that the Gateway rodent missions can address include those related to visual impairment (VIIP) and radiation risks to central nervous system, cardiovascular disease, as well as countermeasure testing. Space Biology focus areas addressed by the Gateway rodent missions include mechanisms and combinatorial effects of microgravity and radiation. The objectives of the work proposed here are to 1) develop capability for semi-autonomous rodent research in cis-lunar orbit, 2) conduct key experiments for testing countermeasures against low gravity and space radiation. The hardware and operations system developed will enable experiments at least one month in duration, which potentially could be extended to one year in duration. To gain novel insights into the health risks to crew of deep space travel (i.e., exposure to space radiation), results obtained from Gateway flight rodents can be compared to ground control groups and separate groups

  15. The CRF system mediates increased passive stress-coping behavior following the loss of a bonded partner in a monogamous rodent.

    Science.gov (United States)

    Bosch, Oliver J; Nair, Hemanth P; Ahern, Todd H; Neumann, Inga D; Young, Larry J

    2009-05-01

    Social relationships significantly influence physiology and behavior, including the hypothalamo-pituitary-adrenal axis, anxiety, and mental health. Disruption of social bonds through separation or death often results in profound grieving, depression, and physical illness. As the monogamous prairie vole forms enduring, selective pair bonds with the mating partner, they provide an animal model to study the physiological consequences of pair bonding and, thus, the loss of the bonded partner. Male prairie voles were paired with a novel female or male sibling. After 5 days, half of the males of each group were separated from the partner. Elevated plus-maze, forced swim, and tail suspension tests were used to assess anxiety-like and passive stress-coping behaviors indicative of depressive-like behavior. Following 4 days of separation from the female but not the male partner, experimental males displayed increased passive stress-coping. This effect was abolished by long-term intracerebroventricular infusion of a nonselective corticotropin-releasing factor (CRF) receptor antagonist without disrupting the bond itself. Both CRF type 1 and 2 receptors were involved in the emergence of passive stress-coping behavior. Furthermore, pairing with a female was associated with elevated CRF mRNA in the bed nucleus of the stria terminalis, and partner loss elicited a pronounced increase in circulating corticosteroid and adrenal weight. We speculate that the CRF system may mediate an aversive affect following separation from the female partner, which may facilitate proximity seeking between the pair-bonded individuals. Hence, the prairie vole model may provide insights into brain mechanisms involved in the psychopathological consequences of partner loss.

  16. Stochastic Modelling of Energy Systems

    DEFF Research Database (Denmark)

    Andersen, Klaus Kaae

    2001-01-01

    is that the model structure has to be adequate for practical applications, such as system simulation, fault detection and diagnosis, and design of control strategies. This also reflects on the methods used for identification of the component models. The main result from this research is the identification......In this thesis dynamic models of typical components in Danish heating systems are considered. Emphasis is made on describing and evaluating mathematical methods for identification of such models, and on presentation of component models for practical applications. The thesis consists of seven...... research papers (case studies) together with a summary report. Each case study takes it's starting point in typical heating system components and both, the applied mathematical modelling methods and the application aspects, are considered. The summary report gives an introduction to the scope...

  17. Stress Erythropoiesis Model Systems.

    Science.gov (United States)

    Bennett, Laura F; Liao, Chang; Paulson, Robert F

    2018-01-01

    Bone marrow steady-state erythropoiesis maintains erythroid homeostasis throughout life. This process constantly generates new erythrocytes to replace the senescent erythrocytes that are removed by macrophages in the spleen. In contrast, anemic or hypoxic stress induces a physiological response designed to increase oxygen delivery to the tissues. Stress erythropoiesis is a key component of this response. It is best understood in mice where it is extramedullary occurring in the adult spleen and liver and in the fetal liver during development. Stress erythropoiesis utilizes progenitor cells and signals that are distinct from bone marrow steady-state erythropoiesis. Because of that observation many genes may play a role in stress erythropoiesis despite having no effect on steady-state erythropoiesis. In this chapter, we will discuss in vivo and in vitro techniques to study stress erythropoiesis in mice and how the in vitro culture system can be extended to study human stress erythropoiesis.

  18. Distribution system modeling and analysis

    CERN Document Server

    Kersting, William H

    2001-01-01

    For decades, distribution engineers did not have the sophisticated tools developed for analyzing transmission systems-often they had only their instincts. Things have changed, and we now have computer programs that allow engineers to simulate, analyze, and optimize distribution systems. Powerful as these programs are, however, without a real understanding of the operating characteristics of a distribution system, engineers using the programs can easily make serious errors in their designs and operating procedures. Distribution System Modeling and Analysis helps prevent those errors. It gives readers a basic understanding of the modeling and operating characteristics of the major components of a distribution system. One by one, the author develops and analyzes each component as a stand-alone element, then puts them all together to analyze a distribution system comprising the various shunt and series devices for power-flow and short-circuit studies. He includes the derivation of all models and includes many num...

  19. Thermoregulation of the subterranean rodent genus Bathyergus ...

    African Journals Online (AJOL)

    The thermoregulation of the largest subterranean rodent, genus Bathyergus, comprising two species, B. suillus and B. janetta,occurring in mesic and semiarid habitats respectively, was investigated and compared with that of other subterranean rodents. Both species display low resting metabolic rates and low body ...

  20. Data management system performance modeling

    Science.gov (United States)

    Kiser, Larry M.

    1993-01-01

    This paper discusses analytical techniques that have been used to gain a better understanding of the Space Station Freedom's (SSF's) Data Management System (DMS). The DMS is a complex, distributed, real-time computer system that has been redesigned numerous times. The implications of these redesigns have not been fully analyzed. This paper discusses the advantages and disadvantages for static analytical techniques such as Rate Monotonic Analysis (RMA) and also provides a rationale for dynamic modeling. Factors such as system architecture, processor utilization, bus architecture, queuing, etc. are well suited for analysis with a dynamic model. The significance of performance measures for a real-time system are discussed.

  1. Model systems in photosynthesis research

    International Nuclear Information System (INIS)

    Katz, J.J.; Hindman, J.C.

    1981-01-01

    After a general discussion of model studies in photosynthesis research, three recently developed model systems are described. The current status of covalently linked chlorophyll pairs as models for P700 and P865 is first briefly reviewed. Mg-tris(pyrochlorophyllide)1,1,1-tris(hydroxymethyl) ethane triester in its folded configuration is then discussed as a rudimentary antenna-photoreaction center model. Finally, self-assembled chlorophyll systems that contain a mixture of monomeric, oligomeric and special pair chlorophyll are shown to have fluorescence emission characteristics that resemble thoe of intact Tribonema aequale at room temperature in that both show fluorescence emission at 675 and 695 nm. In the self-assembled systems the wavelength of the emitted fluorescence depends on the wavelength of excitation, arguing that energy transfer between different chlorophyll species in these systems may be more complex than previously suspected

  2. Prebiotic Effect of Fructooligosaccharides from Morinda officinalis on Alzheimer’s Disease in Rodent Models by Targeting the Microbiota-Gut-Brain Axis

    Directory of Open Access Journals (Sweden)

    Diling Chen

    2017-12-01

    Full Text Available Gut microbiota influences the central nervous system disorders such as Alzheimer’s disease (AD. The prebiotics and probiotics can improve the host cognition. A previous study demonstrated that fructooligosaccharides from Morinda officinalis (OMO exert effective memory improvements in AD-like animals, thereby considered as potential prebiotics; however, the underlying mechanism still remains enigma. Thus, the present study investigated whether OMO is effective in alleviating AD by targeting the microbiota-gut-brain axis. OMO was administered in rats with AD-like symptoms (D-galactose- and Aβ1-42-induced deficient rats. Significant and systematic deterioration in AD-like animals were identified, including learning and memory abilities, histological changes, production of cytokines, and microbial community shifts. Behavioral experiments demonstrated that OMO administration can ameliorate the learning and memory abilities in both AD-like animals significantly. AD parameters showed that OMO administration cannot only improve oxidative stress and inflammation disorder, but also regulate the synthesis and secretion of neurotransmitter. Histological changes indicated that OMO administration ameliorates the swelling of brain tissues, neuronal apoptosis, and down-regulation of the expression of AD intracellular markers (Tau and Aβ1-42. 16S rRNA sequencing of gut microbiota indicated that OMO administration maintains the diversity and stability of the microbial community. In addition, OMO regulated the composition and metabolism of gut microbiota in inflammatory bowel disease (IBD mice model treated by overdosed antibiotics and thus showed the prebiotic potential. Moreover, gut microbiota plays a major role in neurodevelopment, leading to alterations in gene expression in critical brain and intestinal regions, thereby resulting in perturbation to the programming of normal cognitive behaviors. Taken together, our findings suggest that the therapeutic

  3. Mobility Models for Systems Evaluation

    Science.gov (United States)

    Musolesi, Mirco; Mascolo, Cecilia

    Mobility models are used to simulate and evaluate the performance of mobile wireless systems and the algorithms and protocols at the basis of them. The definition of realistic mobility models is one of the most critical and, at the same time, difficult aspects of the simulation of applications and systems designed for mobile environments. There are essentially two possible types of mobility patterns that can be used to evaluate mobile network protocols and algorithms by means of simulations: traces and synthetic models [130]. Traces are obtained by means of measurements of deployed systems and usually consist of logs of connectivity or location information, whereas synthetic models are mathematical models, such as sets of equations, which try to capture the movement of the devices.

  4. Stochastic Models of Polymer Systems

    Science.gov (United States)

    2016-01-01

    Distribution Unlimited Final Report: Stochastic Models of Polymer Systems The views, opinions and/or findings contained in this report are those of the...ADDRESS. Princeton University PO Box 0036 87 Prospect Avenue - 2nd floor Princeton, NJ 08544 -2020 14-Mar-2014 ABSTRACT Number of Papers published in...peer-reviewed journals: Number of Papers published in non peer-reviewed journals: Final Report: Stochastic Models of Polymer Systems Report Title

  5. Methods for Dissecting Motivation and Related Psychological Processes in Rodents.

    Science.gov (United States)

    Ward, Ryan D

    2016-01-01

    Motivational impairments are increasingly recognized as being critical to functional deficits and decreased quality of life in patients diagnosed with psychiatric disease. Accordingly, much preclinical research has focused on identifying psychological and neurobiological processes which underlie motivation . Inferring motivation from changes in overt behavioural responding in animal models, however, is complicated, and care must be taken to ensure that the observed change is accurately characterized as a change in motivation , and not due to some other, task-related process. This chapter discusses current methods for assessing motivation and related psychological processes in rodents. Using an example from work characterizing the motivational impairments in an animal model of the negative symptoms of schizophrenia, we highlight the importance of careful and rigorous experimental dissection of motivation and the related psychological processes when characterizing motivational deficits in rodent models . We suggest that such work is critical to the successful translation of preclinical findings to therapeutic benefits for patients.

  6. National Energy Outlook Modelling System

    Energy Technology Data Exchange (ETDEWEB)

    Volkers, C.M. [ECN Policy Studies, Petten (Netherlands)

    2013-12-15

    For over 20 years, the Energy research Centre of the Netherlands (ECN) has been developing the National Energy Outlook Modelling System (NEOMS) for Energy projections and policy evaluations. NEOMS enables 12 energy models of ECN to exchange data and produce consistent and detailed results.

  7. A 3D imaging system integrating photoacoustic and fluorescence orthogonal projections for anatomical, functional and molecular assessment of rodent models

    Science.gov (United States)

    Brecht, Hans P.; Ivanov, Vassili; Dumani, Diego S.; Emelianov, Stanislav Y.; Anastasio, Mark A.; Ermilov, Sergey A.

    2018-03-01

    We have developed a preclinical 3D imaging instrument integrating photoacoustic tomography and fluorescence (PAFT) addressing known deficiencies in sensitivity and spatial resolution of the individual imaging components. PAFT is designed for simultaneous acquisition of photoacoustic and fluorescence orthogonal projections at each rotational position of a biological object, enabling direct registration of the two imaging modalities. Orthogonal photoacoustic projections are utilized to reconstruct large (21 cm3 ) volumes showing vascularized anatomical structures and regions of induced optical contrast with spatial resolution exceeding 100 µm. The major advantage of orthogonal fluorescence projections is significant reduction of background noise associated with transmitted or backscattered photons. The fluorescence imaging component of PAFT is used to boost detection sensitivity by providing low-resolution spatial constraint for the fluorescent biomarkers. PAFT performance characteristics were assessed by imaging optical and fluorescent contrast agents in tissue mimicking phantoms and in vivo. The proposed PAFT technology will enable functional and molecular volumetric imaging using fluorescent biomarkers, nanoparticles, and other photosensitive constructs mapped with high fidelity over robust anatomical structures, such as skin, central and peripheral vasculature, and internal organs.

  8. Aerodynamic and Mechanical System Modelling

    DEFF Research Database (Denmark)

    Jørgensen, Martin Felix

    This thesis deals with mechanical multibody-systems applied to the drivetrain of a 500 kW wind turbine. Particular focus has been on gearbox modelling of wind turbines. The main part of the present project involved programming multibody systems to investigate the connection between forces, moments...

  9. Experimental Modeling of Dynamic Systems

    DEFF Research Database (Denmark)

    Knudsen, Morten Haack

    2006-01-01

    An engineering course, Simulation and Experimental Modeling, has been developed that is based on a method for direct estimation of physical parameters in dynamic systems. Compared with classical system identification, the method appears to be easier to understand, apply, and combine with physical...

  10. Assessment of In Vivo Antidiabetic Properties of Umbelliferone and Lupeol Constituents of Banana (Musa sp. var. Nanjangud Rasa Bale) Flower in Hyperglycaemic Rodent Model.

    Science.gov (United States)

    Ramu, Ramith; S Shirahatti, Prithvi; S, Nanjunda Swamy; Zameer, Farhan; Lakkappa Dhananjaya, Bhadrapura; M N, Nagendra Prasad

    2016-01-01

    Banana is an extensively cultivated plant worldwide, mainly for its fruit, while its ancillary product, the banana flower is consumed as a vegetable and is highly recommended for diabetics in the traditional Indian medicine system. This study is based on an investigation of the in vivo antihyperglycaemic activity of Umbelliferone (C1) and Lupeol (C2) isolated from the ethanol extract of banana flower (EF) in alloxan induced diabetic rat model. Diabetic rats which were administered with C1, C2 and EF (100 and 200 mg/kg b. wt.) for 4 weeks showed deterioration in fasting hyperglycaemia and reversal of abnormalities in serum/urine protein, urea and creatinine, when compared to the diabetic control group of rats. The diabetic group of rats fed with EF, C1 and C2 (100 mg/kg b. wt.) once daily, for a period of 28 days resulted in a significant reduction of diabetic symptoms viz., polyphagia, polydipsia, polyuria and urine sugar together with an improved body weight. HbA1c extent was reduced whereas levels of insulin and Hb were increased. Both the extract and compounds wielded positive impacts in diabetic rats by reversal of altered activities of hepatic marker enzymes viz., aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP); glycolytic enzyme (hexokinase); shunt enzyme (glucose-6-phosphate dehydrogenase); gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase, lactate dehydrogenase) and pyruvate kinase. The characteristic diabetic complications such as hypercholesterolemia and hypertriacylglycerolemia also significantly reverted to normal in the serum/liver of diabetic rats. Besides these, the treatment increased the activities of enzymatic and non-enzymatic antioxidants in the serum and liver. The histological observations revealed a marked regeneration of the β-cells in the drug treated diabetic rats. In conclusion, the present study illustrates that EF, C1 and C2 enhances the glycolytic activities, besides

  11. Assessment of In Vivo Antidiabetic Properties of Umbelliferone and Lupeol Constituents of Banana (Musa sp. var. Nanjangud Rasa Bale Flower in Hyperglycaemic Rodent Model.

    Directory of Open Access Journals (Sweden)

    Ramith Ramu

    Full Text Available Banana is an extensively cultivated plant worldwide, mainly for its fruit, while its ancillary product, the banana flower is consumed as a vegetable and is highly recommended for diabetics in the traditional Indian medicine system. This study is based on an investigation of the in vivo antihyperglycaemic activity of Umbelliferone (C1 and Lupeol (C2 isolated from the ethanol extract of banana flower (EF in alloxan induced diabetic rat model. Diabetic rats which were administered with C1, C2 and EF (100 and 200 mg/kg b. wt. for 4 weeks showed deterioration in fasting hyperglycaemia and reversal of abnormalities in serum/urine protein, urea and creatinine, when compared to the diabetic control group of rats. The diabetic group of rats fed with EF, C1 and C2 (100 mg/kg b. wt. once daily, for a period of 28 days resulted in a significant reduction of diabetic symptoms viz., polyphagia, polydipsia, polyuria and urine sugar together with an improved body weight. HbA1c extent was reduced whereas levels of insulin and Hb were increased. Both the extract and compounds wielded positive impacts in diabetic rats by reversal of altered activities of hepatic marker enzymes viz., aspartate transaminase (AST, alanine transaminase (ALT, alkaline phosphatase (ALP; glycolytic enzyme (hexokinase; shunt enzyme (glucose-6-phosphate dehydrogenase; gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase, lactate dehydrogenase and pyruvate kinase. The characteristic diabetic complications such as hypercholesterolemia and hypertriacylglycerolemia also significantly reverted to normal in the serum/liver of diabetic rats. Besides these, the treatment increased the activities of enzymatic and non-enzymatic antioxidants in the serum and liver. The histological observations revealed a marked regeneration of the β-cells in the drug treated diabetic rats. In conclusion, the present study illustrates that EF, C1 and C2 enhances the glycolytic activities

  12. Modeling Multi-Level Systems

    CERN Document Server

    Iordache, Octavian

    2011-01-01

    This book is devoted to modeling of multi-level complex systems, a challenging domain for engineers, researchers and entrepreneurs, confronted with the transition from learning and adaptability to evolvability and autonomy for technologies, devices and problem solving methods. Chapter 1 introduces the multi-scale and multi-level systems and highlights their presence in different domains of science and technology. Methodologies as, random systems, non-Archimedean analysis, category theory and specific techniques as model categorification and integrative closure, are presented in chapter 2. Chapters 3 and 4 describe polystochastic models, PSM, and their developments. Categorical formulation of integrative closure offers the general PSM framework which serves as a flexible guideline for a large variety of multi-level modeling problems. Focusing on chemical engineering, pharmaceutical and environmental case studies, the chapters 5 to 8 analyze mixing, turbulent dispersion and entropy production for multi-scale sy...

  13. Pembangunan Model Restaurant Management System

    Directory of Open Access Journals (Sweden)

    Fredy Jingga

    2014-12-01

    Full Text Available Model design for Restaurant Management System aims to help in restaurant business process, where Restaurant Management System (RMS help the waitress and chef could interact each other without paper limitation.  This Restaurant Management System Model develop using Agile Methodology and developed based on PHP Programming Langguage. The database management system is using MySQL. This web-based application model will enable the waitress and the chef to interact in realtime, from the time they accept the customer order until the chef could know what to cook and checklist for the waitress wheter the order is fullfill or not, until the cahsier that will calculate the bill and the payment that they accep from the customer.

  14. Early monitoring of external radiation therapy by [18F]-fluoromethylcholine positron emission tomography and 3-T proton magnetic resonance spectroscopy: an experimental study in a rodent rhabdomyosarcoma model

    International Nuclear Information System (INIS)

    Rommel, Denis; Abarca-Quinones, Jorge; Bol, Anne; Peeters, Frank; Lhommel, Renaud; Lonneux, Max; Labar, Daniel; Gregoire, Vincent; Duprez, Thierry

    2010-01-01

    Purpose: To assess early radiation therapy (RT)-induced variations in total choline (tCho) concentration measured by proton magnetic resonance spectroscopy (H-MRS) and in 18 F-labelled fluoromethylcholine (FCH) uptake measured by PET in a rodent tumour model. Methods: Nine rats bearing syngenic rhabdomyosarcoma grafts in both thighs were irradiated (13 Gy, one fraction). H-MRS data and FCH-PET were acquired in the same imaging session prior to and 3, 9 and 16 days after external RT. Total choline concentration was expressed in arbitrary units as the area under the curve of the 3.2-ppm peak on H-MR spectra. FCH uptake was expressed as maximum standardized uptake value (SUV max ) and as the % of injected dose per gram (%ID/g) after precise tumour delineation on hybrid PET-MR images. Pre- and post-RT data were compared using the Student's paired t test, and results were expressed as mean±S.D. Results: Seventeen tumours were available for analysis. A mean drop in choline concentration of 45% was observed 3 days after irradiation (P max of 41% was observed (P=.006). Choline concentration reincreased on later time points. Conclusions: Opposite trend between increased FCH uptake and decreased tCho peak was observed at 3 days. Later (9 and 16 days), uptake remained stable and tCho peak reincreased.

  15. Wild Rodent Ectoparasites Collected from Northwestern Iran

    Directory of Open Access Journals (Sweden)

    Zabihollah Zarei

    2017-04-01

    Full Text Available Background: Rodents play an important role as reservoir of some pathogens, and the host of some ectoparasites as well. These ectoparasites can transmit rodents’ pathogens to human or animals. The aim of this study was to assess the distribution and infestation load of ectoparasites on rodents in Meshkin-Shahr District, northwestern Iran.Method: Rodents were captured using baited live traps in spring 2014 from Meshkin-Shahr District and were trans­ferred to the laboratory for identification to the species level. Their ectoparasites were collected, mounted and identi­fied.Results: Three rodent species including Meriones persicus (74%, Mus musculus (16.9% and Cricetulus migrato­rius (9% were identified. Among all rodents, 185 specimens (90.69% were infested with a total of 521 ectopara­sites. Overall, 10 arthropods species were collected, including fleas (97.6%, one mite (1.6% and one louse species (0.6% as follows: Xenopsylla nubica, X. astia, X. buxtoni, X. cheopis, Nosopsyllus fasciatus, N. iranus, Cten­ocephalides felis, Ctenophthalmus rettigismiti, Ornithonyssus sp and one species of genus Polyplax. The most prev­alent ectoparasites species was X. nubica (89%.Conclusion: Nearly all rodent species were infested with Xenopsylla species. Monitoring of ectoparasites on infested rodents is very important for awareness and early warning towards control of arthropod-borne diseases.

  16. Modeling the dual pacemaker system of the tau mutant hamster.

    Science.gov (United States)

    Oda, G A; Menaker, M; Friesen, W O

    2000-06-01

    Circadian pacemakers in many animals are compound. In rodents, a two-oscillator model of the pacemaker composed of an evening (E) and a morning (M) oscillator has been proposed based on the phenomenon of "splitting" and bimodal activity peaks. The authors describe computer simulations of the pacemaker in tau mutant hamsters viewed as a system of mutually coupled E and M oscillators. These mutant animals exhibit normal type 1 PRCs when released into DD but make a transition to a type 0 PRC when held for many weeks in DD. The two-oscillator model describes particularly well some recent behavioral experiments on these hamsters. The authors sought to determine the relationships between oscillator amplitude, period, PRC, and activity duration through computer simulations. Two complementary approaches proved useful for analyzing weakly coupled oscillator systems. The authors adopted a "distinct oscillators" view when considering the component E and M oscillators and a "system" view when considering the system as a whole. For strongly coupled systems, only the system view is appropriate. The simulations lead the authors to two primary conjectures: (1) the total amplitude of the pacemaker system in tau mutant hamsters is less than in the wild-type animals, and (2) the coupling between the unit E and M oscillators is weakened during continuous exposure of hamsters to DD. As coupling strength decreases, activity duration (alpha) increases due to a greater phase difference between E and M. At the same time, the total amplitude of the system decreases, causing an increase in observable PRC amplitudes. Reduced coupling also increases the relative autonomy of the unit oscillators. The relatively autonomous phase shifts of E and M oscillators can account for both immediate compression and expansion of activity bands in tau mutant and wild-type hamsters subjected to light pulses.

  17. The clearance of Pu and Am from the respiratory system of rodents after the inhalation of oxide aerosols of these actinides either alone or in combination with other metals

    International Nuclear Information System (INIS)

    Stather, J.W.; James, A.C.; Brightwell, J.; Rodwell, P.

    1979-01-01

    In this series of studies in rodents the lung clearance and tissue distribution of both plutonium and americium have been measured following their inhalation as mixed actinide oxides either alone or in combination with other metals. The aerosols used were materials to which workers in the nuclear industry may be occupationally exposed or which could be generated in the event of an accident in a reactor core or fuel fabrication plant. The studies showed that, at least for some PuO 2 aerosols, the lung model currently being used by ICRP for estimating tissue doses from inhaled actinides may overestimate, by about a factor of ten, the amount of plutonium translocated to the blood. The presence of oxides of other metals can, however, appreciably influence the clearance of plutonium from the lung. While in some mixtures plutonium dioxide behaves as an insoluble (Class Y) compound and in others as a soluble (Class W) compound, it may also have transportability characteristics between these two extremes. Americium-241 behaves as a soluble (Class W) compound when inhaled as the oxide. However, if it is present in trace quantities in mixed-oxide aerosols its behaviour depends upon that of the materials present in greatest mass. (author)

  18. Models of complex attitude systems

    DEFF Research Database (Denmark)

    Sørensen, Bjarne Taulo

    search algorithms and structural equation models. The results suggest that evaluative judgments of the importance of production system attributes are generated in a schematic manner, driven by personal value orientations. The effect of personal value orientations was strong and largely unmediated...... that evaluative affect propagates through the system in such a way that the system becomes evaluatively consistent and operates as a schema for the generation of evaluative judgments. In the empirical part of the paper, the causal structure of an attitude system from which people derive their evaluations of pork......Existing research on public attitudes towards agricultural production systems is largely descriptive, abstracting from the processes through which members of the general public generate their evaluations of such systems. The present paper adopts a systems perspective on such evaluations...

  19. Stirling Engine Dynamic System Modeling

    Science.gov (United States)

    Nakis, Christopher G.

    2004-01-01

    The Thermo-Mechanical systems branch at the Glenn Research Center focuses a large amount time on Stirling engines. These engines will be used on missions where solar power is inefficient, especially in deep space. I work with Tim Regan and Ed Lewandowski who are currently developing and validating a mathematical model for the Stirling engines. This model incorporates all aspects of the system including, mechanical, electrical and thermodynamic components. Modeling is done through Simplorer, a program capable of running simulations of the model. Once created and then proven to be accurate, a model is used for developing new ideas for engine design. My largest specific project involves varying key parameters in the model and quantifying the results. This can all be done relatively trouble-free with the help of Simplorer. Once the model is complete, Simplorer will do all the necessary calculations. The more complicated part of this project is determining which parameters to vary. Finding key parameters depends on the potential for a value to be independently altered in the design. For example, a change in one dimension may lead to a proportional change to the rest of the model, and no real progress is made. Also, the ability for a changed value to have a substantial impact on the outputs of the system is important. Results will be condensed into graphs and tables with the purpose of better communication and understanding of the data. With the changing of these parameters, a more optimal design can be created without having to purchase or build any models. Also, hours and hours of results can be simulated in minutes. In the long run, using mathematical models can save time and money. Along with this project, I have many other smaller assignments throughout the summer. My main goal is to assist in the processes of model development, validation and testing.

  20. System Convergence in Transport Modelling

    DEFF Research Database (Denmark)

    Rich, Jeppe; Nielsen, Otto Anker; Cantarella, Guilio E.

    2010-01-01

    A fundamental premise of most applied transport models is the existence and uniqueness of an equilibrium solution that balances demand x(t) and supply t(x). The demand consists of the people that travel in the transport system and on the defined network, whereas the supply consists of the resulting...... level-of-service attributes (e.g., travel time and cost) offered to travellers. An important source of complexity is the congestion, which causes increasing demand to affect travel time in a non-linear way. Transport models most often involve separate models for traffic assignment and demand modelling...... iterating between a route-choice (demand) model and a time-flow (supply) model. It is generally recognised that a simple iteration scheme where the level-of-service level is fed directly to the route-choice and vice versa may exhibit an unstable pattern and lead to cyclic unstable solutions. It can be shown...

  1. Transformation of the rodent malaria parasite Plasmodium chabaudi

    OpenAIRE

    Spence, Philip J; Cunningham, Deirdre; Jarra, William; Lawton, Jennifer; Langhorne, Jean; Thompson, Joanne

    2011-01-01

    The rodent malaria parasite Plasmodium chabaudi chabaudi shares many features with human malaria species, including P. falciparum, and is the in vivo model of choice for many aspects of malaria research in the mammalian host, from sequestration of parasitized erythrocytes, to antigenic variation and host immunity and immunopathology. this protocol describes an optimized method for the transformation of mature blood-stage P.c. chabaudi and a description of a vector that targets efficient, sing...

  2. Studies into abnormal aggression in humans and rodents: Methodological and translational aspects.

    Science.gov (United States)

    Haller, Jozsef

    2017-05-01

    Here we review the principles based on which aggression is rendered abnormal in humans and laboratory rodents, and comparatively overview the main methodological approaches based on which this behavior is studied in the two categories of subjects. It appears that the discriminating property of abnormal aggression is rule breaking, which renders aggression dysfunctional from the point of view of the perpetrator. We show that rodent models of abnormal aggression were created by the translation of human conditions into rodent equivalents, and discuss how findings obtained with such models may be "translated back" to human conditions when the mechanisms underlying aggression and its possibilities of treatment are investigated. We suggest that the complementary nature of human and rodent research approaches invite a more intense cross-talk between the two sides of aggression research than the one presently observed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Model Reduction of Hybrid Systems

    DEFF Research Database (Denmark)

    Shaker, Hamid Reza

    gramians. Generalized gramians are the solutions to the observability and controllability Lyapunov inequalities. In the first framework the projection matrices are found based on the common generalized gramians. This framework preserves the stability of the original switched system for all switching...... is guaranteed to be preserved for arbitrary switching signal. To compute the common generalized gramians linear matrix inequalities (LMI’s) need to be solved. These LMI’s are not always feasible. In order to solve the problem of conservatism, the second framework is presented. In this method the projection......High-Technological solutions of today are characterized by complex dynamical models. A lot of these models have inherent hybrid/switching structure. Hybrid/switched systems are powerful models for distributed embedded systems design where discrete controls are applied to continuous processes...

  4. Numerical Modeling of Microelectrochemical Systems

    DEFF Research Database (Denmark)

    Adesokan, Bolaji James

    incorporates the finite size of ionic species in the transport equation. The model presents a more appropriate boundary conditions which describe the modified Butler-Volmer reaction kinetics and account for the surface capacitance of the thin electric double layer. We also have found analytical solution...... at the electrode in a microelectrochemical system. In our analysis, we account for the finite size properties of ions in the mass and the charge transport of ionic species in an electrochemical system. This term characterizes the saturation of the ionic species close to the electrode surface. We then analyse......The PhD dissertation is concerned with mathematical modeling and simulation of electrochemical systems. The first three chapters of the thesis consist of the introductory part, the model development chapter and the chapter on the summary of the main results. The remaining three chapters report...

  5. Executive Information Systems' Multidimensional Models

    Directory of Open Access Journals (Sweden)

    2007-01-01

    Full Text Available Executive Information Systems are design to improve the quality of strategic level of management in organization through a new type of technology and several techniques for extracting, transforming, processing, integrating and presenting data in such a way that the organizational knowledge filters can easily associate with this data and turn it into information for the organization. These technologies are known as Business Intelligence Tools. But in order to build analytic reports for Executive Information Systems (EIS in an organization we need to design a multidimensional model based on the business model from the organization. This paper presents some multidimensional models that can be used in EIS development and propose a new model that is suitable for strategic business requests.

  6. Respiratory insufficiency correlated strongly with mortality of rodents infected with West Nile virus.

    Directory of Open Access Journals (Sweden)

    John D Morrey

    Full Text Available West Nile virus (WNV disease can be fatal for high-risk patients. Since WNV or its antigens have been identified in multiple anatomical locations of the central nervous system of persons or rodent models, one cannot know where to investigate the actual mechanism of mortality without careful studies in animal models. In this study, depressed respiratory functions measured by plethysmography correlated strongly with mortality. This respiratory distress, as well as reduced oxygen saturation, occurred beginning as early as 4 days before mortality. Affected medullary respiratory control cells may have contributed to the animals' respiratory insufficiency, because WNV antigen staining was present in neurons located in the ventrolateral medulla. Starvation or dehydration would be irrelevant in people, but could cause death in rodents due to lethargy or loss of appetite. Animal experiments were performed to exclude this possibility. Plasma ketones were increased in moribund infected hamsters, but late-stage starvation markers were not apparent. Moreover, daily subcutaneous administration of 5% dextrose in physiological saline solution did not improve survival or other disease signs. Therefore, infected hamsters did not die from starvation or dehydration. No cerebral edema was apparent in WNV- or sham-infected hamsters as determined by comparing wet-to-total weight ratios of brains, or by evaluating blood-brain-barrier permeability using Evans blue dye penetration into brains. Limited vasculitis was present in the right atrium of the heart of infected hamsters, but abnormal electrocardiograms for several days leading up to mortality did not occur. Since respiratory insufficiency was strongly correlated with mortality more than any other pathological parameter, it is the likely cause of death in rodents. These animal data and a poor prognosis for persons with respiratory insufficiency support the hypothesis that neurological lesions affecting respiratory

  7. Morphological and Biomechanical Differences in the Elastase and AngII apoE−/− Rodent Models of Abdominal Aortic Aneurysms

    Directory of Open Access Journals (Sweden)

    Evan H. Phillips

    2015-01-01

    Full Text Available An abdominal aortic aneurysm (AAA is a potentially fatal cardiovascular disease with multifactorial development and progression. Two preclinical models of the disease (elastase perfusion and angiotensin II infusion in apolipoprotein-E-deficient animals have been developed to study the disease during its initiation and progression. To date, most studies have used ex vivo methods to examine disease characteristics such as expanded aortic diameter or analytic methods to look at circulating biomarkers. Herein, we provide evidence from in vivo ultrasound studies of the temporal changes occurring in biomechanical parameters and macromolecules of the aortic wall in each model. We present findings from 28-day studies in elastase-perfused rats and AngII apoE−/− mice. While each model develops AAAs specific to their induction method, they both share characteristics with human aneurysms, such as marked changes in vessel strain and blood flow velocity. Histology and nonlinear microscopy confirmed that both elastin and collagen, both important extracellular matrix molecules, are similarly affected in their levels and spatial distribution. Future studies could make use of the differences between these models in order to investigate mechanisms of disease progression or evaluate potential AAA treatments.

  8. Neuroimmune Pathways in Alcohol Consumption: Evidence from Behavioral and Genetic Studies in Rodents and Humans

    Science.gov (United States)

    Robinson, Gizelle; Most, Dana; Ferguson, Laura B.; Mayfield, Jody; Harris, R. Adron; Blednov, Yuri A.

    2014-01-01

    Immune or brain proinflammatory signaling has been linked to some of the behavioral effects of alcohol. Immune signaling appears to regulate voluntary ethanol intake in rodent models, and ethanol intake activates the immune system in multiple models. This bidirectional link raises the possibility that consumption increases immune signaling, which in turn further increases consumption in a feed-forward cycle. Data from animal and human studies provide overlapping support for the involvement of immune-related genes and proteins in alcohol action, and combining animal and human data is a promising approach to systematically evaluate and nominate relevant pathways. Based on rodent models, neuroimmune pathways may represent unexplored, nontraditional targets for medication development to reduce alcohol consumption and prevent relapse. Peroxisome proliferator-activated receptor agonists are one class of anti-inflammatory medications that demonstrate antiaddictive properties for alcohol and other drugs of abuse. Expression of immune-related genes is altered in animals and humans following chronic alcohol exposure, and the regulatory influences of specific mRNAs, microRNAs, and activated cell types are areas of intense study. Ultimately, the use of multiple datasets combined with behavioral validation will be needed to link specific neuroimmune pathways to addiction vulnerability. PMID:25175860

  9. Turboelectric Distributed Propulsion System Modelling

    OpenAIRE

    Liu, Chengyuan

    2013-01-01

    The Blended-Wing-Body is a conceptual aircraft design with rear-mounted, over wing engines. Turboelectric distributed propulsion system with boundary layer ingestion has been considered for this aircraft. It uses electricity to transmit power from the core turbine to the fans, therefore dramatically increases bypass ratio to reduce fuel consumption and noise. This dissertation presents methods on designing the TeDP system, evaluating effects of boundary layer ingestion, modelling engine perfo...

  10. Public health implications of changing rodent importation patterns— United States, 1999–2013

    Science.gov (United States)

    Lankau, Emily W.; Sinclair, Julie R.; Schroeder, Betsy A.; Galland, G. Gale; Marano, Nina

    2015-01-01

    Summary The United States imports a large volume of live wild and domestic animal species; these animals pose a demonstrated risk for introduction of zoonotic diseases. Rodents are imported for multiple purposes, including scientific research, zoo exhibits, and the pet trade. Current U.S. public health regulatory restrictions specific to rodent importation pertain only to those of African origin. To understand the impacts of these regulations and the potential public health risks of international rodent trade to the United States, we evaluated live rodent import records during 1999 –2013 by shipment volume and geographic origin, source (e.g., wild -caught versus captive-or commercially bred), intended purpose, and rodent taxonomy. Live rodent imports increased from 2,737 animals during 1999 to 173,761 animals during 2013. Increases in both the number and size of shipments contributed to this trend. The proportion of wild-captured imports declined from 75% during 1999 to guinea pigs, and hamsters arriving from other countries in North America were predominant taxa underlying this trend . After 2003, African-origin imports became sporadic events under the federal permit process. These patterns suggest development of large -scale captive rodent breeding markets abroad for commercial sale in the United States. While the shift from wild-captured imports alleviates many conservation concerns and risks for novel disease emergence, such consolidated sourcing might elevate exposure risks for zoonotic diseases associated with high-density rodent breeding(e.g. , lymphocytic choriomeningitis or salmonellosis). A responsive border health system must periodically re-evaluate importation regulations in conjunction with key stakeholders to ensure a balance between the economic benefits of rodent trade against the potential public health risks. PMID:26245515

  11. Public Health Implications of Changing Rodent Importation Patterns - United States, 1999-2013.

    Science.gov (United States)

    Lankau, E W; Sinclair, J R; Schroeder, B A; Galland, G G; Marano, N

    2017-04-01

    The United States imports a large volume of live wild and domestic animal species; these animals pose a demonstrated risk for introduction of zoonotic diseases. Rodents are imported for multiple purposes, including scientific research, zoo exhibits and the pet trade. Current U.S. public health regulatory restrictions specific to rodent importation pertain only to those of African origin. To understand the impacts of these regulations and the potential public health risks of international rodent trade to the United States, we evaluated live rodent import records during 1999-2013 by shipment volume and geographic origin, source (e.g. wild-caught versus captive- or commercially bred), intended purpose and rodent taxonomy. Live rodent imports increased from 2737 animals during 1999 to 173 761 animals during 2013. Increases in both the number and size of shipments contributed to this trend. The proportion of wild-captured imports declined from 75% during 1999 to guinea pigs and hamsters arriving from other countries in North America were predominant taxa underlying this trend. After 2003, African-origin imports became sporadic events under the federal permit process. These patterns suggest development of large-scale captive rodent breeding markets abroad for commercial sale in the United States. While the shift from wild-captured imports alleviates many conservation concerns and risks for novel disease emergence, such consolidated sourcing might elevate exposure risks for zoonotic diseases associated with high-density rodent breeding (e.g. lymphocytic choriomeningitis or salmonellosis). A responsive border health system must periodically re-evaluate importation regulations in conjunction with key stakeholders to ensure a balance between the economic benefits of rodent trade against the potential public health risks. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  12. Novel Therapeutic Approaches for the Treatment of Depression and Cognitive Deficits in a Rodent Model of Gulf War Veterans’ Illness

    Science.gov (United States)

    2017-10-01

    hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate. Toxicol Sci 116 (2), 623- 631. 5...hippocampus. J Neurophysiol 88 (3), 1270-1278. 21. Deshpande, L.S., Carter, D.S., Phillips, K.F., Blair, R.E. and DeLorenzo, R.J. (2014) Development of status ... epilepticus , sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication. Neurotoxicology 44, 17-26. 22

  13. Video distribution system cost model

    Science.gov (United States)

    Gershkoff, I.; Haspert, J. K.; Morgenstern, B.

    1980-01-01

    A cost model that can be used to systematically identify the costs of procuring and operating satellite linked communications systems is described. The user defines a network configuration by specifying the location of each participating site, the interconnection requirements, and the transmission paths available for the uplink (studio to satellite), downlink (satellite to audience), and voice talkback (between audience and studio) segments of the network. The model uses this information to calculate the least expensive signal distribution path for each participating site. Cost estimates are broken downy by capital, installation, lease, operations and maintenance. The design of the model permits flexibility in specifying network and cost structure.

  14. Mechanisms of anti-D action in the prevention of hemolytic disease of the fetus and newborn: what can we learn from rodent models?

    Science.gov (United States)

    Brinc, Davor; Denomme, Gregory A; Lazarus, Alan H

    2009-11-01

    Hemolytic disease of the fetus and newborn can be effectively prevented by administration of anti-D to the mother. In this setting, the IgG purified from the plasma of D-alloimmunized donors prevents the maternal immune response to D-positive red blood cells (RBC). Several monoclonal anti-D antibodies have recently been developed for potential use in the setting of hemolytic disease of the fetus and newborn; the functional assays used to assess the potential success of these antibodies have often assumed antigen clearance as the predominant mechanism of anti-D. Unfortunately, the in-vivo success of these monoclonal antibodies has thus far been limited. A similar inhibitory effect of IgG has been observed in animal models with a vast array of different antigens, referred to as antibody-mediated immune suppression (AMIS). Here, studies of AMIS are reviewed and the relevance of these findings for anti-D-mediated immunoprophylaxis is discussed. In animal models of AMIS, IgG-mediated antigen clearance was not sufficient for prevention of the antibody response to RBC. Furthermore, anti-RBC IgG inhibited B-cell priming to foreign RBC, but failed to prevent a T-cell response and immunological memory. The applicability of AMIS models for determining the true mechanism of anti-D, though uncertain, may nevertheless provide knowledge as to potential mechanisms of action of anti-RBC antibodies.

  15. Information Systems Outsourcing Relationship Model

    Directory of Open Access Journals (Sweden)

    Richard Flemming

    2007-09-01

    Full Text Available Increasing attention is being paid to what determines the success of an information systems outsourcing arrangement. The current research aims to provide an improved understanding of the factors influencing the outcome of an information systems outsourcing relationship and to provide a preliminary validation of an extended outsourcing relationship model by interviews with information systems outsourcing professionals in both the client and vendor of a major Australian outsourcing relationship. It also investigates whether the client and the vendor perceive the relationship differently and if so, how they perceive it differently and whether the two perspectives are interrelated.

  16. Adolescent Atomoxetine Treatment in a Rodent Model of ADHD: Effects on Cocaine Self-Administration and Dopamine Transporters in Frontostriatal Regions

    Science.gov (United States)

    Somkuwar, Sucharita S; Jordan, Chloe J; Kantak, Kathleen M; Dwoskin, Linda P

    2013-01-01

    Cocaine abuse and attention deficit/hyperactivity disorder (ADHD) are often comorbid. Preclinical research indicates that medial prefrontal (mPFC) and orbitofrontal (OFC) cortices are important neural substrates for both disorders. Using the spontaneously hypertensive rat (SHR) model of ADHD, we reported that adolescent treatment with the stimulant methylphenidate, a dopamine (DAT) and norepinephrine (NET) transporter inhibitor, enhanced cocaine self-administration during adulthood, and was associated with increased DAT function in mPFC. This study investigates the effects of atomoxetine ((R)-N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride) treatment, a selective NET inhibitor, during adolescence on cocaine self-administration and on DAT function and cell-surface expression in mPFC and OFC during adulthood. SHR acquired cocaine self-administration faster than Wistar–Kyoto and Wistar. Across cocaine doses, SHR earned more cocaine infusions and had higher progressive-ratio breakpoints than Wistar–Kyoto and Wistar, demonstrating that the SHR phenotype models comorbid ADHD and cocaine abuse. Prior atomoxetine treatment did not augment cocaine self-administration in SHR, but acquisition was enhanced in Wistar–Kyoto. No strain differences were found for DAT kinetic parameters or cellular localization in the vehicle controls. Atomoxetine did not alter DAT kinetic parameters or localization in SHR mPFC. Rather, atomoxetine decreased Vmax and DAT cell surface expression in SHR OFC, indicating that inhibition of NET by atomoxetine treatment during adolescence indirectly reduced DAT function and trafficking to the cell surface in OFC, specifically in the ADHD model. Thus, atomoxetine, unlike methylphenidate, does not enhance vulnerability to cocaine abuse in SHR and may represent an important alternative for teens with ADHD when drug addiction is a concern. PMID:23822950

  17. Six week follow-up of metabolic effects induced by a high-fat diet and streptozotocin in a rodent model of type 2 diabetes mellitus.

    Science.gov (United States)

    Atanasovska, Emilija; Tasic, Velibor; Slaninka-Miceska, Maja; Alabakovska, Sonja; Zafirov, Dimce; Kostova, Elena; Pavlovska, Kristina; Filipce, Venko; Labacevski, Nikola

    2014-01-01

    This study was initiated to refine and characterize a nongenetic experimental model of type 2 diabetes mellitus and to follow up various metabolic parameters up to six weeks after diabetes induction. Male Wistar rats were divided into 4 groups: CON group--consumed standard rat chow and served as control; HFD group--consumed high-fat diet (45% calories as fat); STZ group-was injected once intraperitoneally with streptozotocin (35 mg/kg) on day 14, and DM-2 group--consumed high-fat diet and was injected with streptozotocin. The metabolic parameters were measured one week after streptozotocin injection (week 3) and at the end of the study (week 9). Our results confirm that HFD-group developed dyslipidaemia, obesity and insulin resistance. All metabolic parameters remained largely unaltered in STZ-group during the study. Only the combination of high-fat diet and streptozotocin (DM-2 group) induced type 2 diabetes that was characterized with moderate hyperglycaemia, insulin resistance, hypertriglyceridaemia, elevated free fatty acids, hypercholesterolaemia and increased plasma glucagon levels at the time of diabetes onset (week 3). The observed changes of the metabolic parameters after six additional weeks demonstrated an aggravated diabetic state, as confirmed from significantly increased fasting plasma glucose values, insufficient insulin secretion, severe hyperlipidaemia, increased glucagon levels, decreased serum adiponectin concentrations and significantly elevated urinary protein excretion. These results indicate that apart from its utility as a model of diabetes aetiology, this model could also be used for elucidating the role of the hormones adiponectin and glucagon in the progression of type 2 diabetes, as well as for investigating the diabetic complications.

  18. Adolescent D-amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood.

    Science.gov (United States)

    Jordan, Chloe J; Taylor, Danielle M; Dwoskin, Linda P; Kantak, Kathleen M

    2016-01-15

    Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Aggregate modeling of manufacturing systems

    NARCIS (Netherlands)

    Lefeber, A.A.J.; Armbruster, H.D.; Kempf, K.G.; Keskinocak, P.; Uzsoy, R.

    2011-01-01

    In this chapter we will present three approaches to model manufacturing systems in an aggregate way leading to fast and effective (i.e., scalable) simulations that allow the development of simulation tools for rapid exploration of different production scenarios in a factory as well as in a whole

  20. Ventilation system in fire modelization

    International Nuclear Information System (INIS)

    Cordero Garcia, S.

    2012-01-01

    There is a model of fire in an enclosure formed by two rooms. In one of them, it will cause the fire and check how the system of ventilation in different configurations responds. In addition, the behavior of selected targets, which will be a configuration of cables similar to those found in nuclear power stations will be analyzed.

  1. An extensible analysable system model

    DEFF Research Database (Denmark)

    Probst, Christian W.; Hansen, Rene Rydhof

    2008-01-01

    , this does not hold for real physical systems. Approaches such as threat modelling try to target the formalisation of the real-world domain, but still are far from the rigid techniques available in security research. Many currently available approaches to assurance of critical infrastructure security...

  2. Aggregate modeling of manufacturing systems

    NARCIS (Netherlands)

    Lefeber, A.A.J.; Armbruster, H.D.

    2007-01-01

    In this report we will present three approaches to model manufacturing systems in an aggregate way leading to fast and effective (i.e., scalable) simulations that allow the development of simulation tools for rapid exploration of different production scenarios in a factory as well as in a whole

  3. Stochastic Modelling of Hydrologic Systems

    DEFF Research Database (Denmark)

    Jonsdottir, Harpa

    2007-01-01

    In this PhD project several stochastic modelling methods are studied and applied on various subjects in hydrology. The research was prepared at Informatics and Mathematical Modelling at the Technical University of Denmark. The thesis is divided into two parts. The first part contains...... an introduction and an overview of the papers published. Then an introduction to basic concepts in hydrology along with a description of hydrological data is given. Finally an introduction to stochastic modelling is given. The second part contains the research papers. In the research papers the stochastic methods...... are described, as at the time of publication these methods represent new contribution to hydrology. The second part also contains additional description of software used and a brief introduction to stiff systems. The system in one of the papers is stiff....

  4. Thermodynamic modeling of complex systems

    DEFF Research Database (Denmark)

    Liang, Xiaodong

    after an oil spill. Engineering thermodynamics could be applied in the state-of-the-art sonar products through advanced artificial technology, if the speed of sound, solubility and density of oil-seawater systems could be satisfactorily modelled. The addition of methanol or glycols into unprocessed well...... is successfully applied to model the phase behaviour of water, chemical and hydrocarbon (oil) containing systems with newly developed pure component parameters for water and chemicals and characterization procedures for petroleum fluids. The performance of the PCSAFT EOS on liquid-liquid equilibria of water...... with hydrocarbons has been under debate for some vii years. An interactive step-wise procedure is proposed to fit the model parameters for small associating fluids by taking the liquid-liquid equilibrium data into account. It is still far away from a simple task to apply PC-SAFT in routine PVT simulations and phase...

  5. Cotangent Models for Integrable Systems

    Science.gov (United States)

    Kiesenhofer, Anna; Miranda, Eva

    2017-03-01

    We associate cotangent models to a neighbourhood of a Liouville torus in symplectic and Poisson manifolds focusing on b-Poisson/ b-symplectic manifolds. The semilocal equivalence with such models uses the corresponding action-angle theorems in these settings: the theorem of Liouville-Mineur-Arnold for symplectic manifolds and an action-angle theorem for regular Liouville tori in Poisson manifolds (Laurent- Gengoux et al., IntMath Res Notices IMRN 8: 1839-1869, 2011). Our models comprise regular Liouville tori of Poisson manifolds but also consider the Liouville tori on the singular locus of a b-Poisson manifold. For this latter class of Poisson structures we define a twisted cotangent model. The equivalence with this twisted cotangent model is given by an action-angle theorem recently proved by the authors and Scott (Math. Pures Appl. (9) 105(1):66-85, 2016). This viewpoint of cotangent models provides a new machinery to construct examples of integrable systems, which are especially valuable in the b-symplectic case where not many sources of examples are known. At the end of the paper we introduce non-degenerate singularities as lifted cotangent models on b-symplectic manifolds and discuss some generalizations of these models to general Poisson manifolds.

  6. Early life stress induces attention-deficit hyperactivity disorder (ADHD)-like behavioral and brain metabolic dysfunctions: functional imaging of methylphenidate treatment in a novel rodent model.

    Science.gov (United States)

    Bock, J; Breuer, S; Poeggel, G; Braun, K

    2017-03-01

    In a novel animal model Octodon degus we tested the hypothesis that, in addition to genetic predisposition, early life stress (ELS) contributes to the etiology of attention-deficit hyperactivity disorder-like behavioral symptoms and the associated brain functional deficits. Since previous neurochemical observations revealed that early life stress impairs dopaminergic functions, we predicted that these symptoms can be normalized by treatment with methylphenidate. In line with our hypothesis, the behavioral analysis revealed that repeated ELS induced locomotor hyperactivity and reduced attention towards an emotionally relevant acoustic stimulus. Functional imaging using ( 14 C)-2-fluoro-deoxyglucose-autoradiography revealed that the behavioral symptoms are paralleled by metabolic hypoactivity of prefrontal, mesolimbic and subcortical brain areas. Finally, the pharmacological intervention provided further evidence that the behavioral and metabolic dysfunctions are due to impaired dopaminergic neurotransmission. Elevating dopamine in ELS animals by methylphenidate normalized locomotor hyperactivity and attention-deficit and ameliorated brain metabolic hypoactivity in a dose-dependent manner.

  7. Multiplex PCR identification of Taenia spp. in rodents and carnivores.

    Science.gov (United States)

    Al-Sabi, Mohammad N S; Kapel, Christian M O

    2011-11-01

    The genus Taenia includes several species of veterinary and public health importance, but diagnosis of the etiological agent in definitive and intermediate hosts often relies on labor intensive and few specific morphometric criteria, especially in immature worms and underdeveloped metacestodes. In the present study, a multiplex PCR, based on five primers targeting the 18S rDNA and ITS2 sequences, produced a species-specific banding patterns for a range of Taenia spp. Species typing by the multiplex PCR was compared to morphological identification and sequencing of cox1 and/or 12S rDNA genes. As compared to sequencing, the multiplex PCR identified 31 of 32 Taenia metacestodes from rodents, whereas only 14 cysts were specifically identified by morphology. Likewise, the multiplex PCR identified 108 of 130 adult worms, while only 57 were identified to species by morphology. The tested multiplex PCR system may potentially be used for studies of Taenia spp. transmitted between rodents and carnivores.

  8. Graph modeling systems and methods

    Science.gov (United States)

    Neergaard, Mike

    2015-10-13

    An apparatus and a method for vulnerability and reliability modeling are provided. The method generally includes constructing a graph model of a physical network using a computer, the graph model including a plurality of terminating vertices to represent nodes in the physical network, a plurality of edges to represent transmission paths in the physical network, and a non-terminating vertex to represent a non-nodal vulnerability along a transmission path in the physical network. The method additionally includes evaluating the vulnerability and reliability of the physical network using the constructed graph model, wherein the vulnerability and reliability evaluation includes a determination of whether each terminating and non-terminating vertex represents a critical point of failure. The method can be utilized to evaluate wide variety of networks, including power grid infrastructures, communication network topologies, and fluid distribution systems.

  9. Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f.

    Directory of Open Access Journals (Sweden)

    Megumi Morimoto

    Full Text Available Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC and skeletal muscle cells (SKMC. SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement

  10. How many food additives are rodent carcinogens?

    Science.gov (United States)

    Johnson, F M

    2002-01-01

    One generally assumes that chemical agents added to foods are reasonably free of risks to human health, and practically everyone consumes some additives in his or her food daily throughout life. In the United States, the 1958 Food Additives Amendment to the Federal Food, Drug and Cosmetic Act of 1938 requires food manufacturers to demonstrate the safety of food additives to the Food and Drug Administration (FDA). The Amendment contains a provision that prohibits approval of an additive if it is found to cause cancer in humans or animals. In the present study, data from the National Toxicology Program rodent bioassay (NTPRB) were used to identify a sample of approximately 50 rodent-tested additives and other chemicals added to food that had been evaluated independently of the FDA/food industry. Surprisingly, the sample shows more than 40% of these food chemicals to be carcinogenic in one or more rodent groups. If this percentage is extrapolated to all substances added to food in the United States, it would imply that more than 1000 of such substances are potential rodent carcinogens. The NTP and FDA test guidelines use similar, though not necessarily identical, rodent test procedures, including near lifetime exposures to the maximum tolerated dose. The FDA specifies that test chemicals should be administered by the oral route. However, the oral route includes three methods of delivering chemicals, that is, mixed in the food or water or delivered by stomach tube (gavage). The NTP data show only 1 of 18 food chemicals mixed in the food are rodent carcinogens, but 16 of 23 gavage-administered food chemicals are carcinogenic to rodents. The distribution suggests that among orally delivered chemicals, those administered in the feed will more likely prove to be noncarcinogens than chemicals given by gavage. The rodent data also reveal that effects may vary according to dose and genotype, as well as by route of administration, to further complicate extrapolation to humans

  11. Effect of cell phone radiofrequency radiation on body temperature in rodents: Pilot studies of the National Toxicology Program's reverberation chamber exposure system.

    Science.gov (United States)

    Wyde, Michael E; Horn, Thomas L; Capstick, Myles H; Ladbury, John M; Koepke, Galen; Wilson, Perry F; Kissling, Grace E; Stout, Matthew D; Kuster, Niels; Melnick, Ronald L; Gauger, James; Bucher, John R; McCormick, David L

    2018-04-01

    Radiofrequency radiation (RFR) causes heating, which can lead to detrimental biological effects. To characterize the effects of RFR exposure on body temperature in relation to animal size and pregnancy, a series of short-term toxicity studies was conducted in a unique RFR exposure system. Young and old B6C3F1 mice and young, old, and pregnant Harlan Sprague-Dawley rats were exposed to Global System for Mobile Communication (GSM) or Code Division Multiple Access (CDMA) RFR (rats = 900 MHz, mice = 1,900 MHz) at specific absorption rates (SARs) up to 12 W/kg for approximately 9 h a day for 5 days. In general, fewer and less severe increases in body temperature were observed in young than in older rats. SAR-dependent increases in subcutaneous body temperatures were observed at exposures ≥6 W/kg in both modulations. Exposures of  ≥10 W/kg GSM or CDMA RFR induced excessive increases in body temperature, leading to mortality. There was also a significant increase in the number of resorptions in pregnant rats at 12 W/kg GSM RFR. In mice, only sporadic increases in body temperature were observed regardless of sex or age when exposed to GSM or CDMA RFR up to 12 W/kg. These results identified SARs at which measurable RFR-mediated thermal effects occur, and were used in the selection of exposures for subsequent toxicology and carcinogenicity studies. Bioelectromagnetics. 39:190-199, 2018. © 2018 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc. © 2018 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc.

  12. Models of breast cancer: quo vadis, animal modeling?

    International Nuclear Information System (INIS)

    Wagner, Kay-Uwe

    2004-01-01

    Rodent models for breast cancer have for many decades provided unparalleled insights into cellular and molecular aspects of neoplastic transformation and tumorigenesis. Despite recent improvements in the fidelity of genetically engineered mice, rodent models are still being criticized by many colleagues for not being 'authentic' enough to the human disease. Motives for this criticism are manifold and range from a very general antipathy against the rodent model system to well-founded arguments that highlight physiological variations between species. Newly proposed differences in genetic pathways that cause cancer in humans and mice invigorated the ongoing discussion about the legitimacy of the murine system to model the human disease. The present commentary intends to stimulate a debate on this subject by providing the background about new developments in animal modeling, by disputing suggested limitations of genetically engineered mice, and by discussing improvements but also ambiguous expectations on the authenticity of xenograft models to faithfully mimic the human disease

  13. The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke

    Science.gov (United States)

    Dohare, Preeti; Hyzinski-García, María C.; Vipani, Aarshi; Bowens, Nicole H.; Nalwalk, Julia W.; Feustel, Paul J.; Keller, Richard W.; Jourd’heuil, David; Mongin, Alexander A.

    2014-01-01

    The contribution of oxidative stress to ischemic brain damage is well established. Nevertheless, for unknown reasons, several clinically tested antioxidant therapies failed to show benefits in human stroke. Based on our previous in vitro work, we hypothesized that the neuroprotective potency of antioxidants is related to their ability to limit release of the excitotoxic amino acids, glutamate and aspartate. We explored the effects of two antioxidants, tempol and edaravone, on amino acid release in the brain cortex, in a rat model of transient occlusion of the middle cerebral artery (MCAo). Amino acid levels were quantified using a microdialysis approach, with the probe positioned in the ischemic penumbra as verified by a laser Doppler technique. Two-hour MCAo triggered a dramatic increase in the levels of glutamate, aspartate, taurine and alanine. Microdialysate delivery of 10 mM tempol reduced the amino acid release by 60–80%, while matching levels of edaravone had no effect. In line with these latter data, an intracerebroventri-cular injection of tempol but not edaravone (500 nmols each, 15 minutes prior to MCAo) reduced infarction volumes by ~50% and improved neurobehavioral outcomes. In vitro assays showed that tempol was superior in removing superoxide anion, whereas edaravone was more potent in scavenging hydrogen peroxide, hydroxyl radical, and peroxynitrite. Overall, our data suggests that the neuroprotective properties of tempol are likely related to its ability to reduce tissue levels of the superoxide anion and pathological glutamate release, and, in such a way, limit progression of brain infarction within ischemic penumbra. These new findings may be instrumental in developing new antioxidant therapies for treatment of stroke. PMID:25224033

  14. Imaging grafted cells with [18F]FHBG using an optimized HSV1-TK mammalian expression vector in a brain injury rodent model.

    Directory of Open Access Journals (Sweden)

    Anne-Sophie Salabert

    Full Text Available Cell transplantation is an innovative therapeutic approach after brain injury to compensate for tissue damage. To have real-time longitudinal monitoring of intracerebrally grafted cells, we explored the feasibility of a molecular imaging approach using thymidine kinase HSV1-TK gene encoding and [18F]FHBG as a reporter probe to image enzyme expression.A stable neuronal cell line expressing HSV1-TK was developed with an optimised mammalian expression vector to ensure long-term transgene expression. After [18F]FHBG incubation under defined parameters, calibration ranges from 1 X 104 to 3 X 106 Neuro2A-TK cells were analysed by gamma counter or by PET-camera. In parallel, grafting with different quantities of [18F]FHBG prelabelled Neuro2A-TK cells was carried out in a rat brain injury model induced by stereotaxic injection of malonate toxin. Image acquisition of the rats was then performed with PET/CT camera to study the [18F]FHBG signal of transplanted cells in vivo.Under the optimised incubation conditions, [18F]FHBG cell uptake rate was around 2.52%. In-vitro calibration range analysis shows a clear linear correlation between the number of cells and the signal intensity. The PET signal emitted into rat brain correlated well with the number of cells injected and the number of surviving grafted cells was recorded via the in-vitro calibration range. PET/CT acquisitions also allowed validation of the stereotaxic injection procedure. Technique sensitivity was evaluated under 5 X 104 grafted cells in vivo. No [18F]FHBG or [18F]metabolite release was observed showing a stable cell uptake even 2 h post-graft.The development of this kind of approach will allow grafting to be controlled and ensure longitudinal follow-up of cell viability and biodistribution after intracerebral injection.

  15. Effect of Combined Exercise Versus Aerobic-Only Training on Skeletal Muscle Lipid Metabolism in a Rodent Model of Type1 Diabetes.

    Science.gov (United States)

    Dotzert, Michelle S; McDonald, Matthew W; Murray, Michael R; Nickels, J Zachary; Noble, Earl G; Melling, C W James

    2017-12-04

    Abnormal skeletal muscle lipid metabolism is associated with insulin resistance in people with type 1 diabetes. Although lipid metabolism is restored with aerobic exercise training, the risk for postexercise hypoglycemia is increased with this modality. Integrating resistance and aerobic exercise is associated with reduced hypoglycemic risk; however, the effects of this exercise modality on lipid metabolism and insulin resistance remain unknown. We compared the effects of combined (aerobic + resistance) versus aerobic exercise training on oxidative capacity and muscle lipid metabolism in a rat model of type 1 diabetes. Male Sprague-Dawley rats were divided into 4 groups: sedentary control (C), sedentary control + diabetes (CD), diabetes + high-intensity aerobic exercise (DAE) and diabetes + combined aerobic and resistance exercise (DARE). Following diabetes induction (20 mg/kg streptozotocin over five days), DAE rats ran for 12 weeks (5 days/week for 1 hour) on a motorized treadmill (27 m/min at a 6-degree grade), and DARE rats alternated daily between running and incremental weighted ladder climbing. After training, DAE showed reduced muscle CD36 protein content and lipid content compared to CD (p≤0.05). DAE rats also had significantly increased citrate synthase (CS) activity compared to CD (p≤0.05). DARE rats showed reduced CD36 protein content compared to CD and increased CS activity compared to CD and DAE rats (p≤0.05). DARE rats demonstrated increased skeletal muscle lipid staining, elevated lipin-1 protein content and insulin sensitivity (p≤0.05). Integration of aerobic and resistance exercise may exert a synergistic effect, producing adaptations characteristic of the "athlete's paradox," including increased capacity to store and oxidize lipids. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  16. Relationships between rodent white adipose fat pads and human white adipose fat depots

    Directory of Open Access Journals (Sweden)

    Daniella E. Chusyd

    2016-04-01

    Full Text Available The objective of this review was to compare and contrast the physiological and metabolic profiles of rodent white adipose fat pads with white adipose fat depots in humans. Human fat distribution and its metabolic consequences have received extensive attention, but much of what has been tested in translational research has relied heavily on rodents. Unfortunately, the validity of using rodent fat pads as a model of human adiposity has received less attention. There is a surprisingly lack of studies demonstrating an analogous relationship between rodent and human adiposity on obesity-related comorbidities. Therefore, we aimed to compare known similarities and disparities in terms of white adipose tissue development and distribution, sexual dimorphism, weight loss, adipokine secretion, and aging. While the literature supports the notion that many similarities exist between rodents and humans, notable differences emerge related to fat deposition and function of white adipose tissue. Thus, further research is warranted to more carefully define the strengths and limitations of rodent white adipose tissue as a model for humans, with a particular emphasis on comparable fat depots, such as mesenteric fat.

  17. Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain.

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    Shigeo Hasegawa

    Full Text Available BACKGROUND: Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A(2 (cPLA(2 in injured dorsal root ganglion (DRG neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA(2 activation to produce tactile allodynia remain to be determined. PRINCIPAL FINDINGS: Here we provide evidence that platelet-activating factor (PAF is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor alpha (TNFalpha and interleukin-1beta (IL-1beta expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of naïve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFalpha and IL-1beta, both of which were inhibited by pretreatment with a PAFR antagonist. CONCLUSIONS: Our results indicate that the PAF/PAFR system has an important role in production of TNFalpha and IL-1beta in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.

  18. Discrete modelling of drapery systems

    Science.gov (United States)

    Thoeni, Klaus; Giacomini, Anna

    2016-04-01

    Drapery systems are an efficient and cost-effective measure in preventing and controlling rockfall hazards on rock slopes. The simplest form consists of a row of ground anchors along the top of the slope connected to a horizontal support cable from which a wire mesh is suspended down the face of the slope. Such systems are generally referred to as simple or unsecured draperies (Badger and Duffy 2012). Variations such as secured draperies, where a pattern of ground anchors is incorporated within the field of the mesh, and hybrid systems, where the upper part of an unsecured drapery is elevated to intercept rockfalls originating upslope of the installation, are becoming more and more popular. This work presents a discrete element framework for simulation of unsecured drapery systems and its variations. The numerical model is based on the classical discrete element method (DEM) and implemented into the open-source framework YADE (Šmilauer et al., 2010). The model takes all relevant interactions between block, drapery and slope into account (Thoeni et al., 2014) and was calibrated and validated based on full-scale experiments (Giacomini et al., 2012).The block is modelled as a rigid clump made of spherical particles which allows any shape to be approximated. The drapery is represented by a set of spherical particle with remote interactions. The behaviour of the remote interactions is governed by the constitutive behaviour of the wire and generally corresponds to a piecewise linear stress-strain relation (Thoeni et al., 2013). The same concept is used to model wire ropes. The rock slope is represented by rigid triangular elements where material properties (e.g., normal coefficient of restitution, friction angle) are assigned to each triangle. The capabilities of the developed model to simulate drapery systems and estimate the residual hazard involved with such systems is shown. References Badger, T.C., Duffy, J.D. (2012) Drapery systems. In: Turner, A.K., Schuster R

  19. Quantum models of classical systems

    International Nuclear Information System (INIS)

    Hájíček, P

    2015-01-01

    Quantum statistical methods that are commonly used for the derivation of classical thermodynamic properties are extended to classical mechanical properties. The usual assumption that every real motion of a classical mechanical system is represented by a sharp trajectory is not testable and is replaced by a class of fuzzy models, the so-called maximum entropy (ME) packets. The fuzzier are the compared classical and quantum ME packets, the better seems to be the match between their dynamical trajectories. Classical and quantum models of a stiff rod will be constructed to illustrate the resulting unified quantum theory of thermodynamic and mechanical properties. (paper)

  20. Influence of Rack Design and Disease Prevalence on Detection of Rodent Pathogens in Exhaust Debris Samples from Individually Ventilated Caging Systems.

    Science.gov (United States)

    Bauer, Beth A; Besch-Williford, Cynthia; Livingston, Robert S; Crim, Marcus J; Riley, Lela K; Myles, Matthew H

    2016-11-01

    Sampling of bedding debris within the exhaust systems of ventilated racks may be a mechanism for detecting murine pathogens in colony animals. This study examined the effectiveness of detecting pathogens by PCR analysis of exhaust debris samples collected from ventilated racks of 2 different rack designs, one with unfiltered air flow from within the cage to the air-exhaust pathway, and the other had a filter between the cage and the air-exhaust pathway. For 12 wk, racks were populated with either 1 or 5 cages of mice (3 mice per cage) infected with one of the following pathogens: mouse norovirus (MNV), mouse parvovirus (MPV), mouse hepatitis virus (MHV), Helicobacter spp., Pasteurella pneumotropica, pinworms, Entamoeba muris, Tritrichomonas muris, and fur mites. Pathogen shedding by infected mice was monitored throughout the study. In the filter-containing rack, PCR testing of exhaust plenums yielded negative results for all pathogens at all time points of the study. In the rack with open air flow, pathogens detected by PCR analysis of exhaust debris included MHV, Helicobacter spp., P. pneumotropica, pinworms, enteric protozoa, and fur mites; these pathogens were detected in racks housing either 1 or 5 cages of infected mice. Neither MPV nor MNV was detected in exhaust debris, even though prolonged viral shedding was confirmed. These results demonstrate that testing rack exhaust debris from racks with unfiltered air flow detected MHV, enteric bacteria and parasites, and fur mites. However, this method failed to reliably detect MNV or MPV infection of colony animals.

  1. Adaptation for rodent pollination in Leucospermum arenarium (Proteaceae) despite rapid pollen loss during grooming.

    Science.gov (United States)

    Johnson, Christopher Michael; Pauw, Anton

    2014-05-01

    Plants are adapted for rodent pollination in diverse and intricate ways. This study explores an extraordinary example of these adaptations in the pincushion Leucospermum arenarium (Proteaceae) from South Africa. Live trapping and differential exclusion experiments were used to test the role of rodents versus birds and insects as pollinators. To explore the adaptive significance of geoflory, inflorescences were raised above ground level and seed production was compared. Captive rodents and flowers with artificial stigmas were used to test the effect of grooming on the rate of pollen loss. Microscopy, nectar composition analysis and manipulative experiments were used to investigate the bizarre nectar production and transport system. Differential exclusion of rodents, birds and insects demonstrated the importance of rodents in promoting seed production. Live trapping revealed that hairy-footed gerbils, Gerbillurus paeba, and striped field mice, Rhabdomys pumilio, both carried L. arenarium pollen on their forehead and rostrum, but much larger quantities ended up in faeces as a result of grooming. Terrarium experiments showed